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A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling

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 phys...

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Autores principales: Koncarevic, Alan, Kajimura, Shingo, Cornwall-Brady, Milton, Andreucci, Amy, Pullen, Abigail, Sako, Dianne, Kumar, Ravindra, Grinberg, Asya V., Liharska, Katia, Ucran, Jeffrey A., Howard, Elizabeth, Spiegelman, Bruce M., Seehra, Jasbir, Lachey, Jennifer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791434/
https://www.ncbi.nlm.nih.gov/pubmed/22549226
http://dx.doi.org/10.1210/en.2012-1016
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author Koncarevic, Alan
Kajimura, Shingo
Cornwall-Brady, Milton
Andreucci, Amy
Pullen, Abigail
Sako, Dianne
Kumar, Ravindra
Grinberg, Asya V.
Liharska, Katia
Ucran, Jeffrey A.
Howard, Elizabeth
Spiegelman, Bruce M.
Seehra, Jasbir
Lachey, Jennifer
author_facet Koncarevic, Alan
Kajimura, Shingo
Cornwall-Brady, Milton
Andreucci, Amy
Pullen, Abigail
Sako, Dianne
Kumar, Ravindra
Grinberg, Asya V.
Liharska, Katia
Ucran, Jeffrey A.
Howard, Elizabeth
Spiegelman, Bruce M.
Seehra, Jasbir
Lachey, Jennifer
author_sort Koncarevic, Alan
collection PubMed
description 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.
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spelling pubmed-37914342013-11-01 A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling Koncarevic, Alan Kajimura, Shingo Cornwall-Brady, Milton Andreucci, Amy Pullen, Abigail Sako, Dianne Kumar, Ravindra Grinberg, Asya V. Liharska, Katia Ucran, Jeffrey A. Howard, Elizabeth Spiegelman, Bruce M. Seehra, Jasbir Lachey, Jennifer Endocrinology Energy Balance-Obesity 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. Endocrine Society 2012-07 2012-05-01 /pmc/articles/PMC3791434/ /pubmed/22549226 http://dx.doi.org/10.1210/en.2012-1016 Text en Copyright © 2012 by The Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Energy Balance-Obesity
Koncarevic, Alan
Kajimura, Shingo
Cornwall-Brady, Milton
Andreucci, Amy
Pullen, Abigail
Sako, Dianne
Kumar, Ravindra
Grinberg, Asya V.
Liharska, Katia
Ucran, Jeffrey A.
Howard, Elizabeth
Spiegelman, Bruce M.
Seehra, Jasbir
Lachey, Jennifer
A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling
title A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling
title_full A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling
title_fullStr A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling
title_full_unstemmed A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling
title_short A Novel Therapeutic Approach to Treating Obesity through Modulation of TGFβ Signaling
title_sort novel therapeutic approach to treating obesity through modulation of tgfβ signaling
topic Energy Balance-Obesity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791434/
https://www.ncbi.nlm.nih.gov/pubmed/22549226
http://dx.doi.org/10.1210/en.2012-1016
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