Tbx15 Defines a Glycolytic Subpopulation and White Adipocyte Heterogeneity

Abstract

Tbx15 is a member of the T-box gene family of mesoder-mal developmental genes. We have recently shown that Tbx15 plays a critical role in the formation and metabolic programming of glycolytic myofibers in skeletal muscle. Tbx15 is also differentially expressed among white adipose tissue (WAT) in different body depots. In the current study, using three independent methods, we show that even within a single WAT depot, high Tbx15 expression is restricted to a subset of preadipocytes and mature white adipocytes. Gene expression and metabolic profiling demonstrate that the Tbx15Hi preadipocyte and adipo-cyte subpopulations of cells are highly glycolytic, whereas Tbx15Low preadipocytes and adipocytes in the same depot are more oxidative and less glycolytic. Likewise, in humans, expression of TBX15 in subcutaneous and vis-ceral WAT is positively correlated with markers of glyco-lytic metabolism and inversely correlated with obesity. Furthermore, overexpression of Tbx15 is sufficient to re-duce oxidative and increase glycolytic metabolism in cul-tured adipocytes. Thus, Tbx15 differentially regulates oxidative and glycolytic metabolism within subpopula-tions of white adipocytes and preadipocytes. This leads to a functional heterogeneity of cellular metabolism within WAT that has potential impact in the understanding of human metabolic diseases.