The role of the activin receptor type IIb (ActRIIB) in glucose and energy homeostasis

The activin receptor type IIb (ActRIIB) is a type II transforming growth factor (TGF)-β superfamily receptor that mediates signaling for ligands such as myostatin, activin A, bone morphogenic protein (BMP)-7 and others (Lee & McPherron, 2001; Lee et al., 2005; Souza et al., 2008). ActRIIB is widely distributed in skeletal muscle, adipose tissue and various metabolic organs (Rebbapragada et et al., 2003). A soluble ActRIIB antibody (ActRIIB-mFc) has been shown to increase muscle mass and strength in wild-type and dystrophic mice (Bogdanovich et et al., 2002; Lee et et al., 2005). We hypothesized that blockade of the ActRIIB would increase lean mass, alter whole body metabolism, and abrogate diet-induced obesity and insulin resistance. In this thesis, we show that inhibition of ActRIIB induced myofiber hypertrophy; altered muscle, adipose, and liver metabolism; and improved hepatic insulin sensitivity. These improvements increased obligatory energy expenditure, reduced body fat, and improved glucose homeostasis in mice on chow or high-fat diets. We identified a temporal relationship between changes in body composition and insulin sensitivity such that muscle hypertrophy precedes the loss of adiposity and improved insulin sensitivity. The hepatic insulin-sensitizing effect of ActRIIB-mFc treatment was associated with increased adiponectin levels. We explored the requirement of adiponectin in the response to ActRIIB inhibition in adiponectin knockout mice and provide preliminary evidence that adiponectin is required for the improvement in hepatic metabolism and insulin sensitivity. The mechanism underlying myofiber hypertrophy with ActRIIB inhibition is unknown. Here, we show that Akt1, Akt2, and mTOR are not critical for the hypertrophic response of ActRIIB inhibition; however, Akt2 was essential for the changes in adipose metabolism. These studies implicate ActRIIB ligands in the control of organ size and the regulation of whole body metabolism and insulin sensitivity