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For instance, Kajimura and colleagues demonstrated that mitophagy removes the excess mitochondria to adopt a white fat—like phenotype after the withdrawal of cold-stimulus or Adrb3-agonist Pharmacologically blocking or deleting genes associated with autophagy-mediated mitochondrial clearance preserves the beige adipocyte phenotype and function.

Moreover, blocking mitophagy promotes the perdurance of beige fat and prevents obesity and glucose intolerance Further investigation into age-associated decline in mitophagy could trigger the precipitous decline in thermogenic fat.

For instance, aging may be associated with changes in autophagy-related genes, such as ATG5, ATG12 or PARK2, rapidly converting thermogenic fat cells into white adipocytes , Consistent with this notion, the age-related downregulation of the epigenetic eraser, Lsd1, a genetic regulator of the mitophagy machinery, leads to the inability to induce thermogenic fat.

Alternatively, overexpressing Lsd1 promotes a thermogenic fat cell phenotype , Moreover, a recent report indicated that brown adipocytes release extracellular vesicles that contain oxidatively damaged mitochondrial parts to avoid thermogenic failure.

BAT resident macrophages remove these extracellular vesicles; however, thermogenesis is dampened if macrophage function or accrual is disrupted Further investigation into mitophagy and mitochondrial regulatory processes could provide new insight into the regulation of thermogenic fat cell viability and longevity, especially in the aged setting.

Thyroid hormones, triiodothyronine T3 and thyroxine T4 , which can activate the thyroid hormone receptor to control gene transcription, can regulate BAT activation and differentiation thereby governing energy expenditure — This effect is exemplified in rodents demonstrating that T3 augments heat loss via the tail vein Yet, T3 can also directly stimulate hypothalamic neurons to engage BAT thermogenesis , While T3 and T4 can induce Ucp1 expression and thermogenic fat formation, aging is associated with a decrease in serum T3 and a reduced conversion of T4 to T3 Correspondingly, human association studies suggest that UCP1 expression corresponds with circulating thyroxine serum levels, suggesting that lower thyroid hormone status could indicate reduced thermogenic potential, particularly with advanced aging Yet, thyroid hormone-induced Ucp1-positive beige adipocytes may be decoys.

Intriguingly, while these cells resemble beige adipocytes and express Ucp1, they appear metabolically inactive without adrenergic stimulation Moreover, selective hyperthyroidism in Ucp1-null mice maintains metabolic and thermogenic responses Suggestively, thyroid-induced hyperthermia is independent of brown and beige adipocytes and may involve Ucp1-independent thermogenic thyroid hormone mechanisms A longitudinal study examining thyroid carcinoma patients undergoing thyroidectomy that receive the thyroid hormone T4 replacement analog, levothyroxine, displays a boost in energy expenditure and glucose uptake into thermogenic fat depots Consistently, a T3 analog, liothyronine, significantly decreased insulin resistance in patients with an insulin receptor mutation While the data suggest that thyroid hormone and its analogs can stimulate hyperthermia, it may be unlikely that these effects are solely thermogenic fat dependent.

Moreover, it is unclear how thyroid levels and thyroid receptor signaling mediate thermogenic fat biogenesis in aged mammals. Further, thyroid analogs show promise in thyroid cancer clinical trials, yet can these thyroid mimetics stimulate active thermogenic fat within the obese and aging populations to augment energy expenditure, remains to be clarified.

Obesity and aging are associated with increased pro-inflammatory cytokine production in white and brown adipose tissue These changes in cytokine composition further recruit and activate M1 macrophages and several other immune cell populations that facilitate tissue disruption and chronic low-grade inflammation Figure 3.

Moreover, pro-inflammatory cytokines disrupt cold-induced thermogenesis by directly suppressing thermogenic gene expression and dampening metabolic fluxes. Cold temperature exposure can remodel white adipose tissue immune cell composition, including M2 macrophages, mast cells, eosinophils, and type 2 innate lymphoid cells ILC2s.

