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Abstract
SummaryIt is well established that aging is associated with metabolic dysfunction such as increased adiposity and impaired energy dissipation; however, the transcriptional mechanisms regulating energy balance during late life stages have not yet been fully elucidated. Here, we show that ablation of the nuclear receptor PPARγ specifically in inguinal fat tissue in aging mice is associated with increased fat tissue expansion and insulin resistance. These metabolic effects are accompanied by decreased thermogenesis, reduced levels of brown fat genes, and browning of subcutaneous adipose tissue. Comparative studies of the effects of PPARγ downregulation in young and mid‐aged mice demonstrate a preferential regulation of brown fat gene programs in inguinal fat in an age‐dependent manner. In conclusion, our study uncovers an essential role for PPARγ in maintaining energy expenditure during the aging process and suggests the possibility of targeting PPARγ to counteract age‐associated metabolic dysfunction.
Highlights
Our studies show that aging mice with deficiency of PPARc in iWAT have increased adiposity, reduced energy expenditure, and insulin resistance
Given that it has been recently shown that PPARc gene target selection is dictated by depot-selective coregulators, such as TLE3 and Prdm16, which can specify alternative programs of lipid storage or thermogenesis (Koppen & Kalkhoven, 2010; Peirce, Carobbio & Vidal-Puig, 2014; Villanueva et al, 2013), it can be envisioned that preponderance of one type of cofactor in an aging tissue may drive PPARc to activate only select gene targets
Future studies will determine whether the preferential binding of PPARc to brown fat gene promoters we observed in 12month-old mice is driven by differential amounts of brown versus white cofactors present in subcutaneous adipose tissues in aging mice
Summary
2.1 | Ablation or downregulation of PPARc selectively in subcutaneous fat tissue of mid-aged mice via adenoviral injections. Detailed molecular analysis demonstrated preferential impairment of brown fat gene programs, with no changes in white gene programs (Figure 4d), and immunohistochemistry of iWAT revealed decreased UCP1 staining in mice with PPARc deficiency (Figure 4e) Together, these data indicate that PPARc is required for the maintenance of brown gene programs in iWAT during aging. Unbiased gene array analyses of iWAT obtained from young and old mice injected with control or shPPARc revealed that young mice with PPARc knockdown have a selective reduction in the expression of white fat gene targets such as Agt, Retn/Resistin, Slc2a4/Glut, Cfd/Adiposin, Adipoq/Adiponectin, and Fabp4/aP2 (Figure 6a,b), FIGURE 3 Impaired glucose and lipid homeostasis in aging mice with PPARc deficiency in iWAT. Data are presented as mean Æ SEM and *, p < .05; **, p < .01
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