Molecular control of beige fat heterogeneity

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PROJECT SUMMARY Emerging evidence illuminates the biological significance of beige fat, an inducible form of thermogenic fat cells, in the regulation of metabolic health. The best-known stimulus of beige fat biogenesis is cold acclimation and subsequent activation of the β3-adrenoceptor (β3-AR) signaling pathway; however, recent studies identified a variety of external stimuli, such as tissue injury and intermittent fasting, that stimulate beige fat biogenesis through β3-AR independent pathways. Furthermore, our recent study identified a previously uncharacterized population of beige fat, referred to as glycolytic beige adipocytes (or g-beige fat), whose developmental regulation and origin are distinct from β3-AR-induced beige fat. These results lead us to hypothesize that beige fat is composed of developmentally diverse cell populations, and that each population plays unique biological roles depending on the nature of external cues (e.g., cold vs. tissue injury). A technical hurdle to test the hypothesis, however, is the lack of genetic tools that enable us to target particular adipocyte progenitor populations. Thus, we employed single-cell RNA (scRNA) analysis and identified two distinct adipocyte progenitor cells (APCs) that give rise to cold-induced beige adipocytes (CD81+ APCs) and g-beige fat from a myogenic lineage (MyoD+ APCs). Accordingly, this proposal aims to test the above hypothesis by determining the developmental regulation, molecular mechanisms, and biological function of beige adipocytes stem from CD81+ APCs and MyoD+ APCs. Our contribution in this proposal is to provide a fundamental understanding as to how heterogeneous beige adipocyte populations are regulated by physiological and pathological cues, and how they contribute to the regulation of metabolic tissue homeostasis, such as fuel oxidation, angiogenesis, innervation, tissue fibrosis, and inflammation.