Roles of activin receptor-like kinase 7 signaling and its target, peroxisome proliferator-activated receptor γ, in lean and obese adipocytes

Abstract

We recently discovered a novel signaling pathway involving activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-β receptors. ALK7 and activated Smads 2, 3, and 4 inhibit the master regulators of adipogenesis, CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) specifically in differentiated adipocytes, but surprisingly increase both the adipocyte size and lipid content by suppressing lipolysis. Here, we show that, although both transcription factors are suppressed by ALK7 in either the obese or lean state, PPARγ, but not C/EBPα, is further suppressed under obesity through an ALK7-independent pathway. As a result, PPARγ and adipose lipolytic activities are severely downregulated in obesity. Reactivation of PPARγ by ALK7 inactivation leads to downregulation of inflammatory adipocytokines and upregulation of adiponectin. We propose that PPARγ promotes lipid turnover and remodeling by stimulating both triglyceride synthesis and breakdown in differentiated adipocytes. Finally, we discuss the physiological and evolutionary roles of the ALK7-signaling pathway and consider it as a potential target of therapy for obesity.