Tbx15 Defines a Glycolytic Subpopulation and White Adipocyte Heterogeneity

Abstract

Tbx15 is a member of the T-box gene family of mesodermal 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 adipocyte 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 visceral WAT is positively correlated with markers of glycolytic metabolism and inversely correlated with obesity. Furthermore, overexpression of Tbx15 is sufficient to reduce oxidative and increase glycolytic metabolism in cultured adipocytes. Thus, Tbx15 differentially regulates oxidative and glycolytic metabolism within subpopulations 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.

Developmental and functional heterogeneity of white adipocytes within a single fat depot

“…Tbx15 mRNA expression, which we previously showed marks a subset of cells in the subcutaneous adipose tissue (Lee et al, 2017a), was~3-fold higher in GFP + preadipocytes derived from the subcutaneous fat of Tagln-cre;Rosa26 mT/mG . Tbx15 mRNA expression, which we previously showed marks a subset of cells in the subcutaneous adipose tissue (Lee et al, 2017a), was~3-fold higher in GFP + preadipocytes derived from the subcutaneous fat of Tagln-cre;Rosa26 mT/mG .…”

“…The most dramatic differences in gene expression were between Type 1 preadipocytes and the other two groups, as can be visualized by a heatmap of the 50 most differential genes and by principal component analysis (Figs 2D and EV1E), however, significant differences were also present between Types 2 and 3, as visualized by a heatmap of the 50 most differential genes between these two groups ( Fig 2E). C Bright-field image of depot-derived cell lines after in vitro adipogenic differentiation and Oil Red O staining (Lee et al, 2017a). In addition, all three clusters were also able to differentiate into osteoblasts and chondrocytes in vitro using conditions that induce bone and cartilage development (Boquest et al, 2005) as visualized by Alizarin Red S staining of calcium deposition and Alcian Blue of acidic mucins, respectively ( Fig EV1F).…”

“…Thus, studies have shown that individual white adipocytes within a single depot may differ in insulin-stimulated glucose uptake, maximal lipogenic rate, response to catecholamines, and uptake of free fatty acids (Salans & Dougherty, 1971;Gliemann & Vinten, 1974;Seydoux et al, 1996;Varlamov et al, 2015;Gao et al, 2017). Our laboratory recently showed that subpopulations of white adipocytes differ in their expression of the mesodermal homeobox gene Tbx15 and that this contributes to differences in oxidative phosphorylation and glycolysis in these cells (Lee et al, 2017a). Our laboratory recently showed that subpopulations of white adipocytes differ in their expression of the mesodermal homeobox gene Tbx15 and that this contributes to differences in oxidative phosphorylation and glycolysis in these cells (Lee et al, 2017a).…”

“…Indeed, lineage tracing analyses have begun to uncover the differential developmental origins of adipocytes even within single fat depots (Chau et al, 2014;Sanchez-Gurmaches & Guertin, 2014). Our laboratory recently showed that subpopulations of white adipocytes differ in their expression of the mesodermal homeobox gene Tbx15 and that this contributes to differences in oxidative phosphorylation and glycolysis in these cells (Lee et al, 2017a). This is distinct from the heterogeneity due to the presence of brown and brite adipocyte populations, although the latter may also have heterogeneity in thermogenic potential (Xue et al, 2015) and anabolic versus catabolic function (Lee et al, 2017b).…”

Heterogeneity of adipose tissue in development and metabolic function

“…T-box protein 15 (Tbx15) regulates adipocyte differentiation and triglyceride accumulation (Gesta et al, 2011) and Gpc4 enhances both insulin receptor signaling and adipocyte differentiation (Ussar et al, 2012). Recently, Lee and colleagues have shown that Tbx15 regulates a switch from oxidative to glycolytic metabolism and marks a glycolytic subpopulation of adipocytes (Lee et al, 2017a). Moreover, Shox2 is highly expressed in cells of flank/psWAT compared with pgWAT, and controls lipolysis rates, orchestrating at least some of the differences between subcutaneous and visceral adipocytes (Lee et al, 2013b).…”