Augmented fat metabolism efficiency -
Widely distributed throughout the body, there are two main representative types of WATs, the visceral WAT vWAT and the subcutaneous WAT scWAT. While one is distributed around organs and provides protective padding, the other is located under the skin and provides insulation against heat or cold, respectively [ 26 ].
In contrast, brown adipocytes display multilocular lipid droplets, a large number of mitochondria, and thermogenic capacity due to elevated uncoupling protein 1 UCP1 amounts anchored in its mitochondrial inner membrane [ 27 ]. The BAT utilizes this high mitochondrial content and elevated UCP1 amounts to uncouple oxidative phosphorylation from adenosine triphosphate ATP synthesis to dissipate chemical energy as heat [ 28 ].
Thus, BAT affects the metabolism of the entire body, being able to alter insulin sensitivity and modify the susceptibility to increase weight. For a long time, BAT was only considered an energy-producing organ in rodents and newborns, undergoing involution with age.
However, BAT has also been identified in human adults near the aorta and within the supraclavicular region of the neck. Nevertheless, the origin of BAT is still under debate [ 26 , 29 ].
Recently, a type of AT showing intermediary characteristics between that of white and brown adipocytes, which has mixed structural features of both, was identified as beige AT [ 29 ]. This type of AT was reported as a set of adipocytes in WAT that might acquire a thermogenic phenotype with higher UCP1 expression, similar to brown adipocytes after enough stimulus [ 29 , 30 ].
There are two major mechanisms described related to beige cells arising: d e novo differentiation which occurs from a progenitor resident cell and transdifferentiation which consist of differentiation of a mature white adipocyte through a molecular mechanism.
The first theory is based on that beige adipocytes come from progenitor cells differentiation induced by adipogenic stimulation such as cold exposure, adrenergic signaling, exercise, natriuretic peptides, thyroid hormones, diets, and food components [ 31 , 32 ].
These adipogenic stimulation actives transcriptional machinery of browning that is characterized by the expression of Ucp1, Prdm16, Zfp, and Pgc1a genes that will promote a beige differentiation [ 36 ].
On the other hand, the transdifferentiation hypothesis proposes beige cells arise from mature white adipocytes, in a reversible process, after adipogenic stimulus without the participation of a progenitor-like state of cells [ 37 ].
The underlying molecular mechanisms for transdifferentiation are under intensive research, but some studies already show that this plasticity process occurs mainly in scWAT depots [ 29 ].
Known as browning, this process has gained increasing attention in the research area as an alternative method of energy stimulation. UCP1 expression can be stimulated when white adipocytes are exposed to stimuli, previously referred as to adipogenic stimulus, [ 20 , 27 , 29 ], driven by a set of molecules known as browning markers.
The non-shivering thermogenesis is a phenomenon that occurs in brown and beige ATs due mostly to the action of UCP1 [ 38 ]. UCPs are transmembrane proteins that belong to the mitochondrial anion carrier family MACF , i.
The UCPs exhibit 5 isoforms, ranging from UCP1 to UCP5 are present in several tissues [ 41 , 42 ]. UCP1 protein is described as participating in thermogenesis by interfering in proton leakage within the chemiosmotic gradient during the mitochondrial oxidative phosphorylation by the translocating fatty acids FAs.
This gradient is obtained from the oxidation of substrates and provides the required force to induce the respiratory machinery to produce ATP. Once UCP1 promotes proton leakage, the energy obtained cannot be stored in the form of ATP and is alternatively dissipated as heat [ 47 , 48 ]. Thus, it is evident that direct regulation of UCP1 protein activity is one of the means of regulating thermogenesis, and that occurs in opposite ways by cytosolic purine nucleotides and long-chain fatty acids LCFA , promoting inhibition or activation of UCP1, respectively [ 49 ].
The other form of regulating UCP1 is at the transcriptional level. UCP1 gene is transcribed only in brown and beige adipocytes, associates with the differentiation state of these cells, and is quantitatively regulated in response to many physiological signals [ 9 ].
Also in the proximity of the site of transcription start, activating transcription factor-2 ATF2 -binding site interacts with transcriptional coregulators, such as PGC-1α, impacting UCP1 gene transcription [ 9 ]. In opposition to these proximal regulatory sites, a strong enhancer region is placed more than 2 kb upstream of the transcription initiation site [ 50 , 53 ] and contains a cluster of response elements for nuclear hormone receptors [ 7 , 54 ].
UCP1 gene activation and repression depend on which trans-acting factors bind to the regulatory region. Another example is the PPARγ binding site found in the distal enhancer region, which associates with gene activation after binding to its main ligand but represses UCP1 transcription when interacting with liver X receptor LXR and its corepressor receptor-interacting protein RIP [ 55 ].
RIP inhibits UCP1 gene transcription by enabling the assembly of DNA and histone methyltransferases on the UCP1 gene, altering the methylation status of CpG islands in the promoter region and histones, impacting gene expression through transcription machinery accessibility [ 56 ].
Although some epigenetic modifications are associated with repressed UCP1 gene expression, as in H3K9 demethylation marks, chromatin modifications indicative of activation of this gene also occur, such as in the case of H3K4 trimethylated marks, which are enriched in BAT [ 57 ].
Also participating in fine-tuning of gene expression, microRNAs miRs are characterized to be a group of short non-coding RNAs ncRNAs generated by the sequential processing of longer ribonucleic acid molecules [ 58 ]. While miR [ 59 ] and miR [ 60 ] are described to be activators of UCP1 gene expression, miR [ 61 , 62 ], and miR [ 63 ] display UCP1 gene transcription inhibitory activity.
The roles of WAT and BAT in metabolic syndrome is well characterized, but the physiological and biochemical modulations of BAT remain unclear [ 64 , 65 , 66 ].
Several studies showed that UCP1-dependent BAT activity was mostly found to be beneficial in decreasing inflammation, and improving cardiometabolic homeostasis [ 67 , 68 , 69 ]. However, this tissue has a lower activity in obese in comparison to healthy individuals [ 70 ].
It is well established that the deficiency of the UCP1 gene is not enough to protect against diet-induced obesity DIO , but can modulate important physiological and metabolic parameters in mice [ 64 , 65 ].
The food intake-induced browning is inhibited in the absence of UCP1, demonstrating the intimate relationship between this differentiation process and UCP1 [ 71 , 72 ]. The lack of UCP1 promotes de novo lipogenesis and hyperplasia of inguinal WAT, leading to an increase in FA trafficking to the liver [ 75 ].
In contrast, the upregulation of UCP1 or even only its activation can perform a paradoxical role in hypermetabolic scenarios and associate with a worse prognosis [ 76 , 77 ]. It is proven that diet-induced whitening is related to the upregulation of this gene.
A greater expression of browning markers e. The browning process is spontaneously induced by tumor-secreted factors and IL-6 during cachexia development, which can lead to full depletion of AT [ 80 , 81 ].
Interestingly, the elicitation of browning after burn injury is associated with the hypermetabolic response, as well as an increase in lipolysis and free fatty acid efflux that can outcome in liver steatosis [ 82 , 83 ].
In addition to the therapeutic impact of the browning process in obesity and metabolic diseases, recent discoveries regarding the impact of UCP1-dependent BAT activity in hypermetabolism conditions should be further investigated in the context of UCP1 to appropriately regulate browning for application in different situations.
Increasing energy expenditure through activation of BAT shows potential for treating metabolic diseases, and that is the reason this approach has been deeply investigated [ 84 ].
β3-ARs are expressed predominantly on white and brown adipocytes [ 86 ]. Murine WAT expresses β3-AR transcripts in a greater proportion compared to other β-ARs, similar to BAT [ 87 ]. Although β3-AR mRNA levels are lower in humans than in rodent AT, its roles seem to be fundamental in the regulation of energy balance and glucose homeostasis [ 88 ].
Browning of WAT occurs mainly by noradrenaline and adrenaline stimulation, which influence lipolysis after binding to different adrenoceptor subtypes on the cell-surface membrane of fat cells. The interaction with β3-AR initiates a cascade of signal transduction that ends with the overexpression of thermogenic proteins, such as UCP-1 [ 88 , 89 ].
The adaptive thermogenic response is initiated by the central CNS and sympathetic SNS nervous systems with the release of norepinephrine NE and stimulation of β3-AR, through the G protein-coupled receptor Gs, which in turn activates the adenylyl cyclase AC , stimulating the production of cyclic adenosine monophosphate cAMP , and activating the protein kinase A PKA pathway.
Then, these signals from the cAMP pathway, finally, upregulate UCP-1 and lipolysis [ 88 , 89 , 90 , 91 , 92 ]. A distinguishing feature of the β3-AR, already seen in past studies, is that it appears to be relatively resistant to desensitization and down-regulation, leading to the hypothesis that one of its functions might be to maintain signaling during periods of sustained sympathetic stimulation, as in diet-associated β3-AR activation or cold exposure [ 87 ].
Cold temperature exposure elicits a coordinated physiological response aimed at maintaining their body temperature. This response activates the mentioned cascade and generates heat in beige adipocytes within scWAT and BAT [ 85 ]. Thus, it was seen that mice with a combined target disruption of the three β1, β2, and β3 adrenergic receptors TKO mice have increased susceptibility to cold-induced hypothermia as well as diet-induced obesity [ 91 ].
Thereby, mice β3-AR activation started to be studied, effectively mimicking cold exposure effects [ 84 , 91 ]. Initial studies demonstrated that WAT UCP1 mRNA and protein levels are strongly decreased in β3-AR knockout KO mice [ 30 , 93 ]. In addition, β3-AR agonists are well-known for inducing ectopic UCP1 expression in WAT coupled with a significant mitochondrial enhancement in rodents, and for augmenting glucose homeostatic activity of their BAT [ 84 , 94 ].
On the other hand, in humans, early efforts to increase browning activation with the use of β3-adrenoreceptor agonists have failed in clinical trials because of their β1- and β2-AR-mediated cardiovascular effects [ 13 , 84 , 94 ]. However, a recent study showed that mirabegron, a selective β3-agonist previously developed for the treatment of overactive bladder, was shown to increase BAT activity as compared to placebo.
This study used an oral dose of mg in healthy male subjects, and despite not having severe cardiovascular side effects, they have been shown to increase heart rate and systolic blood pressure [ 84 ]. That is the reason long-term studies are warranted to investigate the effectiveness and cardiovascular safety of this type of treatment to induce weight loss and metabolic health improvements.
Genetic factors must be considered in influencing adipocyte lipolysis regulation. Genetic variance in β3-AR and its specific G-coupling protein has functional effects on lipolysis.
Polymorphism in the G-β3 gene, for example, influences catecholamine-induced lipolysis in human fat cells by altering the coupling of β3-AR to G-proteins [ 88 ]. This proves once again the importance of the β3-AR presence for the thermogenic process. It is well established that temperature can modulate biochemical, inflammatory, and immunological processes systemically, displaying relevant physiological impact [ 95 , 96 ].
Despite this, the influence of warmer temperatures is better described compared to cold conditions due to their immediate danger.
Fever, triggered by infectious and inflammatory processes, was associated with a worse prognosis in the past centuries, demanding greater medical attention for a long time [ 97 ]. However, currently, it is recognized that both hyper and hypothermia, in properly regulated circumstances, are beneficial response mechanisms to infection in mild and severe profiles, respectively [ 98 ].