For example, while ILC2s can support tissue homeostasis, they appear necessary for mediating energy balance in response to changes in environmental temperatures , ILC2s are recruited and activated by the cytokine, interleukin IL , and once activated, produce an opioid-like peptide, methionine-enkephalin MetEnk peptide, that can stimulate beige fat development.

It is unspecified if MetEnk mediates de novo beige adipogenesis or white-to-beige interconversion or its function mechanism Alternatively, ILC2 and eosinophil byproducts, such as IL and IL-4, have been shown to directly act on beige adipocyte progenitors to stimulate proliferation and differentiation , Likewise, beige APCs also have been shown to produce and secrete IL to facilitate a positive-beige-ILC2 adipogenic feedback circuit , Nevertheless, this circuit may deteriorate with advanced aging and obesogenic signals, causing changes to beige fat generation, yet the exact mechanisms remain unknown Moreover, a recent study showed the emergence of an age-dependent regulatory cell ARC population within white adipose tissue.

ARCs resemble APCs but lack adipogenic capacity; instead, these cells secrete high levels of pro-inflammatory chemokines, including Ccl6, to inhibit the proliferation and differentiation of neighboring adipose precursors Yet, the involvement of ARCs in beige fat biogenesis is unknown. Consistent with changes in pro-inflammatory cytokines, suppressing interleukin IL induces thermogenic gene expression, whereas deleting the IL receptor enhances beige fat formation and blunts obesity More broadly, using single-cell RNA sequencing, Farmer and colleagues developed a comprehensive atlas of the cellular and transcriptional changes varying between cold temperature exposure and Adrb3-agonism.

Yet, the physiological function and molecular mechanisms of why certain beige stimuli favor specific immune populations remain to be fully understood. While the beneficial effects of exercise on human health are well appreciated, the ability of exercise to induce thermogenic fat biogenesis and activation appears mixed and may be species-specific reviewed in For instance, a bout of exercise in rodents can generate thermogenic fat cells and upregulate the expression of thermogenic genes such as Prdm16 and Ucp1 in white adipose tissue , Yet, in humans, there is a lack of association between exercise and thermogenic fat production in white fat depots — For example, lean and obese individuals that underwent endurance exercise training for weeks did not elevate thermogenic gene expression in subcutaneous adipose tissue Additionally, no changes in Ucp1 expression have been observed in human populations with active lifestyles compared to sedentary populations , It is still being determined why these differences between humans and rodents exist.

As discussed above, a potential confound could be the differences in ambient temperatures in which the experiments were conducted. These findings also pose an interesting physiological question, why would exercise generate thermogenic fat cells?

The rodent exercise-induced beiging appears counterintuitive to the actual heat dissipation function of thermogenic fat cells , A possible explanation is that exercise could diminish BAT function to maintain homeostatic temperature. This is conceivable because both thermogenic fat and exercise increase energy expenditure and thermogenesis , Simplistically, exercise can also stimulate sympathetic activity, thus, by default, enhancing thermogenic fat biogenesis On the other hand, exercise can stimulate the release of muscle- and adipocyte-derived secretory hormones myokines and adipokines that can facilitate thermogenic fat development.

For example, irisin , myostatin , meteorin-like1 Metrnl , lactate , and b-aminoisobutyric acid BAIBA can be released from muscle during exercise to stimulate thermogenic fat development. Even less convincing is the effect of exercise on classical BAT. For example, several studies have reported no effect or a decrease in BAT activity in response to exercise , However, cold water swim tests suggest cooperation between cold temperature exposure and exercise to increase BAT mass.

Nevertheless, human BAT exercise studies are lacking, which could be attributed to the decline in thermogenic fat tissue in aging humans. Additional exploration into the physiology and molecular mechanisms underlining the effects of exercise on thermogenic fat adaptation and decline remains to be fully elucidated.

Most individuals do not prefer to spend several hours per day in a cold chamber activating thermogenic fat. Thus, developing and implementing more tolerable and potentially desirable methods should be employed to promote thermogenic fat biogenesis.

