Shox2 is a molecular determinant of depot-specific adipocyte function

Abstract

Visceral and s.c. fat exhibit different intrinsic properties, including rates of lipolysis, and are associated with differential risk for the development of type 2 diabetes. These effects are in part related to cell autonomous differences in gene expression. In the present study, we show that expression of Shox2 (Short stature homeobox 2) is higher in s.c. than visceral fat in both rodents and humans and that levels are further increased in humans with visceral obesity. Fat-specific disruption of Shox2 in male mice results in protection from high fat diet-induced obesity, with a preferential loss of s.c. fat. The reduced adipocyte size is secondary to a twofold increase in the expression of β3 adrenergic receptor ( Adrb3 ) at both the mRNA and protein level and a parallel increase in lipolytic rate. These effects are mimicked by knockdown of Shox2 in C3H10T1/2 cells. Conversely, overexpression of Shox2 leads to a repression of Adrb3 expression and decrease lipolytic rate. Shox2 does not affect differentiation but directly interacts with CCAAT/enhancer binding protein alpha and attenuates its transcriptional activity of the Adrb3 promoter. Thus, Shox2 can regulate the expression of Adrb3 and control the rate of lipolysis and, in this way, exerts control of the phenotypic differences between visceral and s.c. adipocytes.

Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications

“…Indeed, two developmental genes (SHOX2, TBX15) have recently been identified as important regulators of adipocyte development and function (17,18). We have previously reported differential expression of TBX15 in GSAT and ASAT (27), which has since been shown to regulate differentiation of brown and "brite" adipocytes (18).…”

“…Supporting this view is the finding that isolated preadipocytes exhibit intrinsic differences in many functional characteristics, including proliferation, apoptosis, and adipogenesis (12). Transcriptional profiling has also identified unique regional mRNA profiles characterized by differential expression of developmental genes (13)(14)(15), some of which correlate with obesity (HOXA5, TBX15) (16) and appear to be important regulators of adipocyte development and function (SHOX2, TBX15) (17,18). The "memory" of these transcriptional signatures can persist in vitro across many cell generations (13), implicating the involvement of epigenetic regulation in regional AT development (19).…”

Heterogeneity of adipose tissue in development and metabolic function

“…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). However, additional studies are needed to fully explore the role of these genes in adipose tissue identity.…”

Dermal white adipose tissue: a new component of the thermogenic response

“…Thus, the heterogeneous cell fractions extracted from distinct WAT depots [stromal vascular fractions (SVFs)], when compared by transcriptional profi ling, show different and characteristic gene expression. Some of these differences have been implicated in the distinct properties of each WAT depot ( 18,19,44 ). For example, each depot has a characteristic capacity to store and mobilize fatty acids in response to specifi c physiological challenges.…”