Hypothermia is also associated with an advantageous mechanism against severe systemic inflammation. In experimental studies, the infectious or aseptic systemic inflammation process is elicited by the intravenous administration of bacterial lipopolysaccharide LPS in mice [ 99 , , ].
The variances of body temperature are modulated by the environmental temperature and concentration of LPS introduced [ ]. Animals housed in hyperthermal conditions or exposed to lower LPS concentrations displayed polyphasic fever. In thermoneutral conditions, the fever was also usually elicited to induce the immunological response.
However, if the mice were housed in cooler acclimation or administered with higher LPS concentrations, the effect elicited was hypothermia, which associates with arterial hypotension aimed to avoid infection spread, followed by polyphasic fever.
The ideal body temperature is obtained by the modulation of blood vessel tension degree, and heat production by thermogenesis. Cutaneous vasoconstriction and thermogenesis processes occur to increase body temperature and avoid heat loss.
Conversely, the opposite effect, skin vasodilatation and thermogenesis inhibition, is stimulated to induce hypothermia [ , , , ].
Temperature is a paradoxical agent with important roles not only in biological events but also in the development of several diseases [ , , , , ].
Hypothermia, specifically, displays a typical profile, in which the energy is preserved. The decrease in body temperature also favors the development of an anti-inflammatory profile and immunosuppression, which can act as a double-edged sword depending on the condition [ , , , ].
On the other hand, hyperthermia is recognized to elicit a more robust immune response against infection, injury, and cancer [ ]. In inflammatory conditions, such as neurological damage, atherosclerosis, systemic inflammation, and hypothermia cryotherapy can be beneficial [ , , , , ].
Cryotherapy benefits are illustrated by an experimental approach that submitted healthy and physical activity practitioners men to intense exercises aimed to induce muscle injury [ ]. It was observed that cryotherapy mediated the increase of IL, reduction of pro-inflammatory cytokine IL-1, reduction of muscle damage and blood cholesterol, decrease oxidative stress and improve the lipid profile not only in healthy patients but also in patients with active-phase ankylosing spondylitis [ , , ].
Cryotherapy also shows to be neuroprotective capacity, alleviating sequelae from ischemic or hemorrhage stroke, cardiac arrest, intracranial pressure elevation, and traumatic brain injury [ ].
In the same line, recent research evaluated the impact of spontaneous body hyperthermia after brain injury. Metabolic modulations were observed as the diminishment of both cerebral and arterial glucose levels and increase of lactate-pyruvate ratio.
However, these changes were not associated with a worse prognostic [ ]. Additionally, induced hyperthermia in healthy men promoted an increase in cerebral metabolic rate of oxygen CMRO 2 , also increase IL-6 and myeloperoxidase MPO systemically, but did not promote the same inflammatory and oxidative phenomenon in the brain [ ].
In peripheral organs such as the liver, hyperthermia is associated with an increase in oxidative metabolism, vasodilation, and an increase of heat shock proteins HSP expression. HSP displays an important role in metabolism such as modulation of both glucose and lipid metabolism in the liver and improving the mitochondrial skeletal muscle functionality [ ].
In addition, temperature modulates directly the shivering and non-shivering thermogenesis processes. The occurrence of these events maintains proper body temperature under adverse thermal acclimation.
Once shivering thermogenesis is decreased in cold acclimation around 4 °C , non-shivering thermogenesis is the major way to produce heat in this context [ 2 , 4 ]. The detection of the thermal changes begins with the capture of sensory stimuli by cutaneous thermoreceptors, which promote the sensitization of afferent nerves.
The stimuli are directed to the CNS, which then induces thermoregulatory responses, including vasoconstriction and catecholamines secretion. These catecholamines, mainly NE, increase BAT activation, hence heat production through a UCP1-dependent manner [ , ].
BAT is a highly innervated and vascularized organ that displays considerable amounts of β3-ARs, which is also expressed in WAT, though at a lower level.
NE binding to β3-ARs promotes systemic adrenergic activation, which induces a signal cascade culminating in the accumulation of adipokines, such as Zinc-α2-glycoprotein ZAG , increase in thermogenesis-related gene expression, as UCP1, thus enabling mobilization and oxidation of free fatty acids FFAs in both tissues, increasing BAT activity and promoting browning in WAT.
It is known that the results observed in humans do not always represent the same effects previously described in mice or even contradictory results can be obtained under similar conditions for the same species [ ].
Unfortunately, this premise can also be applied to cold-induced browning. Leitner and colleagues showed that in human fewer than half of the BAT deposits is stimulated by cold exposure, hence, the thermogenic function was lower than expected [ 44 ].
Brychta and others demonstrated that the profile of men with obesity was associated with a reduced tolerance limit to chill temperatures, suggesting that thermogenesis was diminished in these individuals, as well as energy expenditure [ ]. Blauw et al. Taking the assessment on a global scale, Kanazawa evaluated the parallel between higher temperatures, weight gain, and obesity.
Notably, the use of cold as a browning inducer has been carefully applied not only because of the side effects that can be displayed at the whole-body level but also due to the contradictory effect observed in humans.
If on one hand, the anti-inflammatory and immunosuppressive role mediated by cold and cold-induced browning is beneficial in healthy individuals, for ill people these same effects may become harmful. In contrast, intriguing research has brought a new perspective on temperature-based browning.
Li and colleagues discovered that a hydrogel-based photothermal therapy leads to a successful increase of beige activation in both mice and humans.
The therapy consists of increasing the local temperature, around 41˚C, without evident stress on skin or adjacent tissues [ ]. This promising study succeeds previous findings that pointed to the occurrence of WAT browning after burn injury [ , ].
The characterization of possible inducers of browning is a strongly growing field since the applicability of these inducers as therapy in humans has proven to be a major clinical hurdle. However, even under promising advances is clear that further investigation regarding the mechanisms triggered by this stimulus pathway should be conducted.
Physical exercising is already associated with improvements in several processes related to the cardiovascular system, skeletal muscle, and ATs [ ].
Following this, several studies show that physical activity provides better quality of life [ ] and helps in the treatment of several metabolic diseases and obesity [ ] through increasing AT lipolysis, vascularization, blood flow, and promoting the secretion of hormones and adipokines [ ].
After physical activities, the adipokine leptin stimulates activity in the sympathetic nerve and together with insulin act synergistically in different neuronal subsets of proopiomelanocortin POMC inducing browning of WAT through decreased hypothalamic inflammation caused by exercise [ ].
During exercise, the increase in glucagon, which already has thermogenic potential [ ], and the decrease in insulin in the liver lead to FGF21 secretion [ ]. The exercise induces pleiotropic effects in the liver, AT, immune system, and skeletal muscle by enabling myokine secretion upon contraction [ ].
After activities, muscle cells increase the expression of PGC-1α, inducing BAT thermogenesis and mitochondrial biogenesis. Among the myokines involved in the browning process, interleukin-6 IL-6 is a modulatory cytokine secreted by several tissues, including skeletal muscle and AT.
A study showed that mouse AT when treated with IL-6 for 6 h induces the expression of PGC-1α and mitochondrial enzymes [ ]. In addition, analyses showed that IL-6 is involved in the increase of UCP1 mRNA in inguinal WAT igWAT stimulated by physical activity [ ].
Another relevant myokine is Irisin; Once exercising increases the expression of PGC-1α, it induces increased levels of the fibronectin domain-containing protein 5 FNDC5 protein, which, after being cleaved, is released as the hormone irisin [ ].
Irisin was shown to stimulate UCP1 expression and thermogenic differentiation of white fat precursor cells in vitro and in vivo [ ]. The myokine myostatin Mstn , a growth factor that limits muscle growth and development, is negatively involved in the WAT browning process, as Mstn-deficient mice showed high expression of genes associated with FA oxidation, mitochondrial biogenesis, lipid transport together with the positive regulation of PGC-1α and UCP1, this mechanism occurs through the phosphorylation of AMPK, necessary for the activation of PGC1α and FNDC5 [ ].
Metrnl, the gene encoding for Meteorin-like protein, is a myokine known to be induced by resistance exercise dependently on PGC-1α4.
Metrnl regulates genes involved in thermogenesis, as it is capable of promoting the activation of M2 macrophages by inciting the expression of IL-4 and thus triggering the production of catecholamines [ ], responsible for favoring thermogenesis in AT [ ].
Beta-Aminoisobutyric acid is another myokine that has increased levels during exercise and can induce the brown adipocyte phenotype in human-induced pluripotent stem cells during differentiation to mature white adipocytes [ ].
Intense physical activity causes increased heart rate and stretching of cardiomyocytes, which cause the secretion of atrial natriuretic peptide ANP and brain natriuretic peptide BNP , molecules that stimulate lipolysis, UCP1 expression, and mitochondrial biogenesis [ ].
It also induces an increase in lactate, which binds to receptor GRP81 on adipocytes, leads to an increase in P38 phosphorylation, and thus mediates the browning of WAT by activating the PGC-1a, PPAR, γ, and Ucp1 genes [ ].
During lipolysis, FAs are not only used as an energy source but also undergo the re-esterification process where they are converted into triglycerides in AT.
This re-esterification consumes ATP generating AMP. AMP in turn can activate AMPK, which then induces greater expression of PGC-1α and mitochondrial biogenesis [ ]. Another the important effect induced by exercise that plays an important role in the browning of WAT is oxidative stress in skeletal muscle, whish it responsible for the increase in H 2 O 2 through the reduction of glutathione levels, a molecule capable of supplying electrons to glutathione peroxidase, thus increasing H 2 O 2 levels.
And also by increasing the activity of superoxide dismutase 2 SOD2 , which reduces ROS to H 2 O 2. When H 2 O 2 enters the circulation, it is directed to WAT and subsequently induces the expression of thermogenic genes [ ].
Exercise also increases the level of succinate, resulting in augmented levels of mitochondrial reactive oxygen species, which in turn promotes the sulphenylation of Cys to increase UCP1 activity [ ]. Although the studies conducted in mice seem promising, the effect of exercise on WAT browning in humans has proven to be controversial.
A survey conducted with sedentary subjects participating in a week bicycle-training program showed scWAT increased expression of UCP1, carnitine palmitoyltransferase 1B CPT1B , TBX1 [ 15 ]. However, other studies have not achieved similar effects.
Tsiloulis and colleagues collected scWAT of obese men after 6 weeks of physical training and the mRNA levels of UCP1, CD, CITED, TBX1, LHX8, and TCF21 were not altered [ ].
Many factors may be involved in this diversity of results since the duration, frequency, and degree of intensity are associated with these effects. Thus, more human studies need to be conducted as many questions still need to be clarified. The fibroblast growth factor family FGF performs a range of cellular metabolic and physiological responses to maintain overall homeostasis.
FGF 21 was first identified in mice and humans in 2, by Nishimura and colleagues through cDNA identification in different organs [ ].
While the gene in mice is located in chromosome 7 and encodes a preprotein of amino acids aa , in humans it is found in chromosome 19 and encodes a preprotein of aa. Most FGF family members have a high affinity to heparin sulfate, except for the endocrine FGF FGF subgroup, which consists of FGF 19 FGF 15 in rodents , FGF 21 e FGF 23 in humans [ ].
FGF molecules lack an extracellular heparin-binding domain and thus can enter the blood system [ ]. FGF 21 binds to a fibroblast growth factor tyrosine kinase receptor FGFR , which can be found in seven isoforms: 1b, 1c, 2b, 2c, 3b, 3c, and 4.
