Obesity, which results from prolonged imbalance between energy intake and energy expenditure, is an independent risk factor for a number of chronic diseases, including type 2 diabetes, coronary artery disease, fatty liver disease, neurodegenerative disorders, and a number of cancers. Simplistically, there are two major ways of combating obesity: to decrease energy intake or to increase energy expenditure. The recent discovery of cold-induced brown/beige fat in humans has generated a great deal of excitement for its therapeutic targeting in humans. However, our current knowledge of the signaling pathways that license thermogenesis in brown/beige adipose tissue is very limited. This application builds on our new discoveries that immune signals license the thermogenic programs in brown adipose tissue of mice. We will utilize techniques from mouse genetics, immunology, genomics, and metabolism to dissect the underlying mechanisms by which immune signals regulate thermogenesis in brown adipose tissue. The three specific questions we will address are: 1) What are the physiologic mechanisms by which immune signals license thermogenesis in brown adipocytes?, 2) What are the cellular signaling pathways by which immunity regulates uncoupled respiration in brown adipocytes?, and 3) How do immune signals regulate mitochondrial protein expression and respiration? The successful completion of these aims will provide novel insights into cellular and molecular pathways that regulate brown fat thermogenesis, thus advancing our understanding of how to therapeutically target this tissue for the treatment of human obesity and type 2 diabetes.

Public Health Relevance

Obesity is a global epidemic that results from chronic imbalance between energy intake and energy expenditure. One potential way of treating obesity is to increase energy expenditure via activating heat production in brown and beige fat. In this application, we will study the molecular and cellular pathways that control the development of functional brown fat. Understanding these pathways might shed new light on how to treat human obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK094641-05A1
Application #
9234437
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2011-09-25
Project End
2020-08-31
Budget Start
2016-09-23
Budget End
2017-08-31
Support Year
5
Fiscal Year
2016
Total Cost
$451,725
Indirect Cost
$166,725
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Paulo, Esther; Wu, Dongmei; Wang, Yangmeng et al. (2018) Sympathetic inputs regulate adaptive thermogenesis in brown adipose tissue through cAMP-Salt inducible kinase axis. Sci Rep 8:11001
Ganeshan, Kirthana; Chawla, Ajay (2017) Warming the mouse to model human diseases. Nat Rev Endocrinol 13:458-465
Wang, Yangmeng; Paulo, Esther; Wu, Dongmei et al. (2017) Adipocyte Liver Kinase b1 Suppresses Beige Adipocyte Renaissance Through Class IIa Histone Deacetylase 4. Diabetes 66:2952-2963
Man, Kevin; Kutyavin, Vassily I; Chawla, Ajay (2017) Tissue Immunometabolism: Development, Physiology, and Pathobiology. Cell Metab 25:11-26
Odegaard, Justin I; Lee, Min-Woo; Sogawa, Yoshitaka et al. (2017) Perinatal Licensing of Thermogenesis by IL-33 and ST2. Cell 171:1707
Tan, Meng How; Li, Qin; Shanmugam, Raghuvaran et al. (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254
Huo, Mingyu; Huang, Yuhong; Qu, Dan et al. (2017) Myeloid Bmal1 deletion increases monocyte recruitment and worsens atherosclerosis. FASEB J 31:1097-1106
Man, Kevin; Loudon, Andrew; Chawla, Ajay (2016) Immunity around the clock. Science 354:999-1003
Tian, Xiao Yu; Ganeshan, Kirthana; Hong, Cynthia et al. (2016) Thermoneutral Housing Accelerates Metabolic Inflammation to Potentiate Atherosclerosis but Not Insulin Resistance. Cell Metab 23:165-78
Odegaard, Justin I; Lee, Min-Woo; Sogawa, Yoshitaka et al. (2016) Perinatal Licensing of Thermogenesis by IL-33 and ST2. Cell 166:841-854

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