ThermoMouse: An In Vivo Model to Identify Modulators of UCP1 Expression in Brown Adipose Tissue
Andrea Galmozzi,
Si B. Sonne,
Svetlana Altshuler-Keylin,
Yutaka Hasegawa,
Kosaku Shinoda,
Ineke H.N. Luijten,
Jae Won Chang,
Louis Z. Sharp,
Benjamin F. Cravatt,
Enrique Saez,
Shingo Kajimura
Affiliations
Andrea Galmozzi
Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Si B. Sonne
UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA
Svetlana Altshuler-Keylin
UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA
Yutaka Hasegawa
UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA
Kosaku Shinoda
UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA
Ineke H.N. Luijten
UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA
Jae Won Chang
Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Louis Z. Sharp
UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA
Benjamin F. Cravatt
Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Enrique Saez
Department of Chemical Physiology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Shingo Kajimura
UCSF Diabetes Center, Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA; Corresponding author
Summary: 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. : Pharmacological activation of brown adipose tissue (BAT) thermogenesis and energy dissipation, a process mediated by UCP1, may be useful to counter the energy imbalance that engenders obesity. Galmozzi et al. have developed an in vivo model to monitor UCP1 expression in real time and identified a small molecule that increases UCP1 levels. Mice treated with this molecule show greater energy expenditure upon adrenergic stimulation. Discovery of compounds with this ability is an important stride toward enhancing BAT function in obese individuals.