The FGF 21 requires its dimerization with a klotho protein, called beta-klotho KLB. Thus, the FGFR-KLB receptors lead to the intracellular cascade that goes through the phosphorylation of FGFR substrate 2α FRS2α and the activation of Ras-MAPKs and PI3K-Akt kinases [ , , ].
Once FGF21 signaling requires KLB to activate FGFRs, the co-expression of these two receptors determines the sensitivity of a tissue or organ to FGF21 [ ]. FGF 21 is defined as a stress-responsive hormone [ ], which effect is subtle in physiological conditions but significantly exacerbated under nutritional, metabolic, oxidative, hormonal, or environmental challenges.
FGF 21 is synthesized mainly in the liver and thymus but is also detected in skeletal muscle, pancreas, intestine, heart, β cells, and WAT and BAT [ ]. As an important metabolic regulator, acting mostly in glucose and lipid homeostasis, FGF 21 triggers lipolysis and FFAs released in circulation from WAT during prolonged fasting or starvation [ 29 , ].
PPAR-α is activated in the presence of FFA and improves FFA oxidation and ketone bodies formation for acting as energy sources during prolonged fasting. Thus, when PPAR-α activity increases, the production of FGF 21 in the liver also augments, leading to energy production, increased ketogenesis, gluconeogenesis, appetite, and systemic glucose uptake as adaptive responses to starvation [ ].
The activity of FGF 21 is not limited to starvation conditions, but it is also increased in adaptation to high-fat HF intake [ ].
Human studies inform that FGF21 production is stimulated in situations of decreased thermogenesis, reduction in adiponectin levels, and tissue breakdown markers, such as transaminases elevation mare than changes in levels of FFAs [ ].
Another means of increasing FGF21 levels, through PPAR-α activity, is through intense physical activity, growth hormone therapy, lactation, and milk ingestion in neonates [ , ].
Macronutrients such as proteins also regulate FGF 21 production through amino acid restriction [ ]. This process starts when the general control non-derepressible 2 GCN2 -eukaryotic initiation factor 2 eIF2 α pathway is activated inducing the binding of activating transcription factor 4 ATF4 to PGC-1 α [ , ].
After being secreted, its most important target is WAT, where FGF21 improves insulin sensitivity [ , ] and increments GLUT1 expression and consequently glucose uptake, as shown by in vitro 3T3-L1 adipocyte analyses [ , ].
The response element-binding protein ChREBP is sensitive to carbohydrates in the liver and ChREBP interaction with PPAR-γ in adipocytes modulates the expression of FGF In other words, the upregulation of ChREBP may induce the expression of this FGF [ ].
Another example of FGF 21 influence on carbohydrate metabolism is through the suppression of hepatic pyruvate dehydrogenase PD complex through PD kinase 4 activity [ ].
Additional transcription factors, such as retinoic acid RA receptor β RARβ , TRβ, cyclic AMP response element-binding protein H CREBH , RA receptor-related orphan receptor α RORα , respond to determinants in the liver and regulates FGF 21 production [ ].
WAT is not only a target of FGF21, but it is the major mediator of its effects. The processes of glucose- and insulin-sensitive responses depend on adiponectin production and secretion by this tissue [ ].
Adiponectin also reduces the levels of sphingolipid ceramides in obese animals, which have been associated with lipotoxicity [ ]. The action of FGF21 in WAT includes paracrine and autocrine actions and is mediated through the induction of PGC-1α protein in cold and through the enhanced levels of the thermogenic protein UCP1, which is a key protein for heat production [ ].
FGF 21 impact derives from increased PGC-1α levels and, consequently, expression of UCP1 [ ]. In conclusion, FGF 21 is involved in glucose uptake, lipogenesis, and lipolysis, depending on the metabolic state of the adipocytes. This dual phenomenon may depend on nutritional condition, FGF21 concentrations reached between pharmacological administration and physiological secretion [ ].
Thyroid Hormone TH is essential for metabolism in mammals and associates with many processes, including organism development, metabolic regulation, neural differentiation, and growth [ ]. TH is produced in the follicles of the thyroid gland and is synthesized through iodination of tyrosine residues in the glycoprotein thyroglobulin [ , ].
The main means of regulator its production is through thyroid-stimulating hormone TSH , which binds to the TSH receptor TSH-R expressed in the thyroid follicular cell basolateral membrane and is released by the anterior pituitary in response to a circulating TH [ ].
The biological response of TH is complex and highly regulated. It is mediated by thyroid hormone nuclear receptors TRs. The TR genes produce two main types of receptors, α and β, and their isoforms α1, α2, α3, β1, β2, and β3, but only α1, β1, β2, and β3 are T3-binding receptors, which are differentially expressed in tissues and have distinct roles in TH signaling [ , ].
TH enters the cell through membrane proteins monocarboxylate transporter 8 MCT8 and solute carrier organic anion transporter family member 1C1 9 OATP1C1 , then interacts with TR in the nucleus, which binds to the genomic thyroid-hormone responsive elements TREs and other nuclear proteins, including corepressors, coactivators, and cointegrators, leading to chromatin remodeling and the regulation of the UCP1 gene transcription [ , ].
This hormone is correlated with weight and energy expenditure. Thus, hypothyroidism, characterized by diminished TH levels, leads to hypometabolism, a condition associated with reduced resting energy expenditure, weight gain, high cholesterol levels, reduced lipolysis, and gluconeogenesis.
On the other hand, hyperthyroidism, and elevated TH levels, induce a hypermetabolic state, characterized by increased resting energy expenditure, lower cholesterol levels, increased lipolysis and gluconeogenesis, and weight loss. Consequently, TH controls energy balance by regulating energy storage and expenditure regulating key metabolic pathways [ ].
TH regulates basal metabolic rate BMR through ATP production, used for metabolic processes, and by generating and maintaining ion gradient [ , , ].
TH maintains the BMR levels through the uncoupling oxidative phosphorylation in the mitochondria. When ATP production is compromised in skeletal muscle, TH increases the leak of protons through the mitochondrial inner membrane, stimulating more oxidation to maintain ATP synthesis [ ].
TH regulates metabolism primarily through actions in the brain, WAT, BAT, skeletal muscle, liver, and pancreas [ ]. This action, as already said, is through TH receptors TR isoforms, WAT has the adrenergic signaling increased by TRα [ ], otherwise BAT expresses TR α and β, as it needs TRα for adrenergic stimulation and TRβ for stimulating of UCP1, both for thermogenesis [ ].
TH regulates several aspects of lipid metabolism and human BAT from lipogenesis to lipoprotein signaling [ ]. Rats administrated with T3 showed how the central nervous system is important to the activation of BAT by TH through inhibition of hypothalamic AMP-activated protein kinase AMPK.
Stimulation of sympathetic nervous system SNS activity leads to thermogenic gene expression in BAT [ ]. As discussed previously, β-AR is stimulated by NE in response to SNS [ 1 ].
The expression of UCP1, required for BAT thermogenesis, is regulated by NE and T3 synergistically, once the induction in separate is twofold, while combined is 20 -fold [ ].
Another way that UCP1 expression and thermogenesis are induced is through bile acid stimulation. G protein-coupled membrane bile acid receptor TGR5 is stimulated in BAT and results in D2 stimulation and local T3 production [ ].
In conclusion, several mechanisms have been proposed for the TH influence in the browning process, including cold exposure, adrenergic activation [ ], and bile acid signal [ ].
Thus, the stimulation of BAT activation and WAT browning increase the energy expenditure, loss of weight [ ], D2 activation, UCP1 level increase, and consequent thermogenesis [ ].
As previously discussed here, several exogenous factors are able to elicit browning of WAT and BAT activation. However, endogenous factors also play an important role in regulating the phenotype and physiology of these tissues. One of the most important endogenous factors that are related to the regulation of AT is the circadian rhythm, which is a refined system that acts as a master biological clock synchronizing daily and seasonal variations with the behavioral, cellular and tissue-autonomous clock, as well as several biological processes that include sleep—wake cycle, hormone secretion, lipid and glucose homeostasis, energy balance and body temperature [ ].
Disruption of circadian rhythm caused by aging, shift-work, irregular sleep, insomnia, or long exposure to light during the night is associated with sleep and metabolic disorders such as cardiovascular diseases, diabetes type 2 and obesity. Regarding metabolic diseases, AT plays a central role in metabolic and whole-body energy homeostasis, once its secretes several adipokines that regulate diverse processes in CNS and peripheral tissues.
Leptin, a hormone mainly produced by adipocytes, is released into the circulation where it crosses the blood—brain barrier BBB , through a saturable system, and interact with its receptor in the hypothalamus LepRb [ , ].
Hsuchou and colleagues demonstrated that leptin signaling disruption through a pan-leptin receptor knockout POKO in mice was able to dysregulate feeding behavior, metabolic and circadian rhythm profile and thus promote an accentuating of obesity [ ].
Beyond control of feeding and metabolic processes, leptin also displays a role in energy balance through the increase of AT thermogenesis in BAT by sympathetic activation [ , ].
Recent studies have proposed that diurnal rhythm promotes differential modulation in activity, thermogenesis and fat oxidation in BAT. It was observed that plasmatic lipid metabolism was improved during daytime with a higher expression of lipoprotein lipase, FA uptake, and modulates lipid plasmatic concentration in BAT [ ].
In the same line, Matsushita and colleagues, assessed forty-four healthy men who received diet-induced thermogenesis DIT under room temperature 27 °C and cold 19 °C in the morning and in the evening by using 18 F-fluorodeoxy-D-glucose positron emission tomography.
It was observed that thermogenic parameters presented better performance during the morning [ ]. Moreover, several studies have established that melatonin directly impacts BAT morphology and function, also, in a mechanism dependent on adrenergic activation mediated by NE release. Melatonin is related to an increase of BAT volume, and thermogenic capacity, associated with the increase of UCP1 mRNA expression and mitochondrial mass and functionality, as well as seric lipid concentration.
These profiles are significatively impaired under melatonin deficiency but reverse with oral melatonin replacement [ , , ]. Growing evidence confirms the intimate relationship between circadian rhythm and AT, with emphasis on metabolic homeostasis and modulation of BAT activity.
The characterization of how this process happens emerges as a strong diagnostic tool as well as a therapeutic approach concerning sleep disorders and metabolic diseases. Several studies suggest that food items can affect AT function. Curcumin stimulation was unable to induce the same effects in the epididymal WAT, though.
This process was mediated by the NE-β3-AR pathway since the levels of NE and β3-AR were elevated in the inguinal WAT [ ]. Although studies are scarce regarding the impact of thyme in the WAT browning process, it was observed that 20 µM of thymol, a substance present in the essential oils of thyme, in the complete medium when placed in contact with 3T3-LI preadipocytes for 6—8 days was able to induce an increased gene and protein expression of the PGC-1α, PPARγ, and UCP1.
Such increases were related to the activation of β3-AR, AMPK, PKA, and Mitogen-activated protein kinase p38 MAPK being accompanied by an increase in mitochondrial biogenesis [ ]. Cinnamon oil contains trans-cinnamic acid, which exposure to 3T3-L1 white adipocytes at µM high gene expression of Lhx8, Ppargc1, Prdm16, Ucp1, and Zic1 and markers of UCP1, PRDM16, and PGC-1α, indicating WAT browning [ ].
Quercetin, a flavonoid present in the onion, also proved to be efficient in the browning process since mice fed for 8 days with 0.
