Parkin is an ubiquitin‐E3 ligase that acts as a key component of the cellular machinery for mitophagy. We show here that Parkin expression is reciprocally regulated in brown adipose tissue in relation to thermogenic activity. Thermogenic stimuli repress Parkin gene expression via transcriptional mechanisms that are elicited by noradrenergic and PPARα‐mediated pathways that involve intracellular lipolysis in brown adipocytes. Parkin‐KO mice show over‐activated brown adipose tissue thermogenic activity and exhibit improved metabolic parameters, especially when fed a high‐fat diet. Deacclimation, which is the return of a cold‐adapted mouse to a thermoneutral temperature, dramatically induces mitophagy in brown adipocytes, with a concomitant induction of Parkin levels. We further reveal that Parkin‐KO mice exhibit defects in the degradative processing of mitochondrial proteins in brown adipose tissue in response to deacclimation. These results suggest that the transcriptional control of Parkin in brown adipose tissue may contribute to modulating the mitochondrial mass and activity for adaptation to thermogenic requirements.

Fibroblast growth factor 21 (FGF21) has been proposed to be an antiaging hormone on the basis of experimental studies in rodent models. However, circulating FGF21 levels are increased with aging in rodents and humans. Moreover, despite the metabolic health‐promoting effects of FGF21, the levels of this hormone are increased under conditions such as obesity and diabetes, an apparent incongruity that has been attributed to altered tissue responsiveness to FGF21. Here, we investigated serum FGF21 levels and expression of genes encoding components of the FGF21‐response molecular machinery in adipose tissue from healthy elderly individuals (≥70 years old) and young controls. Serum FGF21 levels were increased in elderly individuals and were positively correlated with insulinemia and HOMA‐IR, indices of mildly deteriorated glucose homeostasis. Levels of β‐Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor‐1 levels were unaltered. Moreover, total ERK1/2 protein levels were decreased in elderly individuals in association with an increase in the ERK1/2 phosphorylation ratio relative to young controls. Adipose explants from aged and young mice respond similarly to FGF21 “ex vivo”. Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21‐responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies.

Lipodystrophy is a major disturbance in people living with HIV-1 (PLWH). Several systemic alterations in PLWH are reminiscent of those that occur in ageing. It is unknown whether the lipodystrophy in PLWH is the consequence of accelerated ageing in adipose tissue. We compared systemic and adipose tissue disturbances in PLWH with those in healthy elderly individuals (~80 y old). We observed similarly enhanced expression of inflammation-related genes and decreased autophagy in adipose tissues from elderly individuals and PLWH. Indications of repressed adipogenesis and mitochondrial dysfunction were found specifically in PLWH, whereas reduced telomere length and signs of senesce were specific to elderly individuals. We conclude that ageing of adipose tissue accounts only partially for the alterations in adipose tissues of PLWH.