For thousands of years, diet, nutritional ingredients, and natural compounds have provided therapeutic and medicinal effects on human metabolism and whole-body physiology. These alternative approaches could harbor tactics to avoid cold exposure or synthetic compounds altogether.

For instance, besides cold exposure, the SNS can also be engaged by stress, inflammation, and diet. Diet is particularly interesting because it can be a modifiable and controllable aspect of human life. Furthermore, diet appears to induce obligatory and facultative thermogenesis.

Obligatory thermogenesis entails heat generation during digestion, absorption, and processing of dietary components, often referred to as the thermogenic effect of food. Facultative thermogenesis is the breakdown of macronutrients and the activation of classical BAT thermogenesis, resulting in heat dispersion from food energy.

Yet, the role of diet in controlling thermogenesis has not been largely undefined; however, studies using specific diets, such as the ketogenic diet, suggest that certain food may potentiate or even block thermogenic fat activity Moreover, single-meal studies suggest that food can alter BAT activity immediately.

For instance, FDG PET scanning revealed less glucose uptake into BAT depots in healthy human participants 90 minutes after a meal , These results suggest that diet may negatively impact BAT activity, yet a possible explanation could involve insulin mediated FDG uptake into muscle, thereby limiting the free FDG for BAT utilization.

This explanation could justify the underestimate in BAT glucose uptake—alternative measurements, such as oxygen uptake, may be more applicable for measuring mitochondrial function and BAT activity Indeed, a recent report demonstrated that BAT oxygen and blood flow rose immediately after a single meal.

In further support, participants with more BAT had higher total energy expenditure after meals than individuals with lower BAT activity These studies suggest that diet can affect BAT activity; however, more investigation is needed to elucidate how cold exposure and diet could be coupled to control BAT activity.

In addition to diet and meals, nutrient composition of food may also affect thermogenic fat biogenesis and activity. For example, capsaicin is a pungent compound found in hot peppers that can induce hypermetabolism and sweating upon consumption Multiple studies using rodents and humans have shown the beneficial effects of acute and chronic administration of capsaicin on total energy expenditure and fatty acid oxidation — Furthermore, overweight or obese subjects that ingested red peppers with meals had reduced adiposity, increased fatty acid oxidation, and enhanced whole-body energy expenditure Nevertheless, due to its spiciness, capsaicin is less palatable, preventing ingestion of large quantities, thus, making capsaicin less desirable and to a lesser extent, a convincing beige fat therapy However, capsinoids, analogs of capsaicin but without the pungency, can be as potent as capsaicin in boosting energy expenditure in rodents and humans For example, after two hours of cold exposure 19°C , test subjects that had received capsinoids 9 mg increased FDG uptake into adipose depots within the supraclavicular and paraspinal regions.

Moreover, energy expenditure increased three-fold in response to cold exposure after oral ingestion of capsinoids but not under warm temperature conditions Mechanistically, capsinoids are a class of vanilloid compounds that directly bind to the TRPV1 channel to increase intracellular calcium signaling, thereby increasing thermogenic action, potentially via Ucp1 and mitochondrial biogenesis 98 , Notably, it appears that two capsinoid molecules may be needed to activate the channel Like capsinoids, other naturally occurring compounds such as allicin and alliin from garlic and onion and ginger-derived compounds can activate TRPV1, suggesting a broad spectrum of nutritional compounds that could elicit thermogenic responses , Thus, while capsinoids provide unique insight into thermogenic activation via non-adrenergic methods, other potential pungent and non-pungent compounds could be exploited as thermogenic ingredients For example, menthol, a compound found in mint, has been shown to stimulate thermogenesis and increase energy expenditure in rodents via TRP channel activation In addition, other food molecules and nutrients, such as retinoic acid, resveratrol, and fish oils, have been shown to stimulate thermogenic responses to improve metabolic fitness — However, the functional utility of retinoic acid and other natural compounds in humans has yet to be fully determined , Additionally, future investigation into relevant mechanisms of nutritional components will highlight the efficacy of these natural compounds in augmenting thermogenic fat formation.

