Search

Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2 , Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4( ?)C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2 , Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy.

Prostate Apoptosis Response-4 (Par-4) is a tumor suppressor ubiquitously expressed in all tissues and able to selectively induce apoptosis in cancer cells. Although well established in the context of cancer, relatively little is known about the function of Par-4 in the healthy and non-tumorigenic context. Observations from our lab showed that Par-4 knockout mouse lines were obese and displayed adipocyte hypertrophy under a normal chow diet when compared to Par-4 wild-type mice. These Par-4 knockout mice exhibited hepatic steatosis and hyperinsulinemia as secondary consequences of obesity. Par-4 knockout mice displayed increased intestinal dietary fat absorption and its subsequent storage in adipocytes. By RNA-Seq analysis, we identified complement factor C3 as a Par-4 downstream target involved in triglyceride storage in the adipose tissue. Deletion of C3 in Par-4 knockout mice rescued the obesity phenotype. Moreover, circulating levels of Par-4 were decreased in obese human subjects when compared to lean individuals, and low levels of Par-4 in non-obese subjects from a cohort study predicted an increased risk of developing obesity later in life. Our ChIP-Seq experiments identified MDM2 as a potential target of Par-4. Further validation studies indicated that Par-4 loss decreased the ubiquitin ligase MDM2 and upregulated its target protein p53 in adipose tissues. Moreover, Par-4 regulated C3 through the MDM2-p53 axis, with p53 activating the C3 promoter. Based on these findings, we conclude that Par-4 regulates adipocyte hypertrophy and obesity, and that low levels of Par-4 in lean human subjects is predictive of future obesity. These effects of Par-4 are mediated by its ability to suppress dietary fat secretion from the enterocytes into the bloodstream and fat storage by inhibition of C3.