Just as the combination of quercetin and resveratrol also induces the WAT browning phenotype [ ]. The resveratrol, present in the bark of grapes and other plants, also increases the expression of UCP-1, PRDM16, and PPARγ, suggesting that resveratrol induces the formation of beige adipocytes through the phosphorylation of AMPK, once treatment coupled with inhibition or the deletion of AMPK did not produce the same effects [ ].
The same was observed in the substances found in the mushroom and honey, which induced increased expression of brown fat markers via AMPK and PGC-1α [ ].
The peppers have capsaicin, an active compound responsible for the burning sensation that is also involved in the browning of WAT. The WT animals showed an increase in the expression of Ucp-1, Pgc-1α, Sirt-1, Prdm16, and exhibited browning of WAT via activation of the transient receptor potential vanilloid 1 TRPV1 , which is related to the synthesis of catecholamine or sirtuin 1 SIRT1 -mediated deacetylation of PPARγ, facilitating PPARγ-PRDM interaction.
Other substances, such as carotenoids, are involved in the WAT browning process. Fucoxanthin, β-carotene, and citrus fruits are efficient in modulating the Ucp1 expression , , Another food component that is involved in the browning process of WAT is berberine, a molecule derived from the plants Coptis chinensis and Hydrastis canadensis.
The group discovered berberine promotes BAT thermogenesis and WAT browning, since the igWAT, but not the epididymal, showed high levels of mRNA and UCP1 protein expression and increased mitochondrial biogenesis after injections.
The brown adipocyte markers PGC-1α, CIDEA, Cox8b, and lsdp5 were also elevated and AMPK and PGC-1α are involved [ ]. In another study, the polyphenols from tea extracts 0. Another analysis with the extract induced In Magnolia Officinalis, two magnolol compounds 20 µM and Honokiol 1—20 µM when used to stimulate 3T3-L1 adipocytes increased protein levels of PGC-1α, PRDM16, and UCP-1 [ ].
Honokiol also increased protein expression levels of CIDEA, COX8, FGF21, PGC-1α, and UCP1 [ ]. The herb panax ginseng contains ginsenoside Rg1 10 μM of ginsenoside Rb1 , which is capable of considerably increasing the mRNA expression of UCP1, PGC-1α, and PRDM16 in mature 3T3-L1 adipocytes via PPARγ [ ], as well as activating the AMP-activated protein kinase pathway [ ].
The fish oil is rich in n-3 polyunsaturated fatty acids PUFAs , components that are associated with the formation of beige adipocytes, among them is eicosapentaenoic acid EPA. Mice fed different diets, including with EPA, for 8 weeks showed increased expression of β3-AR, PGC-1α, and UCP1 and exhibited high expression of PPAR [ ], though this effect is controversial since another animal study investigating a diet containing pure EPA 3.
Docosahexaenoic acid DHA 1. However, knockout mice for TRPV1 did not achieve the same effect, showing that such events were mediated by SNS, TRPV1, and catecholamines [ ]. Conjugated linoleic acids CLAs also showed potential to induce browning process in the WAT [ ].
Once the overwhelming impact of infectious diseases has been alleviated by the development of efficient therapeutics, life expectancy has been continuously increasing World Health Organization, Age-associated diseases, including type 2 diabetes T2D , cardiovascular diseases CVDs , neurodegenerative pathologies, and obesity statistics are alarming and correlates with changes in the lifestyle of individuals throughout the world, including the diet, and impair the health spam rise.
Western diets WDs are composed by food items enriched in processed sugar, white flour and salt and poor in fibers, vitamins and minerals [ ]. At the same time, the diet may be the remedy against the burden caused by these chronic diseases.
While overnutrition often correlates with inflammatory and metabolic detrimental effects at molecular level, undernutrition without starvation presents many benefits.
Calorie restriction CR and intermittent fasting IF are promising interventions against the overweight and obesity numbers, climbing specially in Western countries [ ]. CR, defined as reduced calorie consumption without malnutrition, is the best studied dietary intervention that increase health spam in experimental models.
A plethora of human studies place CR as beneficial for expanding the health spam [ ]. These studies proceeded Weindruch and Sohal positive correlations between CR and health spam [ ] Click or tap here to enter text..
AT plasticity is one of the connections between CR and health benefits. Fabbiano and colleagues analyzed mice under CR and described that this regimen induces functional beige fat development in WAT, phenomenon that occur via enhanced type 2 immune response and SIRT1 expression in AT macrophages [ ].
The stress resistance provided by the IF practice places this regimen as a feasible dietary intervention against various devastating complex pathologies.
Differently from CR, intermittent fasting IF does not influence the meal size, but decrease the number of meals in a given period [ ]. The fasting state leads to a metabolic switch, which increases the usage of free fatty acid FFA as energy source in comparison to glucose.
In addition, IF favors the synthesis of ketone bodies KBs by the liver, molecules that act as an energy source during nutrient deprivation and induce a plethora of beneficial effects on the organism by acting upon the muscle, liver, heart, brain, intestine and AT [ , , ]. IF also impacts positively on AT remodeling.
A DIO animal model submitted to repetitive fasting cycles displayed increased glucose tolerance, and diminished adipocyte hypertrophy and tissue inflammation [ ]. Mouse studies show that IF induces WAT mass decrease, elevation of AT UCP1 expression and thermogenic capacity [ , ], and augmented beige pre-adipocytes recruitment to WAT [ , , ] Fig.
The impact of circadian rhythm and different diets on the WAT browning modulation. The secretion of melatonin, a circadian rhythm regulating neurohormone, is mediated by the release of Norepinephrine NE , which binds to β-adrenergic receptors. Adrenergic activation is one of the main mechanisms of WAT browning induction and BAT activation.
Intermittent fasting IF associates with weight reduction, improved metabolic status due to increased glycemic tolerance, decreased white adipocyte hypertrophy and AT inflammation, and augmented expression of thermogenic genes such as UCP1 and recruitment of beige adipocytes.
IF is also modulates the intestinal microbiome composition and diversity, a shift closely related to the induction of browning in the WAT. Caloric restriction CR is also associated with weight loss, promotes greater recruitment of beige adipocytes through the participation of M2 macrophage and eosinophil infiltration and in WAT.
Finally, obesity-inducing diets correlate with increased lipid accumulation, WAT unhealthy expansion and dysregulation. Abnormal expansion of WAT promotes ER stress, greater induction of adipose cell apoptosis and inflammation through NF-κB transcription factor activation and increased pro-inflammatory cytokines secretion.
An elegant study conducted by Li and colleagues informed that mice under IF cycles display an intestinal microbiome composition shift associated with increased levels of the fermentation products lactate and acetate. They also show that the modulation of the gut microbiota by IF is crucial for its browning effect, as microbiota-depleted mice present impaired IF-induced AT beiging and fecal microbiota transfer from these mice to antibiotics treated animals display increased browning of WAT [ ] Fig.
Unexpectedly, a human study conducted by von Schwartzenberg and colleagues showed that CR may diminish bacterial abundance, deeply change gut microbiome composition and diversity, impair nutrient absorption, and favor the outgrowth of the pathobiont Clostridioides difficile.
This diet also led to a decrease in bile acid BA levels [ ]. BA, nonesterified fatty acids, are synthesized during the browning of WAT, a phenomena associated with the potentiation of the lipolytic machinery [ ]. These fatty acids can not only activate UCP-1 allosterically, but also serve as fuel for oxidative phosphorylation and consequently heat generation in BAT [ 1 ].
Furthermore, in the liver they are used for the generation of acylcarnitines and VLDL which is used as source for thermogenesis [ ]. Moreover, studies show that the increase in brite and brown adipocytes in WAT leads to an elevation in lipoprotein lipase LPL activity and subsequently an increase in circulating lipids available for BAT through intravascular hydrolysis of chylomicron triglycerides [ ].
Consequently, these mechanisms result in the generation of cholesterol-enriched lipoprotein remnants, which upon activation of BAT accelerates the flow of cholesterol to the liver [ ].
BA are steroid acids derived from dietary cholesterol catabolism. These acids are synthesized in the liver and act to aid digestion and absorption of fat in the intestine, in addition to playing an essential role in lipid metabolism.
BA act in other tissues, such as AT, as signaling molecules through interaction with the nuclear Farnesoid X receptor FXR and the G protein-coupled membrane receptor TGR5 [ ]. Recent studies have shown that BA play a relevant role in BAT activation and increased thermogenesis in adipocytes.
In rodents, the activation of BAT by BA is dependent on its interaction with the TGR5 receptor and expression of the enzyme type 2 iodothyronine deiodinase DIO2. Additionally, experiments with oral supplementation of BA in humans indicated increased BAT activity in humans [ , ].
Another experiment performed under thermoneutrality, demonstrated an improvement in glycemic metabolism and lipogenesis in the liver and fat accumulation in the TA and also induced an improvement in thermogenic parameters and mitigation of the impact of diet-induced obesity after feeding mice with HFD associated with BA [ ].
Moreover, BAT activation also promotes liver protection. As the severity of heart failure increases, this will have a direct impact on glucose oxidation rate. This was shown in a number of studies where a mouse model of pressure-overload-heart failure with severe cardiac dysfunction showed a marked impaired glucose oxidation rates 93 — However, Osorio et al.
Unfortunately, cardiac glycolytic rates were not measured in the study by Osorio et al. In a TAC model of murine heart failure, an increase in the proportion of glucose oxidized by the hearts was also seen The reason for these discrepant findings is unclear.
However, it should be acknowledged that high pyruvate supply from increased glycolysis has the potential to augment glucose oxidation Indeed, the study by Kolwicz et al. In severe heart failure, it is possible that mitochondrial calcium control is compromised, potentially leading to mitochondrial calcium accumulation, and activation of the PDH complex due to calcium activation of PDH phosphatase The reduction in glucose oxidation that occurs in the failing heart is due, in part, to an overall deterioration in mitochondrial oxidative capacity, as well as due to an impaired activity of PDH, the rate-limiting enzyme for glucose oxidation 13 , 14 , 92 , There is also some evidence that the machinery of glucose oxidation could be impaired in the failing heart Gupte et al.
In line, Dodd et al. Of importance, is that PDH complex impairment was progressive and proportional to the degree of cardiac dysfunction.
As it was discussed earlier see Glycolysis section , it is generally accepted that insulin-induced stimulation of glucose oxidation is markedly attenuated in obesity and diabetes , , contributing to myocardial metabolic inflexibility Impairment in insulin signaling and development of insulin resistant myocardium precedes cardiac dysfunction in heart failure and it is a major determine of its progression 14 , 94 , Rutter et al.
In consistence, Peterson et al. Taken together, it seems plausible to suggest that insulin resistance is, at least in part, responsible for the reduction in glucose oxidation in heart failure. In a rat model of streptozotocin-induced diabetic cardiomyopathy, insulin resistance is associated with a marked decrease in PDH flux and diastolic function Of interest, is that dichloroacetate DCA , a PDK inhibitor that enhances PDH activity, treatment reversed insulin resistance, increase PDH flux and improving cardiac function This further emphasizes the potential therapeutic applications of improving glucose oxidation to mitigate cardiac dysfunction in heart failure.
Consistent with this, Sankaralingam et al. Collectively, this further emphasizes the crucial role of insulin resistance and high circulating FFAs in the pathogenesis of heart failure. Another mechanism by which glucose oxidation could be attenuated in heart failure is through heart failure-induced mitochondrial hyperacetylation.
