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

Abstract

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.

Conclusion: Our findings show that disruption of ActRIIB signaling is a viable pharmacological approach for treating obesity and diabetes.

Figure 1

Effects of 4 weeks RAP-031 treatment (white bar) or vehicle (black bar) on (A) body weight, (B) lean, and (C) fat mass. (D-F) skeletal muscle weights. Data are mean ± SEM, N=10; *P<0.05 vs vehicle; **P<0.01 vs vehicle; ***P<0.001 vs vehicle. NC, normal chow diet; HF, high-fat diet.

Figure 2

Effects of 4 weeks RAP-031 treatment (white bar) or vehicle (black bar) on EDL muscle fiber cross-sectional areas in mice on normal chow diet (A, B) or high-fat diet (C, D). Data are mean ± SEM. N=5; *P<0.01 vs vehicle. NC, normal chow diet; HF, high-fat diet.

Figure 3

Effects of 4 weeks RAP-031 treatment (white bar) or vehicle (black bar) on oxygen consumption (VO₂) under (A) basal and (B) peak treadmill exercise conditions, (C) grip strength, and (D, E) ex vivo EDL contraction. Data are mean ± SEM. N=5; *P<0.05 vs vehicle, **P<0.01 vs vehicle, ***P<0.001 vs vehicle. NC, normal chow diet; HF, high-fat diet.

Figure 4

Basal glucose production and hyperinsulinemic-euglycemic clamp in chow (NC) or high-fat (HF) fed mice treated with RAP031 (white bar) or vehicle (black bar) for 4 weeks. (A) Glucose kinetics under basal and clamp conditions on NC diet; (B) WAT and muscle glucose uptake on NC diet; (C) Glucose kinetics under basal and clamp conditions on HF diet; (D) WAT and muscle glucose uptake on HF diet. Data are mean ± SEM. N=5. *P<0.05 vs vehicle.

Figure 5

Effects of 10 weeks RAP-031 treatment (white bar) or vehicle (black bar) on (A) body weight, (B) lean mass, (C) fat mass. Data are mean ± SEM. N=5; *P<0.01 vs vehicle; **P<0.001 vs vehicle. NC, normal chow diet; HF, high-fat diet. Photographs showing the effects of (D) vehicle and (E) RAP-031 treatment on muscle and fat in the dorsal region of NC mice. Effects of (F, G) vehicle or (H, I) RAP-031 treatment on fat and muscle in HF mice.

Figure 6

Basal glucose production and hyperinsulinemic-euglycemic clamp in mice chow (NC) or high-fat (HF) fed mice, treated with RAP-031 (white bar) or vehicle (black bar) for 10 weeks. (A) Glucose kinetics under basal or clamp conditions on NC diet; (B) WAT and muscle glucose uptake on NC diet; (C) Glucose kinetics under basal and clamp conditions on HF diet; (D) WAT and muscle glucose uptake on HF diet. Data are mean ± SEM. N=5. *P<0.01, **P<0.001 vs vehicle.