Overview of tissue adaptations and processes with diet-induced obesity. While discussing inflammation from DIO, it is important to consider the composition of the experimental diets, as the dietary profile and energy density of a given diet likely will impact the resultant inflammatory profile in each preclinical model reviewed in Hariri and Thibault, For example, diets rich in fat elicit different types of glucose intolerance compared to diets rich in sugar, whereby dietary fat largely compromises muscular glucose tolerance, and sugar challenges liver lipogenic and gluconeogenic enzyme activities Sumiyoshi et al.

As such, different dietary composition may yield different findings or differences in the severity of disease outcomes.

Fat and sugar dietary constituents can contribute to different animal phenotypes, whereby animals on a high sugar diet do not necessarily gain weight, but demonstrate a conversion of lean body mass to fat body mass Sumiyoshi et al.

Diets high in saturated fat, however, generally result in increased body fat and body mass, although the type of fat employed i. To add to the complexity of this matter, many animal species, like humans, demonstrate obesity prone and obesity resistant phenotypes Schemmel et al.

Arguably, skeletal muscle oxidative metabolism Shahrokhi et al. This feature allows for the experimental evaluation of animals that are exposed to the same amounts of an obesogenic diet, but develop disparate increases in body mass.

With MSK disease, this is an important consideration, as tissue damage can be evaluated between animals with similar mass, but increased body fat and low-level inflammation Hariri and Thibault, Epidemiological studies reveal MetS can also occur in individuals with typical body weight or that are underweight e.

Mitochondria are the primary cellular organelles that generate adenosine triphosphate ATP. Mitochondrial dysfunction is attributed to excessive nutrient processing, resulting in the uncoupling of oxidative phosphorylation, effectively increasing reactive oxygen species ROS generation and decreasing ATP production Weiss et al.

The free radical theory states that an imbalance between the generation of ROS and antioxidants produced by peroxisomes can result in ROS stealing electrons from other cellular sources, resulting in cellular damage Ashok and Ali, When exposed to nutrient overload, nutrient sensors [i.

AMPK activity also plays a role in bone homeostasis, as an essential mediator of fat and glucose metabolism on bone remodeling Jeyabalan et al. In skeletal muscle, leptin has been shown to activate AMPK Salminen and Kaarniranta, , inhibiting FA synthesis, increasing FA oxidation and glucose uptake Minokoshi et al.

Moreover, limiting nutrient supply and the associated increase in SIRT-1 activity are hypothesized to enhance muscle cell proliferation, while nutrient overload, or age-related loss of SIRT-1, is expected to provide an unfavorable environment for cell proliferation Akhmedov and Berdeaux, Likely, reduced cell proliferation occurs, in part, through age-related loss of SIRT, potentially as a consequence of reduced AMPK activity, which may result in loss or dysfunction of mitochondrial activity Wang et al.

In chondrocytes from human OA patients, mitochondrial activity is deficient, leading to a catabolic cascade of responses. Mitigating age-related changes in oxidative stress in cartilage i. As a by-product of mitochondrial metabolism and homeostasis, ROS are produced and are highly regulated.

With cell damage, mitochondrial dysfunction, or oxidative stress, ROS levels accumulate and are associated with the onset of metabolic dysfunction Serra et al.

ROS accumulation can lead to: lipid peroxidation and disruption of the cellular membrane; ER stress, resulting in protein mis-folding and unfolding, and a decrease in protein synthesis, ultimately rendering cells incapable of clearing misfolded proteins; and activation of Caspase-3 and cell apoptosis Weiss et al.

Furthermore, oxidative stress in tissues is reported to be an important pathogenic mechanism of MetS onset Furukawa et al. Increased fat mass has been linked to increased systemic markers of oxidative stress in humans and mice Figure 7 Furukawa et al. For example, increased peroxide and reduced endothelial nitric oxide synthase have been associated with cancellous bone loss in an obesity model Ohnishi et al.

In bone, reactive oxygen species and oxidative stress are critical to osteoclast differentiation. As such, ROS may contribute to osteoporosis and bone catabolism, through activation of RANKL—or receptor activator of NF-κB ligand- influencing osteoclast activity, as well as other pathways downstream such as NF-κB Callaway and Jiang, With increased systemic inflammation associated with obesity, bone marrow macrophages and their progenitors can be increased Singer et al.

Yue and co-workers also reported that leptin produced from obese adipose tissue can bind to leptin receptors on mesenchymal stem cells promoting differentiation to adipocytes and inhibiting osteoblast formation Yue et al.

The central effects of leptin can also promote cancellous bone loss via the sympathetic nervous system Ducy et al. In skeletal muscle, although low-levels of ROS are necessary for force production, high levels of ROS can result in great susceptibility to fatigue and contractile dysfunction Powers et al.

There may be a link between dysfunctional repair and overuse tendinopathies through ROS production, but this idea remains to be tested experimentally Bestwick and Maffulli, ; Longo et al. Although the signaling pathway between ROS and osteoarthritis is not clear, there are examples of antioxidant therapy e.