Hyperacetylation occurs in the failing heart and hyperacetylation of PDH has previously been shown to have an inhibitory effect on its activity , Thus, heart-failure induced hyperacetylation could inhibit PDH activity and decrease glucose oxidation rates.
It has also been reported that hyperacetylation can increase the activity of fatty acid oxidation enzymes, such as LCAD and β-HAD As such, enhancing the activity of these ß-oxidation enzymes could negatively feedback to inhibit glucose oxidation through the Randle cycle 38 , While it is generally agreed that the failing heart has reduced cardiac energetics, mitochondrial TCA cycle activity and overall oxidative metabolism 9 , 70 , 71 , it is less clear whether myocardial fatty acid oxidation rates are also decreased.
It is generally assumed that cardiac fatty acid oxidation is decreased in heart failure 10 , — , which is supported by decreased transcription of a number of enzymes involved in fatty acid oxidation 10 , — However, direct measurements of fatty acid oxidation rates in both human and experimental models of heart failure do not always support this assumption.
Heart failure can be associated with an increase in circulating FFA levels due to high lipolysis rates 96 , , Of importance, is that increased level of circulating FFAs in failing heart is an important determinant of fatty acid oxidation rates in the heart. For example, decompensated heart failure patients show an increase in circulating FFAs levels, which is accompanied by enhanced myocardial fatty acid uptake and fatty acid oxidation , In support of this, Taylor et al.
In contrast, Dávila-Román et al. Neglia et al. Animal studies also show differing results as to what happens to fatty acid oxidation in the failing heart. Studies in mice in which heart failure was produced secondary to pressure overload or a myocardial infarction have shown that cardiac fatty acid oxidation rates are unchanged 94 , 95 , Mori et al.
However, it should be recognized that these maintained rates were seen despite a decrease in cardiac function, suggesting that fatty acid oxidation per unit work may actually increase in heart failure. In addition, these studies showed that the contribution of fatty acid oxidation to total ATP production increased, due primarily to a decreased contribution of glucose oxidation to ATP production.
Others have also shown that with compensatory heart failure, fatty acid oxidation enzymes are preserved 21 , In contrast, Byrne et al. In rats subjected to TAC, Doenst et al. Moreover, a reduction in fatty acid oxidation rates was also seen in canine models of severe heart failure , Even in the absence of heart failure, fatty acid oxidation rates are elevated under these conditions , — These high cardiac fatty acid oxidation rates persist if evidence of heart failure is seen in obesity and diabetes , , The reasons for the confusion as to what is happening to fatty acid oxidation in heart failure, may be related to alterations in the control of fatty acid oxidation at multiple levels, including changes in fatty acid supply to the heart, alterations in allosteric control of fatty acid oxidation, alterations in transcriptional control of fatty acid oxidation, and alterations in post-translational control of fatty acid oxidation.
Increased fatty acid supply to the heart will increase fatty acid oxidation, as will the presence of insulin resistance Indeed, Tuunanen et al. As discussed, in heart failure a marked cardiac insulin resistance occurs 13 , 14 , This includes a decreased ability of insulin to inhibit fatty acid oxidation 14 , As result, an increased cardiac insulin resistance in heart failure may contribute to maintaining fatty acid oxidation rates.
Heart failure is often associated with impairment in insulin signaling which could have a marked impact on energy metabolism in the heart. Insulin has an inhibitory effect on fatty acid oxidation through enhancing the activity of acetyl CoA carboxylase which increases the tissue level of malonyl CoA thereby decreasing mitochondrial fatty acid uptake.
Insulin-induced inhibition of fatty acid oxidation is impaired in the failing heart leading to an increase in fatty acid contribution to the total ATP production, despite being inefficient substrate during heart failure.
Furthermore, inactivation of the carnitine shuttle system increases cytosolic fatty acyl CoA levels or long chain acyl CoA and, in addition to the accumulation of TAG and diacylglycerol DAG , can have a negative impact on insulin signaling 14 , , For instance, excess lipid metabolites can phosphorylate serine residues on IRS-1 by activating IKK-NF-κB, JNK-AP-1, and the PKC pathway all of which can reduce glucose uptake by decreasing Akt and PI3K activity 14 , Changes at the transcriptional level of genes involved in fatty acid oxidation are often cited as a key reason why cardiac fatty acid oxidation rates may be decreased in heart failure , A down regulated gene expression of fatty acid oxidative enzyme LCAD, MCAD has been observed in heart failure patients, as well as during the progression of heart failure in animal models PPAR and the retinoid X receptor RXR complex are transferred to the nucleus to bind with a specific PPAR response element PPRE , which is located in the target gene's promoter.
An inducible PPARγ coactivator-1α PGC-1α is also correlated with the transcriptional activity of PPAR superfamily , Again in heart failure patients, cardiac PPARa expression was shown to down regulated , The expression of PGC-1α, important for mitochondrial biogenesis, is also down regulated in heart failure [ 20 , 21 , 48 , ].
In pressure-overload-induced heart failure, abnormal mitochondrial morphology and reduced mitochondrial density is seen, which is associated with altered electron transport chain proteins expression Patients with heart failure also show a reduction in mitochondrial DNA contents which was accompanied by down regulation of PGC-1α-associated proteins Furthermore, based on DNA microarray analysis, it has been shown that a subset of downstream gene targets of PGC-1a are also down-regulated in the failing heart, which is correlated with the reduced left ventricular ejection fraction However, it is still not clear whether this attenuation in the role of PGC-1α in heart failure is enough to manipulate mitochondrial biogenesis.
However, a reduction in the number of mitochondria could contribute to the changes in fatty acid oxidation observed in heart failure. Post-translational modifications may also alter fatty acid oxidation in the failing heart This includes mitochondrial lysine acetylation, in which an acetyl group is transferred to a lysine residues or mitochondrial proteins.
Acetylation can be mediated through histone and non-histone acetyl-transferase Furthermore, mitochondrial acetyltransferase, namely GCN5L, has also been shown to promote acetylation On the reverse reaction, sirtuins SIRTs act as deacetylases to reverse the effect of acetylation , Acetylation controls the activity of number of metabolic enzymes Hyperacetylation of LCAD and ßHAD results in an increase in fatty acid oxidation rates In obese mice with heart failure, an elevated GCN5L expression in abdominal aortic constriction-induced heart failure is associated with increased in LCAD acetylation and an increase in fatty acid oxidation Furthermore, switching to a low fat diet in obese mice showed the opposite effect on the post-translational modification associated with reduced fatty acid oxidation Moreover, we also showed glucose oxidation could be inhibited through hyperacetylation in heart failure Taken together, post-translational modifications may be another factor to be considered which might to explain the metabolic inflexibility during heart failure.
Glucose and fatty acid metabolism are tightly controlled by insulin signaling in the heart. Evidence from clinical studies have shown a strong association between insulin resistance and cardiac dysfunction , Moreover, patients with insulin resistance have high rates of lipolysis in adipose tissue with increases in TAG hydrolysis — Of importance, insulin resistance-induced shifts in favor of fatty acid oxidation and is associated with attenuation of glucose uptake by the heart [see review by ].
This change in metabolic preference was also observed in an experimental setting 13 , 14 , 91 , and clinical studies of heart failure 82 , Of interest, insulin resistance precedes any changes in cardiac energy metabolism in mice subjected to abdominal aortic constriction Impairment in insulin signaling primarily has a direct inhibitory effect on fatty acid oxidation by increasing the malonyl CoA levels and secondarily inhibiting glucose oxidation through a negative feedback effect of the Randle cycle Moreover, increasing fatty acid oxidation rates could also indirectly cause attenuation in glucose oxidation by triggering the activity of PDK and limiting the activity of the PDH complex.
These results are further supported as PDK deletion improved the HFpEF-induced reduction in glucose oxidation A major determinant of ketone oxidation rates in the heart are the levels of circulating ketones. Earlier studies have suggested that blood ketone levels are elevated in congestive heart failure with reduced ejection fraction patients proportional to the severity of cardiac dysfunction , These results were recently challenged by Melenovsky et al.
However, in support of the earlier observations by Lommi et al. It is interesting to note however that Zordoky and colleagues also found that HFpEF patients had significantly higher blood ketone levels than HFrEF patients while HFrEF patients had lower ketone levels than healthy controls The discrepancy in reported levels of circulating ketones in heart failure patients may be due to multiple reasons including differences in severity, duration and type of heart failure.
This is especially the case in severe heart failure where insulin resistance-induced increases in hepatic ketogenesis could be inevitably contributing to increases in circulating ketones In addition, it is important to note that cardiac ketone levels are dynamic.
In general, the circulating levels and cellular uptake of ketones is proportional to its contribution to ATP production In that regard, it is difficult to pin point cardiac ketone levels without concurrently considering pathological circulating serum levels, uptake, oxidative rates and secretion rates of ketone For example, it is still not clear whether HFrEF patients, with lower blood ketone levels than HFpEF patients , have a greater reliance on ketone bodies and increased myocardial ketone body oxidation.
Alternatively, it is possible that HFpEF patients with high circulating ketone body levels could be associated with increased muscle uptake and oxidation of ketone bodies. Therefore, changes in circulating ketone body levels are temporal, indefinite, and direct measurements of flux through myocardial ketone body oxidation rates are required.
Arterio-venous measurements for ßOHB in HFrEF patients, a surrogate for myocardial ketone body utilization, reported no differences compared to healthy controls , and a slight increase, however not significant, in HFrEF patients However, recent studies have suggested that myocardial ketone body oxidation is increased in heart failure.
In a mouse model of compensated and decompensated pressure overload cardiac hypertrophy, proteomics data demonstrated that a key enzyme involved in ketone body oxidation, namely ß-hydroxybutyrate dehydrogenase BDH1 , was up-regulated 2 to 3-fold Moreover, the myocardial metabolite profile of mice with heart failure was comparable to mice fed a 4-week ketogenic diet.
In parallel, Bedi et al. We have also seen an increase in myocardial ketone body oxidation rates in the ex vivo isolated failing murine heart unpublished data Taken together, these studies suggest that the failing heart has an increased reliance on ketone body oxidation.
Nevertheless, Nagao et al. In vitro , subjecting cardiomyocytes to oxidative stress also resulted in elevated levels of βOHB, increased levels of anti-oxidative factors, and concurrent down-regulation of the rate limiting enzyme in ketone body oxidation, SCOT These findings would suggest that ketone body oxidation decreases during heart failure to maintain elevated levels of βOHB as a compensatory response to protect the heart against oxidative stress.
The reason for the contradictory results could be due to the severity and duration of heart failure in these studies 15 , Since heart failure is a chronic condition, it seems plausible to suggest that in the early stage of heart failure, βOHB may have an antioxidant role and only become an adaptive fuel source in the end-stage heart failure It is worth mentioning that βOHB has previously been shown to be an HDAC inhibitor and protects against oxidative stress However, with this uncertainty comes the question of whether ketone body oxidation in heart failure is adaptive or maladaptive 23 , ?
To address whether ketones are adaptive or maladaptive in failing hearts, several recent studies have investigated this. Schugar et al. Similarly, overexpression of cardiac BDH1, the first enzyme in the ketone body oxidation pathway, mitigated oxidative stress and attenuated cardiac remodeling following pressure overload-induced hypertrophy Together, these studies suggest that heart failure-induced increases in ketone body oxidation are adaptive for a failing heart.
