OR23-1 The TR Agonist GC-1 Ameliorates Obesity By Evoking A Functional Conversion of White To Brown Fat

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR23-Metabolic & Stress Receptors in Energy Homeostasis
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:15 AM
Room 256 (Moscone Center)
Jean Z Lin1, Alexandro J Martagon1, Daniel Davila1, Stephanie L Cimini1, Willa Ann Hsueh1, John D Baxter1, Chin-Yo Lin2, Paul Webb1, Jan-Åke Gustafsson2 and Kevin J Phillips*1
1Methodist Hospital Research Institute, Houston, TX, 2University of Houston, Houston, TX
Mammals possess both white (WAT) and brown adipose tissue (BAT). WAT has low metabolic potential and is associated with obesity and the maladies of metabolic syndrome, while BAT has high metabolic potential and is associated with resistance to obesity. Due to the unique potential of BAT to carry out thermogenesis and dispose of excess energy as heat there has long been a desire to convert WAT into BAT. In the past year, numerous studies have demonstrated that it is indeed possible to induce BAT-like function within WAT, an effect often referred to as 'beiging'. However, these studies have generally utilized genetically engineered mice and the metabolic changes have typically been modest. Thus, the pharmacological potential of beiging is unclear. Thyroid hormone receptors (TRs) have long been associated with metabolic regulation and thermogenesis, although the mechanistic rationale behind these effects is unclear. Here, we report that the TR agonist GC-1 evokes a profound functional conversion of WAT into BAT. GC-1 treatment of obese (ob/ob) mice dramatically increases UCP-1 expression and upregulates the entire program of thermogenesis, uncoupled respiration, and mitochondrial biogenesis in WAT. GC-1 induced beiging increases systemic metabolism by over 60%, causing ob/ob mice to lose the majority of their fat mass in 2 weeks. Consistent with the suggestion that increased metabolic rate is mediated entirely by WAT, this effect does not require functional brown fat and increases in metabolic rate correlate with adiposity. This data demonstrates that TR activation can elicit a functional white to brown fat conversion and establishes the profound pharmacological potential of beiging.

Nothing to Disclose: JZL, AJM, DD, SLC, WAH, JDB, CYL, PW, JG, KJP

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Grant RC4 DK090849
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