Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice

Adipocyte complement-related protein (30 kDa) (Acrp30), a secreted protein of unknown function, is exclusively expressed in differentiated adipocytes; its mRNA is decreased in obese humans and mice. Here we describe novel pha rmacological properties of the protease-generated globular head domain of A crp30 (gAcrp30). Acute treatment of mice with gAcrp30 significantly decreas ed the elevated levels of plasma free fatty acids caused either by administ ration of a high fat test meal or by i.v. injection of Intralipid. This eff ect of gAcrp30 was caused, at least in part, by an acute increase in fatty acid oxidation by muscle. As a result, daily administration of a very low d ose of gAcrp30 to mice consuming a high-fat/sucrose diet caused profound an d sustainable weight reduction without affecting food intake. Thus, gAcrp30 is a novel pharmacological compound that controls energy homeostasis and e xerts its effect primarily at the peripheral level.