A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling (original) (raw)

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1Acceleron Pharma, Inc. Preclinical Pharmacology (A.K., M.C-B., A.P., J.S. and J.L.), Cambridge, Massachusetts 02139

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3University of California, San Francisco Diabetes Center and Department of Cell and Tissue Biology (S.K.), University of California, San Francisco, San Francisco 94143

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1Acceleron Pharma, Inc. Preclinical Pharmacology (A.K., M.C-B., A.P., J.S. and J.L.), Cambridge, Massachusetts 02139

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2Bioanalytical Development and Cell Biology (A.A., D.S., R.K., A.V.G., K.L., J.A.U. and E.H.), Cambridge, Massachusetts 02139

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1Acceleron Pharma, Inc. Preclinical Pharmacology (A.K., M.C-B., A.P., J.S. and J.L.), Cambridge, Massachusetts 02139

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2Bioanalytical Development and Cell Biology (A.A., D.S., R.K., A.V.G., K.L., J.A.U. and E.H.), Cambridge, Massachusetts 02139

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2Bioanalytical Development and Cell Biology (A.A., D.S., R.K., A.V.G., K.L., J.A.U. and E.H.), Cambridge, Massachusetts 02139

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2Bioanalytical Development and Cell Biology (A.A., D.S., R.K., A.V.G., K.L., J.A.U. and E.H.), Cambridge, Massachusetts 02139

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2Bioanalytical Development and Cell Biology (A.A., D.S., R.K., A.V.G., K.L., J.A.U. and E.H.), Cambridge, Massachusetts 02139

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2Bioanalytical Development and Cell Biology (A.A., D.S., R.K., A.V.G., K.L., J.A.U. and E.H.), Cambridge, Massachusetts 02139

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05 January 2012

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Alan Koncarevic, Shingo Kajimura, Milton Cornwall-Brady, Amy Andreucci, Abigail Pullen, Dianne Sako, Ravindra Kumar, Asya V. Grinberg, Katia Liharska, Jeffrey A. Ucran, Elizabeth Howard, Bruce M. Spiegelman, Jasbir Seehra, Jennifer Lachey, A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling, Endocrinology, Volume 153, Issue 7, 1 July 2012, Pages 3133–3146, https://doi.org/10.1210/en.2012-1016
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Obesity results from disproportionately high energy intake relative to energy expenditure. Many therapeutic strategies have focused on the intake side of the equation, including pharmaceutical targeting of appetite and digestion. An alternative approach is to increase energy expenditure through physical activity or adaptive thermogenesis. A pharmacological way to increase muscle mass and hence exercise capacity is through inhibition of the activin receptor type IIB (ActRIIB). Muscle mass and strength is regulated, at least in part, by growth factors that signal via ActRIIB. Administration of a soluble ActRIIB protein comprised of a form of the extracellular domain of ActRIIB fused to a human Fc (ActRIIB-Fc) results in a substantial muscle mass increase in normal mice. However, ActRIIB is also present on and mediates the action of growth factors in adipose tissue, although the function of this system is poorly understood. In the current study, we report the effect of ActRIIB-Fc to suppress diet-induced obesity and linked metabolic dysfunctions in mice fed a high-fat diet. ActRIIB-Fc induced a brown fat-like thermogenic gene program in epididymal white fat, as shown by robustly increased expression of the thermogenic genes uncoupling protein 1 and peroxisomal proliferator-activated receptor-γ coactivator 1α. Finally, we identified multiple ligands capable of reducing thermogenesis that represent likely target ligands for the ActRIIB-Fc effects on the white fat depots. These data demonstrate that novel therapeutic ActRIIB-Fc improves obesity and obesity-linked metabolic disease by both increasing skeletal muscle mass and by inducing a gene program of thermogenesis in the white adipose tissues.

Copyright © 2012 by The Endocrine Society

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