Moreover, might these natural ingredients have the potential to avoid age and obesity-induced effects on thermogenic function? In the United States, the adult obesity prevalence is The defining feature of obesity is excess white fat mass, increasing the risk for metabolic disorders and premature death Thus, identifying potential and tangible therapies is rapidly needed to counteract this public health problem The ability to generate thermogenic fat is a feasible and highly desirable anti-obesity target due to its ability to increase energy expenditure and futilely burn substrates Figure 1 4 , , Unequivocally, the generation of thermogenic fat in rodents and healthy humans suggests metabolic potential Figure 1 — Skeptically, it could and has been argued that the amount of thermogenic fat needed to alter whole-body human metabolism is more than what can be generated.

Still, the human thermogenic fat field is nascent and has only begun detecting human thermogenic fat with the possibility of new depots being discovered. The development and advancement of imaging and the need for substrate tracer technology are considered critical for defining and characterizing thermogenic fat deposits and metabolic sink potential.

Moreover, studies involving obese subjects will be required to understand human thermogenic fat-induced metabolic reprogramming. Additionally, cold exposure may provide its own therapeutic effect, independent of thermogenic fat development, which may boost metabolism, lower adiposity, and reduce inflammation.

Several rodent therapeutic strategies have successfully targeted thermogenic fat; however, these tools may not apply to human adipocytes. For instance, a recent study showed that Adrb2 drives human thermogenic fat biogenesis, not Adrb3 But another study suggests that Adrb3 does mediate human thermogenic fat biogenesis Nevertheless, as observed from Adrb agonists, such as Mirabegron, targeting Adrbs can alter energy homeostasis but may be contraindicative in the larger population.

Therefore, the development of targeted therapies, such as gene-based or tissue-specific pharmaceuticals, is ideal, providing precision in thermogenic fat biogenesis and limiting off-target side effects Furthermore, thermogenic adipocytes appear heterogenic and are derived from various cellular sources.

Hence, a continued examination of cell ontology, lineage tracing, and genetic profiling will help unearth the complexity and lineage relationships.

For example, while single-cell transcriptomics provides resolution on cellular populations and their trajectories, incorporating lineage tracing and spatial-niche reconstruction technology such as RNA-fluorescence in situ hybridization FISH will provide information on cellular utility, tissue microenvironment, and adipogenic competency , Previous studies have posited that adipose tissues are homogenous; however, identifying brown and beige adipocyte subpopulations provides new insights into how adipocytes are potentially formed, activated, and metabolically induced.

A potential, but unexplored node of nutritional research, is the advancement of dietary thermogenic inducers Critically, mechanistic insights into nutritional thermogenic regulators still need to be improved, which would be necessary to provide tailored thermogenic fat development.

For instance, do capsaicinoids stimulate thermogenic progenitors or white-beige interconversion, and what is the metabolic substrate preference of capsaicinoid-induced thermogenic fat? Moreover, these new thermogenic regulators could offer a vast pharmacopeia of agents to ignite thermogenesis, hoping to circumvent pesky cold exposure altogether.

However, these efforts may all be in vain, especially if thermogenic fat fails with age, beginning in our mids For that matter, increased adiposity also slows the development of thermogenic fat biogenesis.

Thus, how can thermogenic fat be renewed in the aging-obese population? Studies targeting the hallmarks of age-dependent thermogenic fat failure will be vital for thermogenic fat renewal. Moreover, aging is a process throughout life, not a terminal age, which may be a critical point for intercepting its decline Nevertheless, there may be hope with the development of senolytics and other pharmaceuticals that have shown promise in restoring thermogenic fat in obese or aged subjects.

In conclusion, the advancement in thermogenic fat formation over the past decade has been substantial. Yet, developing new biomedical technologies coupled with basic cellular and molecular biological research will foster new developments into the full potential of thermogenic fat as a possible therapy to thwart obesity and metabolic disease.

