Targeting brown adipose tissue content or activity has therapeutic potential for treating obesity, diabetes and the metabolic syndrome by increasing energy expenditure. Understanding of the differentiation and function of human adipose tissue is key to formulating therapeutic interventions to treat these metabolic disorders. A major impediment for these studies is the lack of human-derived brown, beige and white fat progenitor cell models. We have successfully generated pairs of immortalized human brown and white fat precursor cells from human neck adipose tissue and characterized their adipogenic differentiation and metabolic function. Using clonal analysis and gene expression profiling, we have defined novel genetic biomarkers in human preadipocytes that could predict the thermogenic potential of mature adipocytes. In addition, using quantitative lipidomics analyses, we have identified new lipid mediators that are able to modulate brown fat-mediated thermogenesis. Building on these preliminary data, we hypothesize that brown fat-mediated thermogenic program is tightly regulated by both genetic and humoral factors. In this grant, we will directly test this hypothesis by determining the role of the identified genetic markers and liid mediators in adipocyte differentiation and mitochondrial functions using the paired human brown and white precursor cells. A series of gain- and loss-of-function experiments will be performed to thoroughly evaluate the impact of these factors on cellular metabolism. The in vivo effects of the human cells will be evaluated after transplantation into immune-deficient nude mice. We will also determine the molecular mechanisms that mediate the effect of these factors on modulating fuel utilization and mitochondrial function of brown or beige adipocytes. Finally, to explore the therapeutic potential of human brown and beige fat, we will test the utility of developing novel human cell surface markers for isolation, imaging and target delivery, and perform chemical screens using the human adipose cells carrying a brown fat specific reporter to identify potential drug candidates. Accomplishing the proposed studies will not only improve our current understanding of human adipocyte biology, but also open up new avenues for developing effective therapies for obesity, diabetes and other metabolic disorders.

Public Health Relevance

Obesity and diabetes are the two major health burdens in the United States. The proposed research aims to understand new molecular mechanisms regulating energy metabolism in brown fat cells of human origin. Given the great potential of brown fat in energy dissipation and improving glucose and lipid profiles in circulation, completion of the proposed studies will lead to new anti-obesity and anti-diabetes therapies, which will benefit millions of Americans living with these metabolic disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Joslin Diabetes Center
United States
Zip Code
Lynes, Matthew D; Shamsi, Farnaz; Sustarsic, Elahu Gosney et al. (2018) Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism. Cell Rep 24:781-790
Bartelt, Alexander; Widenmaier, Scott B; Schlein, Christian et al. (2018) Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med 24:292-303
Gao, Fei; McDaniel, Justice; Chen, Emily Y et al. (2018) Adapted MS/MSALL Shotgun Lipidomics Approach for Analysis of Cardiolipin Molecular Species. Lipids 53:133-142
Sustarsic, Elahu G; Ma, Tao; Lynes, Matthew D et al. (2018) Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis. Cell Metab 28:159-174.e11
Lynes, Matthew D; Tseng, Yu-Hua (2018) Deciphering adipose tissue heterogeneity. Ann N Y Acad Sci 1411:5-20
Hou, Yanyan; Kitaguchi, Tetsuya; Kriszt, Rókus et al. (2017) Ca2+-associated triphasic pH changes in mitochondria during brown adipocyte activation. Mol Metab 6:797-808
Mo, Qianxing; Salley, Jordan; Roshan, Tony et al. (2017) Identification and characterization of a supraclavicular brown adipose tissue in mice. JCI Insight 2:
Ramirez, Alfred K; Lynes, Matthew D; Shamsi, Farnaz et al. (2017) Integrating Extracellular Flux Measurements and Genome-Scale Modeling Reveals Differences between Brown and White Adipocytes. Cell Rep 21:3040-3048
Shamsi, Farnaz; Tseng, Yu-Hua (2017) Protocols for Generation of Immortalized Human Brown and White Preadipocyte Cell Lines. Methods Mol Biol 1566:77-85
Shamsi, Farnaz; Zhang, Hongbin; Tseng, Yu-Hua (2017) MicroRNA Regulation of Brown Adipogenesis and Thermogenic Energy Expenditure. Front Endocrinol (Lausanne) 8:205

Showing the most recent 10 out of 50 publications