ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue

  • Cell Rep. 2014 Dec 11;9(5):1584-1593. doi: 10.1016/j.celrep.2014.10.066.
Andrea Galmozzi  1 ,  Si B Sonne  2 ,  Svetlana Altshuler-Keylin  2 ,  Yutaka Hasegawa  2 ,  Kosaku Shinoda  2 ,  Ineke H N Luijten  2 ,  Jae Won Chang  1 ,  Louis Z Sharp  2 ,  Benjamin F Cravatt  1 ,  Enrique Saez  3 ,  Shingo Kajimura  4
Affiliations
  • 1. Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 2. UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
  • 3. Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
  • 4. UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA. Electronic address: [email protected].
PMID: 25466254 DOI: 10.1016/j.celrep.2014.10.066
Abstract

Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.

Products