Accumulation of lipids and lipid by-products can result in dysfunction in myocyte metabolic pathways. Lipid concentration is considered a strong indicator of the sensitivity of myocytes insulin-mediated pathways, as well as adipocyte and hepatocyte insulin sensitivity, significantly affecting substrate metabolism and circulating metabolite concentrations Weiss et al.

The adverse metabolic effects associated with ectopic lipid storage are supported by lipodystrophy studies, showing that muscle lipid accumulation can result in severe insulin resistance and diabetes Weiss et al.

In addition to the liver, primarily utilized for short term energy storage when circulating nutrient levels are elevated, skeletal muscle is a primary site of glucose uptake and utilization Yu et al. In response to low-level inflammation from DIO, extracellular matrix remodeling may contribute to the onset of insulin resistance, thereby inducing collagen synthesis and muscle fibrosis, and contributing to decreased insulin signaling Williams et al.

Insulin resistance can also impact tissues of the joint organ system, because insulin resistance has been linked to chondrocyte dysfunction, and insulin appears to have a protective role for synoviocytes, whereby insulin blunts TNF-induced matrix metalloproteinase release Hamada et al.

However, patients with diabetes exhibit increased synovial levels of TNF-α and macrophages, suggesting that insulin resistance may impair the protective effect of insulin in the joint Hamada et al.

Elevated levels of oxidative stress can result in incomplete substrate oxidation. These impairments can lead to the excessive accumulation of toxic lipid metabolites e.

Fatty acid trafficking in muscle may be one of the key factors involved in the onset of insulin resistance, by changing the availability of substrates involved in formation and clearance of harmful lipid intermediates diacylglycerides and ceramide Mittendorfer, The balance between synthesis and breakdown of these intermediates may influence the balance between the formation and breakdown of FA and TGs, resulting in the storage and development of lipid depots in non-adipose tissues Mittendorfer, from alterations in clearance mechanisms.

Advanced glycation end products AGEs have a pronounced effect on many proteins, particularly collagen.

Generally, AGEs accumulate in tissues and form cross-links with targeted proteins, alter cell structure, and interact with receptors that induce oxidative stress and inflammation, resulting in tissue damage Sanguineti et al.

Specifically, AGEs can alter the physiological failure behavior of some tissues, including tendons Fessel et al. Moreover, AGEs affect growth and modulate the physiological processes of OA Franke et al. AGEs can induce muscle atrophy in a RAGE-mediated AMPK down-regulated manner Chiu et al.

In bone, AGEs are associated with decreased bone mineral density and impaired bone quality, eliciting oxidative stress and inflammatory responses in bone cells, while altering material properties of bone collagen fibers via cross-linking Yamamoto and Sugimoto, It is well-established that the gut microbiota is altered with DIO in a manner that promotes a pro-inflammatory environment Cani et al.

Through changes in tight junction proteins and intestinal barrier integrity, components of gram-negative bacteria may leak into the systemic circulation, resulting in increased systemic LPS concentrations in obese animals including humans Figure 8 Cani et al.

Systemic LPS, inflammation, and metabolic disturbance resulting from altered gut microbiota and a leaky gut are believed to be key initiating factors leading to insulin resistance Cani et al.

In the context of musculoskeletal disease, an impaired gut barrier function has been implicated in rheumatoid arthritis and OA, and may present a viable therapeutic approach for disease management Scher and Abramson, However, to date, cause and effect relations between rheumatoid arthritis and the gut microbiota are still being explored Bravo-Blas et al.

Figure 8. Systemic mediators and compromised muscle integrity are associated with Metabolic OA onset and progression, adapted from Collins et al. We were among the first to identify a significant linkage between constituents of the gut microbiota Methanobrevibacter and Lactobacillis spp.

These findings link systemic serum and local synovial fluid to LPS and musculoskeletal changes with diet-induced obesity Huang et al. Using a fecal transplant intervention, lipid profiles can be transferred from donors to germ-free hosts, and altered muscle integrity can be recapitulated, suggesting that the gut microbiota may have a direct effect on muscle development and integrity Yan et al.

The gut-OA pathophysiological link indicates that dietary and microbiota-based interventions may be important therapeutic opportunities that should be evaluated in the context of MSK health Collins et al. There is a need for studies detailing the causal mechanisms of interactions among the gut-microbiota, LPS, and MSK changes.

However, given the short-term changes in gut microbiota composition, as well as the decrease in variance in relative abundance across species, studies promoting gut microbiota diversity could be useful in this context.

One such candidate is evaluating the impact of prebiotic fiber, which may positively modulate the gut microbiota to promote improved host interactions Bomhof et al. Figure 9. Conceptual framework for inflammatory initiation by a presumptive inflammatory source i.

Whether associated motion segment tissues becomie inflammatory sources, affecting a presumptive inflammatory source, as well as whether damage is reversible in these tissues, represent interesting open research questions in this area.

Information regarding pharmacologic management for obesity and metabolic syndrome can be found elsewhere Apovian et al. Table 3. Remaining questions, research agenda, and evidence-supported candidate pathways, targets, and conservative care opportunities.

