Activin Actions in Adipocytes

Abstract

Obesity is a growing global health problem characterized by excess fat accumulation. Though causes of obesity are multifactorial, glucagon-like peptide 1 receptor agonists have emerged as effective weight loss drugs. Nevertheless, these agents are expensive, not uniformly available, and must be used continuously. Moreover, side effects and low efficacy limit the use of these and related molecules in some individuals. Therefore, there is continued interest in characterizing mechanisms regulating adiposity to aid in the development of novel treatments. In recent years, there has been a growing appreciation for ligands of the TGFβ family, the activins, in adipocyte proliferation, differentiation, and function. Here, we review recent progress in understanding the role of these molecules, with a particular focus on the hepatokine, activin E, in lipolysis and diet-induced obesity.

Keywords: TGFβ; adipose; ligand; lipolysis; obesity.

Figure 1.

Signaling pathways of activins and other TGFβ related ligands in adipocytes. Activin A and B bind to the type II receptors, ACVR2A or ACVR2B. The type II receptors phosphorylate the type I receptors, ALK4 or ALK7. The type I receptors then phosphorylate SMAD2/3. Phosphorylated-SMAD2/3 complex with SMAD4 and accumulate in the nucleus to inhibit Pparγ and Cebp transcription in concert with other transcription factors. Activins C and E and GDF3 activate a similar signaling pathway but exclusively utilize ALK7 as their type I receptor (Nodal and Cripto contribute to GDF3 signaling but are not pictured). BMPs bind to several type II receptors, including ACVR2A, ACVR2B, and the bone morphogenetic protein receptor 2 (BMPR2). These receptors phosphorylate the type I receptors ALK1, ALK2, ALK3, and ALK6 to stimulate SMAD1/5/8 signaling in adipocyte precursors to promote preadipocyte commitment. Follistatin and inhibins are negative regulators of some of these ligands. Figure created in BioRender. Abbreviations: ACVR2A, activin type II receptor A; ACVR2B, activin type II receptor B; ALK, activin receptor-like kinase; BMP, bone morphogenetic protein; GDF, growth differentiation factor.

Figure 2.

Role of BMPs, activins, and GDF3 in adipogenesis. BMPs stimulate the commitment of preadipocytes by upregulating Zfp423 and Pparγ transcription via SMAD1. In contrast, activins A and B promote preadipocyte cell proliferation but inhibit their differentiation. Activin signaling through SMAD3 leads to an increase in Cd24 expression and decreases in Pparγ and Cebp transcription. Activins B, C, and E and GDF3 signaling via ALK7/SMAD3 downregulate the transcription of lipases (Hsl, Pnpla2) and the β3 adrenergic receptor (Adrb3). Figure created in BioRender. Abbreviations: ALK, activin receptor-like kinase; BMP, bone morphogenetic protein; GDF, growth differentiation factor.