Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages

Previous genetic studies in mice have shown that functional loss of activin receptor-like kinase 7 (ALK7), a type I transforming growth factor (TGF)-β receptor, increases lipolysis to resist fat accumulation in adipocytes.Although growth/differentiation factor 3 (GDF3) has been suggested to function as a ligand of ALK7 under nutrient-excess conditions, it is unknown how GDF3 production is regulated.Here, we show that a physiologically low level of insulin converts CD11c -adipose tissue macrophages (ATMs) into GDF3-producing, CD11c + macrophages ex vivo, and directs ALK7dependent accumulation of fat in vivo.Depletion of ATMs by clodronate upregulates adipose lipases and reduces fat mass in ALK7-intact obese mice, but not in their ALK7deficient counterparts.Furthermore, depletion of ATMs or transplantation of GDF3deficient bone marrow negates the in vivo effects of insulin on both lipolysis and fat accumulation in ALK7-intact mice.The GDF3-ALK7 axis between ATMs and adipocytes represents a previously unrecognized mechanism by which insulin regulates both fat metabolism and mass.