The inflammatory interface between damage to MSK components and MetS should be a critical consideration, as protecting and preserving MSK structural integrity could be a key approach to conservative management of MetS.

Presently, clinical guidelines indicate that weight loss and exercise are good evidence-based conservative approaches for MSK conditions McAlindon et al. In the context of osteoarthritis specifically, the combined effect of months of dietary modulation and a combination program involving both aerobic and strength training-based exercise was found to induce weight loss, reduce knee compressive forces, reduce serum IL-6 levels, decrease infrapatellar fat pad size, decrease pain, and increase function in overweight or obese adults with knee OA Messier et al.

As such, careful characterization of exercise and dietary interventions in human and other animal models is needed to implement these strategies.

Although there are several candidates for dietary intervention, prebiotic fiber and probiotic supplementation targeting the microbiome Nicolucci et al.

As the onset of MSK damage with metabolic disturbance does not have a readily identified starting point, studies are needed to evaluate the efficacy and utility of these dietary modulations in the patient population of interest e. reversibility and acute vs. chronic , as well as unintended consequences of these modifications.

It would be critical to monitor muscle, tendon, bone, and cartilage tissues simultaneously while evaluating these dietary interventions, to facilitate an understanding of the benefits and interconnectedness of these MSK tissue changes and diseases.

There are several gaps in the current understanding of the effects of low-level systemic inflammation vs. metabolic disturbance on musculoskeletal health. Many of these gaps are summarized in Table 3. Whether muscle is a primary target tissue in the motion segment, and whether muscular changes directly result in subsequent changes in bone, tendon, and joints, remains to be assessed and clarified.

The studies presented here underscore the need for evaluating multiple musculoskeletal tissues and diseases in concert with MetS as well as defining which elements of the MetS are responsible for which consequences of obesity.

At present, it is unclear if: MetS-related inflammation increases in severity with chronicity; systemic inflammation is constant with continued metabolic disturbance; or MetS-related inflammation is dynamic and fluctuating.

This conceptual framework is demonstrated in the data from our previous studies, which suggest a systemic-to-local time-course shift from serum to synovial fluid, and serum to muscle changes Collins et al. Briefly, metabolic dysregulation initiates an inflammatory cascade, whereby an early perturbation in a presumptive inflammatory source i.

Although the source of the inflammation is unclear, as are the specific pathways involved, target tissue inflammation and damage may affect subsequent associated motion segment tissues i.

Furthermore, adaptation and impact of sources of inflammation on target tissues are important knowledge gaps that need to be addressed. It would be of value to determine if metabolic dysfunction and regulation are integrated and interdependent, or if source tissues and target tissues of the motion segment are regulated and affected differently and independently, at least in a first approximation.

Identifying the potential for reversibility of tissue damage with diet-induced obesity is another critical area of research that should be addressed.

The mechanism s by which target tissue or motion segment tissue changes may contribute to MetS and inflammation are incompletely understood at this time. Time-course studies are needed to answer these questions. Discussion of the impact of metabolic disturbance on neuroregulatory systems, and a role for neuroinflammation-mediated influence on loss of musculoskeletal integrity was limited in this review, but this may be a potentially important area for future research.

Nearly all of the tissues of a motion segment discussed are innervated except for adult cartilage, and thus, neuro-regulation and how it is affected primarily and secondarily by MetS associated inflammation, may be critical in understanding the underlying mechanistic considerations.

In particular, how these changes in neuroregulation and neuroinflammation contribute to a loss of muscle integrity is an interesting area for future research. Studies presented in this review implicate several pathways that may be critical for the onset and progression of systemic inflammation due to metabolic disturbance and musculoskeletal damage.

Some of the pathways that could be involved are mitogen-activated protein kinases MAPK, p38 MAPK, JNK , myeloid differentiation primary response gene 88 MyD88 , NFκB, and the NLRP3 inflammasome.

Likely, some or all of these pathways may be activated in parallel creating a potentially positive-feedback based redundant system. Investigations targeting specific pathways in the context of metabolic disturbance and MSK disease will provide much needed mechanistic insights to better understand the consequences of diet-induced obesity.

A motion segment, such as a leg is comprised of a number of interdependent components i. There are many important and relevant gaps in this research area, and addressing them will provide valuable insights into the relations among the motion segment, common inflammatory pathways, and resulting MSK disease.

KC was responsible for conception and design, collection, and assembly of data analysis and interpretation of the data, drafting of the article, critical revision of the article for important intellectual content and final approval of the article.

WH, GM, RR, JR, IS, and RZ were responsible for conception and design, collection and assembly of data analysis, interpretation of the data, critical revision of the article for important intellectual content and final approval of the article.

DH was responsible for conception and design, analysis and interpretation of the data, drafting of the article, critical revision of the article for important intellectual content and final approval of the article.

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 work was supported by the Canadian Institutes of Health Research RT and MOP , the Canada Research Chair Programme, the Alberta Innovates Health Solutions Osteoarthritis Team Grant, Alberta Innovates Health Solutions, Alberta Health Services Strategic Clinical Network Program, Canadian Institutes of Health Research Banting and Best Canada Graduate Scholarship, and the Killam Foundation.

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