Targeting Brown Fat for Aging-related Obesity and Type 2 Diabetes

PROJECT SUMMARY: Aging is a risk factor for the development of obesity and type 2 diabetes. Recently, brown adipose tissue (BAT) has come under intense investigation as a therapeutic target to counteract the obesity epidemic. As a thermogenic tissue, BAT has a high capacity for both glucose and lipid oxidation, making BAT a potential target to combat obesity and type 2 diabetes. However, reduced BAT mass and/or activity has been observed in aged rodent and humans. Therefore, approaches to increase BAT mass and/or activity could be a potential therapeutic to improve the metabolic impairment that occur with aging. We have identified a novel role of CD47 (a ubiquitously expressed cell membrane receptor that is upregulated in aging or obese conditions) in negative regulation of energy homeostasis and the development of obesity in rodent model, which is supported by human association studies. Moreover, blocking CD47 signing (through a genetic mouse model) stimulates brown fat activity, increases energy expenditure and protects mice from diet-induced obesity and its comorbidities. It also protects mice from aging related obesity and glucose intolerance. Interestingly, BAT morphology and function are well preserved in aged CD47 deficient mice. These exciting findings suggest that blocking CD47 signaling may rejuvenate aging BAT and serve as novel therapeutics for aging-related obesity and diabetes. Therefore, in this pilot application, we will test the therapeutic potential of humanized anti-CD47 antibody in aging-associated metabolic diseases by using both male and female aging mice. These studies may lead to novel anti-aging therapeutics and have translational significance.