The CIDE genes might serve as novel targets for therapeutic intervention of obesity.

摘要

The health risks of overweight and obesity have been well documented. The overweight and obesity problem became an epidemic disease, especially in developed countries. Recently a novel family of cell death-inducing DFF45 (DNA fragmentation factor 45)-like effectors (CIDEs) has been identified, it includes CIDE-A, CIDE-B, and CIDE-3 in humans, and fat-specific gene 27 (FSP27, a homologue of the human CIDE-C gene) in mice [1-4]. Brown adipose tissue (BAT) is the major site of adaptive thermogenesis in rodents. The thermogenic activity of BAT is mediated by uncoupling proteins (Ucp1), which is expressed at high levels in BAT . Impaired BAT activity is believed to have an important role in the development of obesity. It was found that CIDE-A is highly expressed in BAT. Interestingly, mice that are deficient for CIDE-A showed an increase in energy expenditure and are resistant to high-fat diet-induced obesity and diabetes . Compared with wild-type mice, CIDE-A-deficient mice exhibited an increased metabolicrate, an elevated level of lipolysis and maintained higher body temperatures when subjected to cold treatment, suggesting an increase in thermogenic potential and energy expenditure in these mice. These mice also showed less lipid accumulation and they had decreased circulating levels of free fatty acids and triglycerides. Despite the increase in lipolysis, the amount of free fatty acids released from BAT explants from CIDE-A-null mice was lower than from wild-type mice . This raised an interesting possibility: fatty acids in the brown adipocytes of CIDE-A-null mice might have alternative fates, either being re-esterified or quickly oxidized. Furthermore, CIDE-A-deficient mice exhibited an increase in the rate of glucose disposal and a resistance to high-fat diet-induced diabetes. Although the precise mechanism by which CIDE-A regulates energy homeostasis is not yet clear, CIDE-A appears to interact with Ucp1 in mammalian cells and inhibits its uncoupling activity when co-expressed in yeast . Therefore, CIDE-A offers a new option to explore the linkage between BAT and obesity. In addition, we recently found that CIDE-B is expressed in pancreas islet, especially in B islet cells. We propose that CIDE-B might regulate the secretion of insulin and in this way it can accommodate the balance between energy intake and expenditure, which is important for the maintenance of body weight and normal physiology. With all these facts, we suggest that the CIDE family might serve as novel targets for therapeutic intervention of obesity and type II diabetes.