effects of a soluble activin type IIB receptor on obesity and insulin sensitivity

• Published in: International Journal of Obesity 2009-11, Vol.33 (11), p.1265-1273
• Main Authors: Akpan, I, Goncalves, M.D, Dhir, R, Yin, X, Pistilli, E.E, Bogdanovich, S, Khurana, T.S, Ucran, J, Lachey, J, Ahima, R.S
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type II - metabolism; activins; adiponectin; animal models; Animals; Biological and medical sciences; Body composition; Body fat; carbohydrate metabolism; Case-Control Studies; Diabetes; Diet; diet-related diseases; Endocrinology; Epidemiology; experimental diets; Fitness equipment; Genetic aspects; Glucose; Glucose Clamp Technique; Health aspects; Health Promotion and Disease Prevention; high fat diet; human diseases; human nutrition; Insulin; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; lean body mass; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; muscle mass; Muscle, Skeletal - metabolism; muscles; Musculoskeletal system; Myostatin; Myostatin - metabolism; NMR; Nuclear magnetic resonance; Obesity; Obesity - drug therapy; Obesity - metabolism; Obesity - physiopathology; original-article; Physiological aspects; Proteins; Public Health; receptors; Risk factors; Signal Transduction; Solubility; Transforming growth factors
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2009.162

Background: Myostatin, also known as Growth and Differentiation Factor 8, is a secreted protein that inhibits muscle growth. Disruption of myostatin signaling increases muscle mass and decreases glucose, but it is unclear whether these changes are related. We treated mice on chow and high-fat diets with a soluble activin receptor type IIB (ActRIIB, RAP-031), which is a putative endogenous signaling receptor for myostatin and other ligands of the TGF-β superfamily. Results: After 4 weeks, RAP-031 increased lean and muscle mass, grip strength and contractile force. RAP-031 enhanced the ability of insulin to suppress glucose production under clamp conditions in high-fat fed mice, but did not significantly change insulin-mediated glucose disposal. The hepatic insulin-sensitizing effect of RAP-031 treatment was associated with increased adiponectin levels. RAP-031 treatment for 10 weeks further increased muscle mass and drastically reduced fat content in mice on either chow or high-fat diet. RAP-031 suppressed hepatic glucose production and increased peripheral glucose uptake in chow-fed mice. In contrast, RAP-031 suppressed glucose production with no apparent change in glucose disposal in high-fat-diet mice. Conclusion: Our findings show that disruption of ActRIIB signaling is a viable pharmacological approach for treating obesity and diabetes.