DESCRIPTION (provided by applicant): Obesity is an accelerating national health crisis which is associated with a variety of comorbidities, often referred to as metabolic syndrome. As obesity is caused by a chronic intake of excess energy, anti-obesity therapies must either decrease energy intake or increase energy output. An intriguing possibility to increase energy expenditure has been to harness the power of adaptive thermogenesis to increase metabolic rate. By uncoupling respiration from ATP synthesis, adaptive thermogenesis enables the conversion of excess energy (such as excess calories) directly to heat. It is well appreciated that thyroid hormone and the TRs are associated with thermogenesis, although the mechanistic basis for this relationship is not clear. While conducting long-term studies aimed at elucidating the mechanistic relationship between thyroid hormone signaling and thermogenesis, a synthetic TR agonist was discovered that elicits substantial anti-obesity effects by markedly inducing a program of adaptive thermogenesis and uncoupled respiration within white adipose tissue (WAT), an effect that has come to be known as 'browning'. TR agonist induced browning of WAT is also accompanied by several beneficial effects that oppose obesity and metabolic syndrome. These results make it clear that pharmacological TR activation can impart brown fat-like function upon WAT and prompts several questions related to this action: "Is WAT browning responsible for the beneficial metabolic effects of the TR agonist (such as fat loss, improved insulin sensitivity, decreased serum triglycerides)?", a question that has obvious implications for the potential of this phenomenon to be used therapeutically in the treatment of metabolic disease. "Does WAT browning represent the mechanism by which thyroid hormone excess elicits 'thyroid thermogenesis'"? And finally, "What is the mechanism by which TR activation leads to induction of the full genetic program of adaptive thermogenesis?" The purpose of this proposal is to answer the aforementioned questions within the following 2 major aims: 1) To determine the pharmacological and physiological significance of TR agonist induced WAT browning and 2) To determine the molecular mechanism by which TR activation leads to the browning of WAT. The approach to the first aim is to use loss of function approach with various mouse lines to define precisely how much adaptive thermogenesis in both BAT and WAT contribute to the systemic effects seen subsequent to TR activation. The approach to the second aim is to exploit the ability to induce browning in vitro to study the mechanistic basis by which TR agonism elicits this action in cell culture.

PUBLIC HEALTH RELEVANCE: Obesity and related health problems are an accelerating national health problem. We recently discovered a new method to turn on thermogenesis in fat cells, which allows fat cells to shrink themselves by burning off excess lipid. This proposal explores the potential to use this effect, the induction of thermogenesis in white fat cells, to trat obesity and metabolic disease.