Failure to maintain systemic energy homeostasis?a balance between energy intake and energy expenditure at the organismal level?is the root cause of obesity and its associated comorbidities. As a result, physiological processes that regulate energy intake and/or expenditure are the subject of intense study and hold great promise as therapeutic targets for obesity. Stimulation of nonshivering thermogenesis (NST)?the generation of heat by futile metabolic cycling in brown (BAT) and beige adipose tissue?has garnered considerable interest as a potential means of increasing energy expenditure in humans to protect against obesity and the metabolic syndrome. However, NST-based therapeutic strategies are limited by the adverse effects of inducing futile cycling in non-BAT tissues. Thus, identifying and characterizing novel BAT-specific proteins could provide opportunities for the development of improved obesity interventions targeting NST. Preliminary studies employing next-generation sequencing, molecular biology, genome editing, and proteomic approaches have led to the discovery of a novel BAT-specific protein of unknown function named BASIC. Basic expression is highly induced by environmental and pharmacological activators of NST in mice, and knockdown of BASIC appears to upregulate the thermogenic gene program in cultured adipocytes, implicating BASIC as a cell- intrinsic negative regulator of adipose thermogenesis. The proposed research plan will first use physiologic and molecular approaches to characterize a newly generated BASIC knockout mouse model and thereby determine the consequence of loss of BASIC function on NST in vivo (Aim 1). Further studies will elucidate BASIC's mechanism of action by defining its subcellular localization and examining its effect on thermogenic signaling pathways in primary brown adipocytes (Aim 2). Completion of the proposed aims will shed light on the function of a hitherto undiscovered BAT-specific protein, which may provide insight into new pathways involved in adipose thermogenesis and reveal a potential target for NST-based therapeutic interventions.

Public Health Relevance

Metabolic diseases such as obesity and diabetes are caused by a chronic imbalance between energy intake and energy expenditure. Non-shivering thermogenesis (NST)?heat production by brown adipose tissue (BAT)?is a physiological process that increases energy expenditure and has the potential to be targeted in humans to protect against the metabolic syndrome. By elucidating the function of a novel BAT-specific protein named BASIC, my proposed research will advance our understanding of the fundamental mechanisms underlying metabolic homeostasis and disease and may reveal new opportunities for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DK123986-01
Application #
9911814
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2019-12-01
Project End
2023-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095