The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity.
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-beta 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.


CONCLUSIONS
Our findings show that disruption of ActRIIB signaling is a viable pharmacological approach for treating obesity and diabetes.
Akpan
I
I
University of Pennsylvania School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, PA 19104, USA.
Goncalves
M D
MD
Dhir
R
R
Yin
X
X
Pistilli
E E
EE
Bogdanovich
S
S
Khurana
T S
TS
Ucran
J
J
Lachey
J
J
Ahima
R S
RS
D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D055435:Myostatin / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D012995:Solubility
D055435:Myostatin; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B