Discovery of the novel fat-accumulating molecule, ALK7
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 inhibits CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) specifically in differentiated adipocytes. Despite the inhibition of these master regulators of adipogenesis, it surprisingly increases both the adipocyte size and lipid content by suppressing lipolysis. The ALK7 signal seems to be activated to store excess nutrients as fat in adipocytes by suppressing adipose lipases. This lipid storage function could reasonably be envisioned as a defense against starvation that confers an evolutionary advantage. However, given the food excess in modern developed countries, sustained activation of the ALK7 signal might impair optimal lipid storage and mobilization. In fact, under the obese state, ALK7 deficiency improves glucose tolerance and insulin sensitivity by preferentially increasing fat combustion in mice. Therefore, inhibition of the ALK7 signal represents a promising mechanism and potential target for therapeutic intervention in obesity and associated metabolic dysfunction (Yogosawa S et al., Diabetes, 62, 115-123, 2013).