SX wrote the draft and revised the review. SX, DL, and DB revised and wrote the final version. All authors contributed to the article and approved the submitted version. 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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

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Rachid, B. Download references. This work was supported by the National Research Foundation, Korea R1A5A and R1A2C to K. We thank Seung-Yoon Oh and Jisoo Jeong for their help in preparing the manuscript for publication. Departments of Oral Biology and Applied Biological Science, BK21 Four, Yonsei University College of Dentistry, Seoul, , Korea.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, , Korea. Departments of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, , Korea. You can also search for this author in PubMed Google Scholar.

All authors involved in data collection and the article fomation. and O. Correspondence to Ki Woo Kim or Obin Kwon. Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Tran, L. Hypothalamic control of energy expenditure and thermogenesis.

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Subjects Endocrine system and metabolic diseases Molecular neuroscience. Abstract Energy expenditure and energy intake need to be balanced to maintain proper energy homeostasis. Introduction Homeostasis is the steady state of conditions for the optimal function of an organism, including humans.

Components of energy expenditure Total energy expenditure comprises resting metabolic rate, the thermic effect of physical activity, and adaptive thermogenesis. Table 1 Components of energy expenditure. Full size table. Hypothalamic control of basal metabolism As mentioned above, basal metabolism accounts for the largest proportion of total energy expenditure.

Lean mass and fat mass Lean mass i. Height Resting energy expenditure in human adults is typically predicted by other additional covariates, including height.

Aging Initial cross-sectional human studies described dramatic declines in the BMR with aging 11 , 38 , although later studies addressed that the degree of those declines was smaller than previously expected 39 , Sex differences When studying mechanisms that affect energy expenditure, males and females do not always have the same phenotype.

Thyroid hormone Thyroid hormone [triiodothyronine T 3 , biologically active form and thyroxine T 4 ] contributes to both obligatory and facultative thermogenesis Hypothalamic control of physical activity Spontaneous physical activity SPA and its contribution to energy expenditure i.

Full size image. Hypothalamic control of diet-induced thermogenesis The arcuate nucleus of the hypothalamus Over the past decades, it has become clear that hypothalamic nuclei, especially the arcuate nucleus of the hypothalamus ARC , play an important role in the regulation of feeding and metabolism , The ventromedial hypothalamus The ventromedial hypothalamus VMH , spanning across the mediobasal hypothalamic area , is a bilateral egg-shaped nucleus whose roles in controlling tissue thermogenesis were defined early.

Preoptic area—dorsomedial hypothalamus leptin signaling The preoptic area POA is a large region lying in the rostral part of the hypothalamus and comprises the median and ventrolateral preoptic nuclei MnPO and VLPO, respectively , the medial and lateral preoptic areas, and the suprachiasmatic nucleus Hypothalamic control of cold-induced thermogenesis To preserve body functions and homeostasis upon exposure to a cold environment, efferent pathways for heat production are activated.

Conclusion Thermogenesis is a crucial component in the maintenance of energy homeostasis. References Morton, G. Article CAS PubMed PubMed Central Google Scholar Kim, B. Article CAS PubMed Google Scholar Saito, M. Article Google Scholar Tseng, Y.

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November 24, - facebook twitter linkedin. Brown and White Adipose Tissue There are two main categories of adipose tissue: brown and white.

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Thank you for Thermogeneis nature. You Arm toning pills using a browser version with Thermofenesis support Herbal anti-inflammatory CSS. Enerty obtain the best experience, we recommend you use a more Ginseng capsules to date Strength-building exercises or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Thank energj for Strength-building exercises nature. You Arm toning pills using a Belly fat burner workout Thermogenesis and energy production Thedmogenesis limited support for CSS. To obtain the Thermogendsis experience, we recommend you use a more prodhction to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Energy expenditure and energy intake need to be balanced to maintain proper energy homeostasis. Energy homeostasis is tightly regulated by the central nervous system, and the hypothalamus is the primary center for the regulation of energy balance.