Adipose tissue usually is classified as either white, brown or beige/brite, based on whether it functions as an energy storage or thermogenic organ. It serves as an important regulator of systemic metabolism, exemplified by the fact that dysfunctional adipose tissue in obesity leads to a host of secondary metabolic complications such as diabetes, cardiovascular diseases and cancer. In addition, adipose tissue is an important endocrine organ, which regulates the function of other metabolic tissues through paracrine and endocrine signals. Work in recent years has demonstrated that tissue heterogeneity is an important factor regulating the functionality of various organs. Here we used single nucleus analysis in mice and men to deconvolute adipocyte heterogeneity. We are able to identify a novel subpopulation of adipocytes whose abundance is low in mice (2~8%) and which is increased under higher ambient temperatures. Interestingly, this population is abundant in humans who live close to thermoneutrality. We demonstrate that this novel adipocyte subtype functions as a paracrine cell regulating the activity of brown adipocytes through acetate-mediated regulation of thermogenesis. These findings could explain, why human brown adipose tissue is substantially less active than mouse tissue and targeting this pathway in humans might be utilized to restore thermogenic activity of this tissue.

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