However, there are still several aspects to consider in light of the preliminary suggestion that ketone body oxidation is adaptive in the setting of heart failure. One factor to consider is the change in cardiac ketone levels, a dynamic concentration that would decrease if heart failure is characterized by elevated myocardial ketone body oxidation rates.
In such a scenario, high cardiac ketone levels would be suggested to be undesirable and accelerating myocardial ketone body oxidation would be adaptive in heart failure. Alternatively, since ßOHB has been shown to be an HDAC inhibitor and recent work has demonstrated that HDAC inhibitors can enhance myofibril relaxation kinetics and improve diastolic function , maintaining ketone levels may indeed be beneficial in the setting of HFpEF as opposed to HFrEF.
Second, another factor to consider are post-translational modifications which may be responsible for myocardial energy metabolic derangements that contribute to the progression of heart failure In this case, increasing myocardial ketone body oxidation and increasing the myocardial acetyl CoA pool has been suggested to provide more substrate for lysine acetylation, ultimately contributing to the failing heart's hyperacetylated state This may or may not be desirable since hyperacetylation of glucose and fatty acid oxidation enzymes , and its effects on enzyme activity, require further investigation in the setting of heart failure.
Ketones have the potential to suppress glucose oxidation and vice versa 37 , 69 , as they both compete for available oxygen and as a source of TCA cycle acetyl CoA. Williamson and Krebs observed that in the presence of insulin, acetoacetate decreased glucose oxidation by half in the perfused rat heart.
This may be explained by the ability of ketones to increase the mitochondrial acetyl-CoA to CoA ratio and consequently inhibit the activity and flux through PDH, the rate limiting enzyme of glucose oxidation — Of importance is whether ketones add a new dimension of complexity to the Randle cycle Furthermore, the influence of ketone levels and its inhibitory effect on glucose oxidation also needs to be characterized to understand whether it is beneficial to enhance either of these pathways.
Recently, ketone bodies were found to decrease myocardial glucose uptake and increase myocardial blood flow in a PET study in healthy humans In connection with this displaced glucose uptake, leucine metabolism into ketone bodies has also been shown to inhibit GLUT4 translocation in cardiomyocytes due to an increase in lysine acetylation, ultimately hampering cardiac glucose uptake Since heart failure is characterized by an increase in acetylation , the failing heart's hyperacetylated state could be potentiating leucine to ketone-mediated GLUT 4 inhibition and partially conferring insulin resistance.
However, this is in contrast to a study that showed that administration of ßOHB and acetoacetate were able to recapitulate insulin-induced improvements in an isolated perfused rat heart's ex vivo cardiac efficiency Since the failing heart is insulin resistant, ketones may be a viable substrate to improve cardiac efficiency in the failing heart However, more studies measuring ketone body oxidation flux in the presence and absence of insulin are required.
It has also been reported that ketones can inhibit myocardial fatty acid oxidation , For example, intravenous infusion of ßOHB suppressed myocardial fatty acid oxidation independent of changes in malonyl-CoA levels or the ratio of acetyl-CoA to CoA in pigs Since fatty acid oxidation rates in heart failure remains controversial, it is unclear whether the inhibitory effects of ketones on myocardial fatty acid oxidation are beneficial or detrimental for the failing heart.
This, however, further underlines the crucial role of ketone bodies in myocardial energy metabolism and implicates ketones as an important role-player that is currently neglected from the Randle cycle.
Targeting glucose metabolism has been shown to be an effective approach to mitigate cardiac remodeling and improve heart function. Ikegami et al. Dichloroacetate DCA is a direct PDK inhibitor which increases glucose oxidation via enhancing PDH complex activity in the setting of heart failure.
In the isolated working rat heart DCA enhances post-ischemic cardiac function and efficiency which is associated with improved coupling between glycolysis and glucose oxidation DCA-induced improvement in coupling between glycolysis and glucose oxidation was also later demonstrated in suprarenal abdominal aortic constriction in rat Similarly, Kato et al.
In line with experimental studies, small clinical studies, although few, have shown promising improvement in cardiac contractility with DCA treatment in patients with coronary artery disease and heart failure Clinical data were not all consistent as DCA infusion in patients with congestive heart failure did not show significant beneficial effects There are number of pharmacological approaches which are shown to successfully reduce fatty acid oxidation.
Two molecules, namely etomoxir and perhexiline, is shown to inhibit CPT1 Figure 3 and limit fatty acid oxidation with parallel increase in glucose oxidation in mouse and rat models of heart failure , In humans, etomoxir showed improvement in ejection fraction and cardiac output , Perhexiline also improves cardiac function and symptoms of heart failure However, clinical trials to validate the preliminary encouraging finding with these two molecules were terminated due to the hepatotoxicity Figure 3.
Future approaches to overcome the metabolic balance or inflexibility: In the healthy heart, a variety of energy substrates produce ATP to maintain metabolic flexibility and cardiac efficiency.
However, in heart failure a reduced ATP production occurs due to a decreased metabolic inflexibility and a less efficient heart. Transcriptional changes and altered mitochondrial biogenesis also contribute to this metabolic inflexibility in heart failure.
Possible approaches to improve metabolic flexibility are shown by stars. DCA, dichloroacetate; SSO, sulfo-N-succinimidyl-oleate; MCD, malonyl CoA dehydrogenase; AA, amino acids. Furthermore, sulfo-N-succinimidyl-oleate SSO is an inhibitor of CD36 and has been shown to decrease fatty acid oxidation followed by an indirect increase in glucose oxidation While these approaches showed beneficial effects in experimental studies involving heart failure, clinical studies with these agents have yet to be performed.
Another approach to inhibiting fatty acid oxidation is to inhibit the last enzyme of fatty acid ß-oxidation, 3-keotacyl CoA thiolase, with trimetazidine Clinically trimetazidine has shown beneficial effects by increasing cardiac efficiency, where there is a shift in myocardial substrate utilization from fatty acid oxidation to glucose oxidation.
It has been using as an antianginal agent in more than countries A combination of chronic trimetazidine treatment along with the other conventional therapy in heart failure patients improves cardiac function in humans Treatment with trimetazidine in heart failure patients with idiopathic dilated cardiomyopathy shows a decrease in myocardial fatty acid oxidation rates, as well as improved left ventricular function and insulin sensitivity A meta-analysis of clinical trials with trimetazidine in heart failure, showed a beneficial effect of trimetazidine on left ventricular systolic function, clinical symptoms for patients with chronic heart failure and importantly may result in decreasing all-cause mortality We have also shown that trimetazidine prevents obesity-related reductions in cardiac function in obese mice with heart failure , Another potential intervention to decrease fatty acid oxidation in heart failure is with ranolazine.
Ranolazine has been clinically used as anti-anginal agent since , However, ranolazines efficacy in treating heart failure has not been extensively studied.
In diabetic cardiomyopathy, ketones have been popularized as a thrifty fuel substrate for the heart , The role of myocardial ketone metabolism has attracted huge attention since empagliflozin, a sodium glucose co-transporter-2 inhibitor used to treat type 2 diabetes, has shown cardioprotective effects in type 2 diabetic patients.
This cardioprotection was associated with increased plasma ketone levels which led to the proposed cardioprotective role of increased ketone body oxidation in the diabetic failing heart — Furthermore, a recent study found that non-diabetic mice with experimental TAC-induced heart failure was protected against heart failure-induced decreases in in vivo and ex vivo function following a 2-week treatment with empagliflozin However, despite the promising and exciting findings, it is still not clear whether empagliflozin increases ketone oxidation in the heart, or whether empagliflozin-mediated cardioprotection is through a ketone-independent mechanism Therefore, future studies are required to elucidate whether empagliflozin's cardiovascular benefits are mediated by changes in myocardial ketone oxidation.
There is a growing recognition and understanding of the importance of metabolic flexibility of the heart and how metabolic inflexibility in heart failure could contribute or even cause deterioration of cardiac contractility and affect the disease progression.
Of importance, is that metabolic inflexibility could also be influenced by other comorbidities such as diabetes, obesity, hyperlipidemia and hypertension.
Taken together, aiming to re-establish metabolic flexibility in the failing heart is shown to be an effective approach to improve cardiac function and therapeutic outcome. Here, we will discuss some of the recent pharmacological interventions which could have clinical value for failing heart patients.
The shift toward utilizing a more oxygen-efficient substrate, namely glucose, could potentially have favorable effects in terms of the energy production and cardiac function of the ischemic failing heart which is oxygen deficient.
This approach would also improve the coupling between glycolysis and glucose oxidation and produce more ATP per mole of glucose oxidized. It would also limit glycolysis-induced acidosis and its consequent inhibitory effect on cardiac contractility.
As discussed earlier, DCA is shown to increase the contribution of glucose to the total ATP production through increasing the glucose oxidation rate with a secondary reduction in fatty acid oxidation in different experimental models and in pilot human studies. However, it is important to note that DCA has a poor pharmacokinetic profile short half-life and a low potency.
Therefore, future investigations using DCA treatment should potentially consider continuous infusion to administer DCA to maintain effective concentration. In the same context of utilizing oxygen efficient energy substrate in a failing heart which is under oxygen deficit, enhancing cardiac function could be achieved by reducing the reliance of the heart on fatty acid oxidation.
While a considerable number of approaches exist that can directly or indirectly inhibit fatty acid oxidation, clinical trials targeting a reduction of fatty acid uptake or enzymatic activity are either limited with the confounding factors or underpowered.
Therefore, framing animal models along with potential drug targeting fatty acid oxidation to optimize its effective dose, length and other possible side effects, under different diseases states i.
obesity, diabetes , different age, and sex should be a prime consideration prior to design future heart failure clinical studies. Unlike etomoxir and perhexiline CPT1 inhibitors , it is not known if SSO cause hepatotoxicity. Another possible therapeutic approach is using malonyl CoA decarboxylase MCD inhibitors.
It has been shown that by increasing malonyl CoA levels, fatty acid oxidation is reduced with a compensatory increase in glucose oxidation 25 , Inhibition of MCD, using the novel compound CBM, increases cardiac malonyl CoA levels and decreases fatty acid oxidation However, MCD inhibitors have yet to be tested in the clinical.
Furthermore, inhibition of beta-oxidation enzymes, such as 3-keotacyl CoA thiolase, also has potential in reducing fatty acids oxidation l. Based on the promising outcomes in animal and human studies described in Therapeutic Approaches section , modulation of fatty acid oxidation using trimetazidine is a potential approach to treating heart failure.
Again, large randomized clinical trials are still needed to confirm this. Of importance, is that modulating a particular energy substrate use byu the mitochondria to enhance the overall oxidative phosphorylation could be hindered by a decrease in the number and quality of the mitochondria in the myocardium.
Targeting PGC1α to enhance mitochondrial biogenesis and improve the transcriptional changes in the failing heart could potentially have a therapeutic application in heart failure.
Furthermore, a combination of the potential therapeutic components trimetazidine, CD36 inhibitors, MCD inhibitors, PDK inhibitors , targeting both fatty acid and glucose oxidation during heart failure could potentially restore metabolic inflexibility and improve cardiac function in heart failure.
Stimulating ketone oxidation has been proposed as a potential approach for improving cardiac function in the failing heart While ketogenic diets are available, the extraneous systemic effects and cardiovascular risk factors associated with these high-fat diets need to be assessed as it may not be appropriate for heart failure patients.
Furthermore, in light of recent work suggesting that increased ketone body oxidation is adaptive in the setting of heart failure , , increasing myocardial ketone body oxidation may be desirable, assuming it is not doing so at the cost of displacing glucose uptake, glucose oxidation or fatty acid oxidation.
