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

International Journal of Obesity volume 33, pages 1265–1273 (2009)Cite this article

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-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.

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Acknowledgements

This work was supported by National Institutes of Health Grants RO1-DK062348 and PO1-DK049210 to RSA, University of Pennsylvania Diabetes Endocrinology Research Center (DERC) Mouse Metabolic Phenotyping Core (P30-DK19525), and World Anti-Doping Agency (WADA, Institution No: 801619) to TSK, and Acceleron Pharmaceuticals.

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Author notes

  1. I Akpan and M D Goncalves: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, University of Pennsylvania School of Medicine, Diabetes and Metabolism, Philadelphia, PA, USA

    I Akpan, M D Goncalves, R Dhir, X Yin & R S Ahima

  2. Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    E E Pistilli, S Bogdanovich & T S Khurana

  3. University of Pennsylvania, Institute for Diabetes, Obesity and Metabolism, Philadelphia, PA, USA

    I Akpan, M D Goncalves, R Dhir, X Yin & R S Ahima

  4. Acceleron Pharma, Cambridge, MA, USA

    J Ucran & J Lachey

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  1. I Akpan
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Correspondence to R S Ahima.

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Akpan, I., Goncalves, M., Dhir, R. et al. The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. Int J Obes 33, 1265–1273 (2009). https://doi.org/10.1038/ijo.2009.162

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  • DOI: https://doi.org/10.1038/ijo.2009.162

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