With a steadily increasing incidence, obesity has become the leading medical disorder of the 21st Century. In particular, the middle-aged population appears to be prone to obesity. Although the reasons for this remain largely enigmatic, several factors are strongly implicated in the development of obesity, such as sedentary lifestyle and poor dietary habits. Genetic factors have also been suggested to control age-dependent obesity. For example, hypothalamic pro-opiomelanocortin neurons, which are involved in the regulation of food intake, are progressively silenced during aging.
Most of the knowledge on fat development stems from experimental studies in which white adipose tissue (WAT) expansion occurs rapidly upon high-fat diet (HFD) feeding. The mechanisms involved in progressive WAT expansion during aging, however, remain mostly unidentified. Because obesity at a later age predisposes to life-threatening conditions such as insulin resistance, type 2 diabetes, and cardiovascular disease, understanding the causal molecular mechanisms of age-related obesity may provide a strategy for treating these disorders.
One of the hallmarks of aging is the functional dysregulation of mitochondria, which constitute the central metabolic hub in many cell types and are the gateway to aerobic metabolism. Mitochondrial oxidative phosphorylation is governed by the electron transport chain (ETC). Oxygen is the final electron acceptor in the ETC, and cytochrome c oxidase (complex IV [CIV]), the terminal enzyme of the ETC, reduces it to H2O after which energy is produced in the form of ATP by the action of ATP synthase.
In mature white adipocytes, mitochondria have a central role in many processes, such as ensuring energy generation through fatty acid β-oxidation in the mitochondrial matrix. Aside from ATP production, mitochondria generate the necessary metabolic intermediates for lipid synthesis, thereby determining lipogenic potential. Moreover, mitochondrial activity in WAT is associated with the release of several adipokines, including adiponectin.
Aging has also been associated with increased adiposity early in the lives of mice and humans. However, it is unclear whether mitochondrial dysfunction in WAT contributes to age-related adipocyte enlargement and whether it can be restored to counteract age-dependent WAT expansion.
Researchers in the journal Cell Reports show that adipocytes of early middle-aged mice already exhibit mitochondrial dysfunction, which is largely associated with a decline of mitochondrial CIV activity and assembly. This decline in CIV activity involves a hypoxia-inducible factor 1A (HIF1A)-dependent reduction of CIV components, including cytochrome c oxidase subunit Vb (Cox5b).
Silencing of Cox5b is sufficient to promote a global decline of CIV assembly, as well as decreased fat oxidation, and contributes to adipocyte enlargement during aging. Conversely, in vivo restoration of COX5B expression counteracts age-dependent white adipocyte enlargement.
Collectively, these findings highlight the potential of targeting mitochondrial CIV to reverse adipocyte expansion during aging.
http://www.cell.com/cell-reports/abstract/S2211-1247(16)31105-6
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