Therefore, future studies characterized by normalizing ketone body oxidation in the setting of heart failure need to be conducted with measurements of the effects on other substrates and its overall cardiac energy metabolic consequences. Recognising the central role of the mitochondria in energy metabolism and how impaired oxidative phosphorylation influences the progression of heart failure, targeting the mitochondria is another approach to regain metabolic flexibility and to improve cardiac function.
Preclinical studies using mitochondrial-targeted antioxidants, such as AP39 and elamipretide, can preserve mitochondrial integrity through a marked reduction in mitochondrial ROS generation, which is associated with an improved post-infarction cardiac function in vivo , Consistent with this, chronic treatment with elamipretide mitigates cardiac dysfunction in an advance heart failure model in dog, induced by a serial intracoronary microembolizations, which is accompanied with enhanced mitochondrial respiration and ATP production Future large clinical trials are warranted to validate the promising effect of Levosimendan in failing heart patients.
Due to the heart's constant high energy demand, a fine balance between energy substrate utilization is crucial in maintaining metabolic flexibility. With regards to the controversial nature of fatty acid oxidation, while the genes involved in fatty acid oxidation are down-regulated, direct measurements of rates have presented conflicting results.
Thus, future studies that consider the transcriptional regulation, post-translational modifications acetylation , absolute metabolic rates, and mitochondrial biogenesis are all required to fully understand the way in which fatty acid oxidation is perturbed in heart failure.
Finally, definitively characterizing the metabolic profile of the failing heart will help direct future pharmacological therapies that can combine approaches to harmonize and normalize the metabolic flexibility of the failing heart.
QK, GU, KH, and GL designed the literature search strategies and contributed to the critical analysis and interpretation of the published data. QK, GU, and KH carried out the literature search, collected the data and wrote the manuscript which was edited by GL and approved my all authors.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study was funded by a Foundation Grant from the Canadian Institutes of Health Research to GL.
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Essentially, this means that FAs stored in adipose tissue can only be used as an energy source to support cellular functions or to provide specific precursors that are needed to replace or expand the structure or signalling functions of FAs.
Some tissues have an obligatory need for glucose brain, red blood cells and retinal cells , while most tissues have the capacity to switch between glucose and FAs. The contribution of different fuels to energy production in specific tissues and the contribution of different tissues to the overall energy production and utilisation in the whole body vary quite markedly.
Because of its relative size in man and most animals, muscle is considered to be a major tissue for the disposal of both glucose James et al. Because of the ability of muscle to substantially increase energy expenditure during exercise Bangsbo , this tissue is also very flexible in its capacity to act as a sink for energy substrates.
The liver has a significant role in the disposal of glucose after a meal and in the provision of glucose to the circulation to maintain blood glucose levels when nutrients are not being absorbed from the gut.
The liver also has the ability to take up FAs, oxidise them or package them in lipoproteins for export and storage in other tissues and is therefore central to lipid and glucose homoeostasis Postic et al. Adipose tissue can, particularly in obese individuals, be the tissue contributing most to whole-body mass, but per unit mass it does not have a major impact on whole-body glucose disposal Kraegen et al.
White adipose tissue also has little impact on the whole-body oxidation of FAs, although there is significant current research interest in investigating whether white adipocytes can acquire a more oxidative brown adipocyte phenotype with a greater contribution to whole-body substrate oxidation and energy expenditure Wu et al.
Although the musculature as a whole is a major contributor to total body glucose and FA metabolism Ng et al. Type 1 red muscle fibres are considered more insulin sensitive, with a greater oxidative capacity for glucose and FAs, while type II white muscle fibres contain less mitochondria, are considered less insulin sensitive and contribute less to FA oxidation Nyholm et al.
Therefore, a higher composition of type 1 red fibres in muscle has been reported to be associated with increased insulin responsiveness Stuart et al. This view has been challenged by some recent studies where genetically manipulated mice Izumiya et al.
It does seem important to consider that the contribution of the skeletal musculature to whole-body energy metabolism and substrate oxidation should not be based on the assessment of these parameters in a single muscle type. Some of these effects correlate with observed shifts in muscle size and fibre type that occur with training Shaw et al.
The pathways by which different fuels are oxidised to support tissue and cellular energy demands in animals are thoroughly dealt with in major textbooks and summarised in Fig. The electrochemical proton gradient generated by the ETC then drives ATP synthesis via ATP synthase Fig.
Because FAs are chemically more reduced molecules than carbohydrates, FAs are theoretically able to produce more energy when completely oxidised than an equivalent carbohydrate molecule. In other words, the complete oxidation of six-carbon glucose consumes six oxygen molecules and produces six carbon dioxide molecules accompanied by the synthesis of 36 ATP molecules.
On the other hand, the complete oxidation of six-carbon hexanoic acid consumes eight oxygen molecules and produces six carbon dioxide molecules for 44 ATP molecules.
Therefore, a switch to the oxidation of FAs as the major energy substrate should result in less efficient ATP production and an increase in whole-body energy expenditure that could lead to a loss of fat mass if energy intake remains constant Clapham a , b , Leverve et al.
Pathways of substrate metabolism in muscle. Oxidation pathways of glucose, FAs and amino acids converge at the level of acetyl CoA. This proton motive force is dissipated by ATP synthesis and by proton leak via the adenine nucleotide transporter ANT and activated uncoupling proteins UCPx.
Demand for ATP and proton leak are greater determinants of oxygen consumption and heat production than the substrate being oxidised.
Citation: Journal of Endocrinology , 2; Indirect calorimetry is often used in human and animal studies to determine total energy expenditure indirectly by the measurement of oxygen consumption and carbon dioxide production , and the measurement of oxygen consumption and carbon dioxide production can also be used to calculate the relative use of glucose and FAs to support that energy expenditure respiratory exchange ratio, RER , assuming that any contribution of protein oxidation is relatively small and constant Ferrannini , Arch et al.
However, in practice, it is unlikely that such theoretical calculations can be applied to the regulation of energy balance with any certainty.
For instance, rarely does the measured RER shift from complete glucose oxidation 1. counter-ion transport and uncoupling protein activity Mazat et al.
The concepts of efficiency and plasticity in the coupling of substrate oxidation to energy conservation ATP synthesis have been expanded on in several authoritative review articles Harper et al.
In reality, coupling efficiency can vary significantly depending on changes in proton leak or ATP demand, but in cell systems at least, changes in substrate oxidation do not appear to influence the relationship between oxygen consumption and ATP synthesis Brand et al.
The above discussion clearly leads to the conclusion that the cost of generating mitochondrial ATP in terms of ETC activity and oxygen consumption can vary significantly and is not affected to any large extent by the substrate being oxidised to provide the reducing equivalents for electron transport.
Despite this, it is not uncommon to read about studies in whole animal systems particularly genetically modified mice where differences in fat mass are often mechanistically related to changes in the mRNA levels of FA metabolism genes in a variety of tissues without appropriate consideration of the contribution of these tissues to whole-body energy expenditure Abu-Elheiga et al.
For example, expression of oxygen consumption or heat production on a kilogram body weight basis can be misleading if animals have significantly different amounts of fat tissue, because the metabolic rate of fat per gram is much lower in tissues such as muscle and liver Frayn et al.
Similarly, the difference in daily food intake needed to contribute to a significant gain of body fat over several weeks in mice can be so small as to be undetectable unless large numbers of mice — are used for the comparison Tschop et al.
Changes in the body weight and body fat of groups of adult mice with different genotypes on different diets should reflect cumulative differences in energy intake and energy expenditure. However, any differences might not be easily detected if animals are assessed for food intake and energy expenditure individually in indirect calorimetry systems, away from their home cage and communal environment for only a 24—h period of the several weeks over which body weight and fat mass have been monitored.
AMP-activated protein kinase AMPK is recognised as a master regulator of energy metabolism, particularly in times of energy stress such as exercise, hypoxia and starvation Hardie et al. The activation of AMPK has been shown to acutely increase FA and glucose uptake and metabolism in a variety of experimental situations including in vitro and in vivo experiments in muscle Iglesias et al.
The long-term effects of AMPK activation in muscle lead to the activation of gene transcription pathways that increase mitochondrial biogenesis and proteins of oxidative metabolism Winder et al.
The acute regulation of FA oxidation by AMPK is largely through the phosphorylation and inactivation of the enzyme acetyl CoA carboxylase 2 ACC2.
The pharmacological activation of AMPK has been shown to produce changes in muscle metabolic pathway capacity similar to those produced by exercise training O'Neill et al. A series of studies employing genetic deletion of Acc2 Acacb have reported reduced fat depots in association with increased FA oxidation in isolated muscle Abu-Elheiga et al.
These results suggest that the inhibition of ACC2 by the activation of AMPK or development of ACC2 inhibitors might promote FA oxidation and produce fat loss. Subsequent studies using independently generated Acc2 -knockout mice did not reproduce these effects, reporting that although these mice exhibited increased FA oxidation at the whole-body and isolated muscle level, there was no measurable difference in energy expenditure, fat mass or food intake Hoehn et al.
However, there was an increased glycogen content in muscle, an effect of AMPK activation noted previously Winder et al. Another study using independently generated genetically manipulated mice has reported no difference in body weight, food intake or fat mass in global or muscle-specific Acc2 gene-deleted mice Olson et al.
Therefore, it would appear that apart from theoretical calculations suggesting that increasing fat oxidation will drive increased energy expenditure, there is little experimental evidence to support the idea that energy expenditure can be increased simply by increasing substrate availability or by switching to oxidise FAs.
From an energy metabolism point of view, the flow of different substrates to tissues for oxidation or storage is largely under the control of the circulating hormone insulin.
After a meal, direct stimulation of the β-cells of the islets of Langerhans of the pancreas by nutrients glucose, FAs and amino acids increases insulin release into the circulation. Certain gut hormones GLP1 and GP can also augment insulin secretion, as can neural signals from the brain Thorens Insulin has many stimulatory and inhibitory actions in different tissues mediated by a complex intracellular signalling pathway, but for the purpose of this discussion, the actions of insulin to stimulate glucose uptake and metabolism in muscle and regulate FA metabolism will be a major focus.
The failure of insulin to appropriately regulate glucose and FA metabolism is termed insulin resistance, and this condition is most frequently observed in the muscle and liver of overweight or obese individuals Eckardt et al.
Insulin resistance is considered a significant predisposing factor for the development of type 2 diabetes T2D and therefore there is considerable research effort put into determining the mechanistic relationship between excess lipid accumulation obesity and insulin resistance, particularly in muscle.
Studies from over 20 years ago first showed that triglyceride accumulation in the muscle of high-fat diet-fed rats coincided with insulin resistance Storlien et al. Since then, the relationship between muscle lipid accumulation and insulin resistance has also been established in humans, and many mechanisms have been put forward to explain how lipid accumulation could generate insulin resistance Bosma et al.
Over the last decade, the major challenge has been determining whether these proposed mechanisms are universal or specific to the model of lipid-induced insulin resistance being studied. It is also possible that different mechanisms are important at different times during the development of insulin resistance and that some proposed mechanisms depend on the experimental methods used to assess insulin action.
All discussions of the relationship between increased fat metabolism and insulin action are dependent on the methodology used to assess insulin resistance and the assumptions associated with different methodologies. As has been mentioned previously, nearly all investigations of lipid-induced insulin resistance in rodent models utilise high-fat diet feeding to increase adiposity, but the methods of assessing insulin action can be quite varied and rely on glucose tolerance tests or insulin tolerance tests and less frequently because of the technical difficulty on hyperinsulinaemic—euglycaemic clamps.
