Obesity, which occurs when energy intake exceeds energy expenditure, is a major contributor to the development of type II diabetes and cardiovascular disease. One significant form of energy expenditure is nonshivering thermogenesis, the dissipation of chemical energy as heat by brown adipose tissue (BAT). The recent rediscovery of BAT in the supraclavicular region in healthy human adults suggests that therapeutic strategies utilizing BAT function could combat obesity and its related metabolic complications in humans. To utilize BAT as a therapeutic tool, we first need to understand how supraclavicular BAT (scBAT) forms and functions using a faithful animal model for human scBAT. We recently identified a mouse scBAT depot that anatomically and molecularly resembles the supraclavicular depot found in humans. New preliminary studies traced the lineage giving rise to scBAT to cardiac progenitor cells in the anterior heart field (AHF) that express Myocyte enhancer factor 2c (Mef2c), revealing a lineage relationship between scBAT and the heart. Knockdown of the Mef2c transcription factor in supraclavicular brown preadipocytes led to the loss of key brown adipogenesis regulators, while selective ablation of scBAT perturbed metabolic homeostasis in healthy chow-fed mice. Together, these findings led us to hypothesize that scBAT is a highly active metabolic BAT depot that originates from cardiac progenitor cells in the anterior heart field and is dependent on Mef2c for the regulation of its metabolic function.
For specific aim 1, we will determine the developmental origin of scBAT by determining if polypotent cardiac progenitor cells can be directly induced to become brown adipocytes, analyzing scBAT for tissue defects after genetic ablation of Mef2c-AHF+ cells, and identifying cell surface markers specific for supraclavicular brown adipocyte progenitors.
For specific aim 2, we will determine the role of Mef2c in the regulation of metabolic function of scBAT. We will investigate the contribution of Mef2c to brown adipogenesis and metabolic function using cells and mice in which Mef2c has been deleted.
For specific aim 3, we will determine the physiological contribution of scBAT to energy and glucose homeostasis in vivo by investigating the effects of loss of scBAT in healthy mice and the underlying mechanism of action by which scBAT regulates metabolism. We will also determine whether loss of scBAT further disrupts metabolic function in high-fat diet induced obese mice. Together these studies should provide fundamental understanding of the origin of, the contribution of Mef2c to the function of, and physiological significance of scBAT in mice and provide new insight into how to potentially utilize the most common active BAT depot in humans to treat obesity and its related metabolic complications.

Public Health Relevance

We have identified a new brown fat depot located in the supraclavicular region of the mouse neck that is the anatomical equivalent of the supraclavicular brown fat depot found in adult humans. The focus of the proposed study is to investigate the origin and function of this depot in order to understand how human supraclavicular brown fat functions and forms. Successful completion of this study will greatly advance our understanding of the thermogenic capacity of and identify the progenitor cells that give rise to supraclavicular brown fat and may provide a foundation for the development of new therapeutic strategies that utilize brown fat to prevent and treat metabolic diseases, such as hypothermia, obesity, type II diabetes, and heart disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK116899-03
Application #
10075922
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Haft, Carol R
Project Start
2019-01-18
Project End
2022-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030