Bu Y (1), Okunishi K (1)*, Yogosawa S (1), Mizuno K (1), Irudayam MJ (2), Brown CW (2), Izumi T (1)* (1: Laboratory of Molecular Endocrinology and Metabolism, IMCR, Gunma University; 2: Division of Genetics, Department of Pediatrics, University of Tennessee, USA) *, corresponding authors
Obesity (i.e. fat accumulation) is the major risk factor for the development of metabolic diseases such as type II diabetes and metabolic syndromes. It is important to understand the mechanism for fat accumulation more in depth to generate new therapeutic strategies for prevention of obesity. In the current study, we clarified the novel mechanism for fat accumulation induced by insulin and adipose tissue macrophages (ATM). We found that insulin increases secretion of GDF3, the ALK7 ligand in vivo, by ATM, and that GDF3 secreted by ATM inhibits lipolysis through activation of its receptor ALK7 on adipocytes. We also confirmed that insulin administration in vivo increases fat mass by inhibiting lipolysis in ALK7 and macrophage-derived GDF3 dependent manners. We thus uncovered a previously unrecognized mechanism by which insulin regulates both fat metabolism and mass. We hope that the new therapy targeting this insulin-GDF3-ALK7 axis can be developed for prevention of obesity in the future.
Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages. Bu Y, Okunishi K, Yogosawa S, Mizuno K, Irudayam MJ, Brown CW, Izumi T. Diabetes 2018 Jun 26. pii: db171201. doi: 10.2337/db17-1201