Various technical considerations of glucose and insulin tolerance tests must be considered when discussing the metabolic implications of these tests for muscle insulin action.
The timing and route of administration of glucose and duration of fast before glucose administration influence the results of glucose tolerance tests Andrikopoulos et al. Insulin tolerance tests were devised largely to assess the effectiveness of counter-regulatory mechanisms in response to insulin-induced hypoglycaemia and therefore the utility of these tests to assess peripheral insulin action is debatable.
Neither glucose tolerance nor insulin tolerance tests give specific data regarding insulin effectiveness in muscle, although several methodological variations have used concurrent injection of radioactive tracers to assess glucose clearance into muscle during a glucose tolerance or insulin tolerance test Crosson et al.
The hyperinsulinaemic—euglycaemic clamp with glucose tracer administration gives the most reproducible assessment of muscle glucose clearance in response to constant insulin stimulation and constant glucose availability Ayala et al.
This technique relies on plasma insulin levels not insulin infusion rates during the comparison of the clamp being matched between the groups. In many studies, plasma insulin levels during the clamp are not reported, making the assessment of muscle insulin action difficult Chapman et al.
In vitro assessment of insulin effectiveness in isolated soleus or extensor digitorum longus muscle is also often used to demonstrate the effects of FA exposure Thompson et al. reliance on diffusion and not on perfusion.
While all the above methods can give useful information about the effects of muscle lipid accumulation on insulin action, this information can be specific for the test employed.
Even the data obtained from hyperinsulinaemic—euglycaemic clamp studies describe fluxes measured after at least an hour of exposure to constant insulin stimulation and constant glucose availability, a situation that is unlikely to ever exist in the normal h feeding—fasting cycle.
Therefore, it would seem important to consider the method used to demonstrate a difference in insulin action with lipid accumulation, when assessing the relevance of various mechanisms to reduced glucose metabolism in muscle when no restrictive experimental conditions e. in vitro assessment, constant infusion and i.
As has been mentioned above, the association between intramyocellular triglyceride IMTG content and insulin resistance is now well established in animals and obese humans, and most studies investigating the mechanisms of insulin resistance in muscle use high-fat diet rodent models. It has also become standard practice in assessing the phenotype of genetically manipulated mice to place them on high-fat diets to investigate whether there is any impact favourable or detrimental of gene manipulation on glucose and energy homoeostasis.
There is a reasonable assumption that, independent of genetic background in animals or humans, overconsumption of energy-dense diets plays a major role in the accumulation of fats and development of metabolic derangements in muscle.
In humans, overconsumption of energy-dense diets for a few weeks is enough to increase fat mass and have detrimental effects on whole-body insulin action Samocha-Bonet et al. In mice, high-fat feeding for as little as a few days can impair glucose tolerance Turner et al.
Studies that improved insulin sensitivity by low-calorie diets in patients with T2D were accompanied by a reduction in IMTG content Jazet et al. Insulin resistance associated with ageing Nakagawa et al. Current opinion is reasonably clear on the fact that IMTG is a useful marker of the level of cytosolic lipid accumulation, but it is more likely that active lipid metabolites such as LCACoAs, DAGs and ceramides or intermediates of FA oxidation pathways interfere with insulin action via a variety of potential mechanisms Fig.
These mechanisms are largely based on the idea that insulin resistance in muscle is the result of reduced transduction of the insulin signal through the phosphorylation cascade leading to the translocation of the glucose transporter GLUT4 to the sarcolemmal membrane Stockli et al. Since that time, research into the molecular mechanism of FA-induced insulin resistance in muscle has mainly focused on linking excess FAs to defects in the insulin signalling pathways that regulate glucose uptake.
However, there are some established and some more speculative mechanisms that also link increased FA metabolism with reduced insulin action, and these are discussed in the subsequent sections. Proposed mechanisms for the build-up of bioactive lipid species and how they interfere with insulin action in muscle to produce insulin resistance.
DAG can activate lipid-sensitive kinases to serine phosphorylate and reduce tyrosine phosphorylation of IRS1. Ceramide can inhibit Akt phosphorylation and reduce transduction through the insulin signalling pathway. Circulating cytokines or FAs themselves are reported to activate inflammatory pathway serine kinases that interfere with insulin signalling.
Reduced or dysregulated FA oxidation in mitochondria could create a build-up of bioactive lipids and generate reactive oxygen species ROS that also activate kinases that interfere with insulin signalling.
IMTGs are considered to be relatively benign with regard to insulin resistance Goodpaster et al. However, despite the general consensus that IMTGs are metabolically inert, it is possible that the expanded IMTG pool generates intermediates of lipid metabolism that are more likely to play a mechanistic role in the development of muscle insulin resistance.
In this respect, the bioactive lipid metabolites DAG and ceramide are leading candidates. The levels of both DAG Turinsky et al.
While less is known about the role of these lipids in humans, it has been reported that acute lipid-induced insulin resistance is associated with muscle DAG accumulation Itani et al. Furthermore, interventions that enhance insulin action, such as exercise training, cause reductions in muscle DAG and ceramide content Bruce et al.
Specifically, DAG accumulation is thought to impair insulin action via the activation of novel protein kinase C PKC isoforms, which subsequently inhibits insulin signal transduction to glucose transport via serine phosphorylation of insulin receptor substrate 1 IRS1; Yu et al.
Ceramide has been reported to cause insulin resistance by impairing insulin signalling at the level of Akt Schmitz-Peiffer et al. In addition, ceramide is a potent activator of inflammatory molecules, including c-Jun N-terminal kinase JNK; Westwick et al.
However, while inflammation has been proposed as a critical factor causing insulin resistance, studies carried out by our group and other groups suggest that inflammation is not involved in the initiation of lipid-induced insulin resistance, but may be more important in the exacerbation and maintenance of insulin resistance once obesity is established Lee et al.
Although there is mounting evidence supporting a role for DAG and ceramide in the regulation of insulin sensitivity, it is important to highlight that the accumulation of these lipids is not always associated with insulin resistance. In fact, a recent study has found that total DAG content is actually elevated in the muscle of highly insulin-sensitive endurance-trained athletes compared with the skeletal muscle of obese individuals Amati et al.
Furthermore, a positive correlation between total muscle ceramide content and insulin sensitivity has been reported Skovbro et al.
These data suggest a more complex role for DAG and ceramide in the regulation of insulin action Amati et al. While the bioactive lipid hypothesis has gained strong support, an alternative concept linking the accumulation of intermediates of mitochondrial FA oxidation with muscle insulin resistance has gained attention Koves et al.
This model proposes that lipid oversupply drives an increase in mitochondrial β-oxidation that exceeds the capacity of the Krebs cycle, leading to the accumulation of by-products of FA oxidation Koves et al.
This is supported by studies demonstrating an increase in incomplete FA oxidation and an accompanying increase in intramuscular acylcarnitine levels in obese rodents Koves et al. While data in humans are currently limited, there is evidence that acylcarnitine does accumulate in the muscle of humans in response to a high-fat diet Putman et al.
However, it is not clear whether acylcarnitine plays a direct role in the modulation of skeletal muscle insulin sensitivity by disrupting signalling processes or whether it simply reflects a state of mitochondrial stress.
Unravelling the role of acylcarnitine in muscle insulin sensitivity will no doubt be a focus of future research. Another prominent theory on the aetiology of insulin resistance implicates abnormalities in mitochondrial function as a major causative factor leading to reductions in insulin sensitivity.
More specifically, defects in mitochondrial metabolism have been suggested to lead to inadequate substrate oxidation, precipitating a build-up of intracellular lipid metabolites, impaired insulin signalling and the subsequent development of insulin resistance Lowell and Shulman , Kim et al.
The initial studies that set the platform for this theory in the late s showed that there was reduced mitochondrial enzyme activity and decreased fat oxidation in the skeletal muscle of obese, insulin-resistant subjects and in individuals with T2D Kelley et al.
Kelley et al. In the following year, two prominent microarray studies were published, describing a coordinated down-regulation of genes involved in mitochondrial biogenesis and oxidative phosphorylation in subjects with T2D and, importantly, also in non-diabetic individuals with a family history of T2D Mootha et al.
In the ensuing decade since the publication of these landmark studies, many groups have reported defects in different mitochondrial parameters in the skeletal muscle of a range of different insulin-resistant populations obese, T2D and PCOS.
Functional studies in muscle biopsy samples or in vivo using magnetic resonance spectroscopy have also reported decreases in mitochondrial oxidative capacity in insulin-resistant individuals Petersen et al.
Collectively, all these studies suggest that at some level, mitochondria in insulin-resistant individuals are not as effective at burning fuel substrates in muscle and this compromises insulin action. Despite the large body of evidence described above, this area is controversial, as many studies report a dissociation between insulin resistance and mitochondrial dysfunction.
For example, providing rodents with excess fat in their diet leads to an enhancement of mitochondrial oxidative capacity in muscle while at the same time inducing insulin resistance Turner et al. Several lines of mice with genetic manipulations that cause compromised mitochondrial function in muscle do not exhibit insulin resistance Vianna et al.
Conversely, two separate lines of muscle-specific Pgc1 α Ppargc1a transgenic mice displayed a significant enhancement in the markers of mitochondrial content and yet were insulin resistant due to excessive FA delivery and reduced GLUT4 SLC2A4 expression in muscle Miura et al.
A growing number of studies in humans have also reported intact mitochondrial function in various insulin-resistant populations De Feyter et al.
Collectively, these studies suggest that mitochondrial dysfunction in muscle is not an obligatory factor required for the accumulation of intramuscular lipids and the development of insulin resistance.
normal free-living conditions Hancock et al. In addition to their role as major sites for energy transduction, mitochondria are also known to be a major source of reactive oxygen species ROS , which are produced as a by-product of normal metabolic reactions Andreyev et al.
ROS have the capacity to damage macromolecules, and when the production of these reactive species is in excess of the antioxidant defences, a state of oxidative stress results. FA catabolism is known to promote mitochondrial ROS production St-Pierre et al.
Importantly, many studies have shown that insulin action is improved when mitochondrial ROS production is attenuated Houstis et al. Before the elucidation of the insulin signalling pathway and recognition of the complex processes involved in the translocation of GLUT4 from intracellular vesicles to sarcolemmal membrane, there was a large amount of experimental data pointing to significant FA regulation of glucose metabolism at the level of PDH Randle et al.
If humans, animals or in vitro preparations of muscle are exposed to an increased availability of FAs in the presence of glucose, the oxidation of FAs increases and the oxidation and uptake of glucose decrease Boden et al.
On the other hand, reduction of the availability of FAs by inhibiting lipolysis Vaag et al. Although the initial observations of Randle and colleagues on the reciprocal relationship between glucose and FA metabolism were made 50 years ago, the idea that increasing or reducing FA availability will reciprocally affect glucose utilisation is no less valid today.
Therefore, in the context FA-induced insulin resistance, a role for substrate competition and regulation at the level of PDH should not be overlooked. As outlined in other sections of this review, the current dogma suggests that the major mechanisms for FA-induced insulin resistance in muscle involve active lipid species interfering with insulin signalling via the activation of various serine kinases Fig.
The canonical insulin signalling cascade comprises scaffolding proteins e.
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