Establishing In Vivo Proof of Concept of Brown Adipogenesis Using Approved Drugs

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 DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2 diabetes, dyslipidemia, and cardiovascular disease. There remains a very significant need for better non- surgical treatments. While most weight loss agents rely on suppressing appetite to reduce caloric intake, strategies that can safely enhance energy expenditure have the potential to effectively treat obesity. Brown adipose tissue (BAT) is a thermogenic tissue that uniquely expresses mitochondrial UnCoupling Protein-1 (UCP1). This protein dissipates the electrochemical gradient in the mitochondria of brown adipocytes as heat. It is increased upon exposure to low temperatures, and plays an important role in the maintenance of body temperature and energy balance in rodents. BAT is also a flexible tissue that normally enlarges or atrophies over time depending on environmental temperature. In many different rodent models, enhancement of BAT mass has convincingly been shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to be effectively nonexistent in adult humans, data obtained in the past several years with PET imaging show that adults in fact have significant BAT, and that this tissue is functional. Other data demonstrate that the amount of active BAT in individuals is strongly correlated with leanness and that the genetic locus most tightly linked with general obesity causes defective recruitment of new brown adipocytes. Until recently no brown adipocyte stem cell had been identified. We discovered a population of human skeletal muscle-resident brown adipocyte progenitors that under appropriate conditions become fully functional brown adipocytes. Following differentiation these cells have high levels of UCP1 and a very high metabolic rate. Using the progenitors we developed an assay for identifying compounds that recruit new, mature brown adipocytes. We then used this to screen a collection of approved drugs and found several that potently recruit brown adipocytes. These hits were validated with dose response testing. In the proposed work, we aim to further characterize these compounds for potential use as anti-obesity therapeutics. We will evaluate their suitability for development first in vitro, followed by studies in a highly predictive animal model of obesity and insulin resistance. If this work is successful, we plan to rapidly advance into a proof of concept clinical study with a potential brown fat recruiting product candidate for the treatment of obesity and diabetes.