Efficacy of Pharmacological Stimulation of BAT and WAT in Lean and Obese Young Adults

Overview

To determine whether pharmacological stimulation of supraclavicular Brown Adipose Tissue (BAT or "Brown Fat") and subcutaneous White Adipose Tissue (WAT) using an FDA-approved beta3 agonist is as effective in increasing oxidative metabolism in BAT and WAT as is the exposure to cold, the investigators will assess the efficacy of an FDA approved beta3 agonist Mirabegron (trade name Myrbetriq, Astellas Pharma, Inc.) for increasing oxidative metabolism in supraclavicular BAT and subcutaneous WAT in lean and obese young adults. The investigators anticipate that both methods to stimulate supraclavicular BAT and subcutaneous WAT will result in similar 18F-labeled fluoro-deoxyglucose (FDG) tracer uptake on positron emission tomography (PET) images as well as oxidative metabolism. This would demonstrate that pharmacological stimulation of BAT is effective and could lead to further, more detailed clinical trials in obese subjects.

Obesity and diabetes have increased to epidemic proportions in the US and in many other countries. In addition, the comorbidities of these metabolic diseases, such as cardiovascular disease, cancer, osteoarthritis are placing a huge burden on the health and health care system of the United States. Finding new avenues for human therapeutics is thus a critical challenge. Brown adipose tissue (BAT or "Brown Fat") functions to dissipate stored chemical energy in the form of heat and serves to defend mammals from hypothermia and obesity. It is now firmly established that humans have functional BAT that can be activated by mild cold stress and imaged by 18F-labeled fluoro-deoxyglucose (FDG) PET imaging. Moreover, it is now understood that there are two distinct types of brown fat cells: the "classical" brown fat (most common in supraclavicular fat depots) that form developmentally from a muscle-like myf5-positive lineage and brown fat cells that can appear in white adipose tissue (WAT) depots upon prolonged exposure to cold or beta-adrenergic signaling. These latter cells originate from a myf5-negative lineage and are referred to as beige cells. Recent data suggests that most adult humans might have both brown and beige fat cells that are inactive but could be activated via the adrenergic system. Once activated, thermogenesis in these cells could affect the body's energy balance and might be instrumental in weight management. Although adrenergic activation using cold exposure has been shown to be highly effective in activating both brown and beige fat cells, it is difficult to implement in daily routine and there is a need for other, more practical, interventions. Mirabegron (trade name Myrbetriq, Astellas Pharma, Inc.) is a drug for the treatment of overactive bladder which was FDA approved in July of 2012. Mirabegron activates the beta3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. There are reports of increased BAT FDG uptake following MIrabegron administration in both rodents and recently in humans. Because pharmacological stimulation of brown/beige fat cells might increase daily energy expenditure, this might represent a novel mechanism for weight management and eventually a new avenue for the treatment for obesity.