315-OR: Two Brown Adipocyte Subpopulations with Distinct Thermogenic Activity Coexist and Undergo Dynamic Interconversions upon Changes in Environmental Temperature

Brown adipose tissue (BAT) exerts beneficial metabolic effects on obesity and insulin resistance. Unmasking the complex physiology of BAT thermogenesis is essential to improve our ability to identify effective therapeutic approaches for metabolic disorders. Utilizing the AdipoChaser mouse, we discovered that there are two subpopulations of “classical” brown adipocytes, adiponectin “low expressers” and “high expressers,” co-existing within the BAT. Single-cell sequencing confirms that there are two brown adipocyte subpopulations that differ by adiponectin expression. Low adiponectin expressers also have lower UCP1 expression. We refer to the adiponectin low expresser as low thermogenic brown adipocyte (BA-L), and adiponectin high expresser as high thermogenic brown adipocyte (BA-H). The BA-L has larger lipid droplets, lower mitochondrial content, and higher mitochondrial membrane potential, reflecting reduced thermogenic activity. The BA-H subpopulation is enriched of genes involved in lipolysis, fatty acid oxidation, glycolysis, and oxidative phosphorylation; while the BA-L subpopulation is enriched of genes involved in fatty acid uptake and cell-to-cell trafficking. Upon changes in environmental temperature, the two brown adipocyte subpopulations undergo dynamic inter-conversions. Cold exposure converts BA-L into BA-H, while a thermoneutral environment does the opposite. Developmentally, brown adipocytes initiate differentiation between embryonic day 10 and 16 and they uniformly develop into BA-H. The BA-L subpopulation emerges postnatally. Importantly, the conversion of BA-L into BA-H upon cold exposure is impaired by age, but not by high fat diet feeding. Our results reveal the functional heterogeneity of brown adipocytes. Rather than being uniformly regulated, the thermogenic activity of BAT is controlled by the number of brown adipocytes recruitable into the BA-H pool. Disclosure A. Song: None. M. Jang: None. X. Wu: None. L. Jiang: None. P.E. Scherer: None. Q. Wang: None. Funding American Diabetes Association (1-19-JDF-023 to Q.W.); National Institutes of Health (K01DK107788R03, HD095414); City of Hope