Optogenetic engineering of thermogenic adipose tissue as a novel cell therapy for obesity

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Obesity and the associated metabolic syndrome represent a profound public health challenge, afflicting over 40% of the United States population and nearly 50% of African Americans and Hispanics. The metabolic consequences of obesity, include heart disease, diabetes, and cancer, make up the leading causes of preventable death in the US. Fundamentally, obesity arises in the setting of nutrient excess when dietary energy intake exceeds energy expenditure from metabolic processes and physical activity. Strategies to combat obesity are thus directed at either decreasing appetite or increasing energy expenditure. While significant progress has been achieved with hormonal suppression of food intake, these medications are have significant side effects, rebound weight gain when discontinued, and are so expensive to manufacture that that their cost to the US healthcare system would exceed $1 Trillion dollars per year to maintain weight loss for all eligible patients. GLP1-based therapeutics are highly effective at reducing energy intake through appetite suppression, however there are currently no approved therapies to increase energy expenditure. This represents a promising avenue of study, as patients who have achieved significant weight loss have an adaptive reduction in basal metabolic rate, resulting in weight loss plateau or regain due to decreased energy expenditure. Exercise is unfortunately ineffective for most patients because it stimulates an increase in food intake that largely offsets energy expenditure. Therefore, there exists a clear therapeutic need for treatments to bolster energy expenditure to compliment GLP1-based initial weight loss and enable long-term weight maintenance. Thermogenic adipose tissue, an evolutionary optimized cellular “furnace” that burns energy in a safe and controlled manner, represents an ideal target to augment energy expenditure. Unfortunately, obese patients possess insufficient native thermogenic adipose to effectively improve metabolism, and efforts to recruit additional thermogenic adipocytes have been plagued by off-target complications. Importantly, the thermogenic machinery is normally quiescent under basal conditions and does not contribute to energy expenditure until stimulated by β-adrenergic signaling. Thus, simply creating more thermogenic adipose fails to activate its full energic potential. This proposal leverages recent breakthroughs from our lab in the discovery of adipose progenitor subpopulations to enable the ex vivo expansion of thermogenic adipose, as well as engineering a molecular switch to regulate energy expenditure. Most notably, this work will directly address the critical requirement for a molecular throttle to control thermogenic adipose stimulation with the innovation of a novel light-activated receptor. This optogenetic approach will not only contribute to our understanding of the metabolic and signaling processes evoked by thermogenic activation, but could ultimately serve as the foundation for the development of first-in-class cell therapeutics to treat obesity.