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Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders

Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human ge...

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Autores principales: Zhao, Min, Okunishi, Katsuhide, Bu, Yun, Kikuchi, Osamu, Wang, Hao, Kitamura, Tadahiro, Izumi, Tetsuro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977491/
https://www.ncbi.nlm.nih.gov/pubmed/36626233
http://dx.doi.org/10.1172/jci.insight.161229
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author Zhao, Min
Okunishi, Katsuhide
Bu, Yun
Kikuchi, Osamu
Wang, Hao
Kitamura, Tadahiro
Izumi, Tetsuro
author_facet Zhao, Min
Okunishi, Katsuhide
Bu, Yun
Kikuchi, Osamu
Wang, Hao
Kitamura, Tadahiro
Izumi, Tetsuro
author_sort Zhao, Min
collection PubMed
description Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist to hip ratios and resistance to development of diabetes. In the present study, treatment with a neutralizing mAb against ALK7 caused a substantial loss of adipose mass and improved glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and oxygen consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term Ab treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and, subsequently, IL-1β release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes.
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spelling pubmed-99774912023-03-02 Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders Zhao, Min Okunishi, Katsuhide Bu, Yun Kikuchi, Osamu Wang, Hao Kitamura, Tadahiro Izumi, Tetsuro JCI Insight Research Article Activin receptor-like kinase 7 (ALK7) is a type I receptor in the TGF-β superfamily preferentially expressed in adipose tissue and associated with lipid metabolism. Inactivation of ALK7 signaling in mice results in increased lipolysis and resistance to both genetic and diet-induced obesity. Human genetic studies have recently revealed an association between ALK7 variants and both reduced waist to hip ratios and resistance to development of diabetes. In the present study, treatment with a neutralizing mAb against ALK7 caused a substantial loss of adipose mass and improved glucose intolerance and insulin resistance in both genetic and diet-induced mouse obesity models. The enhanced lipolysis increased fatty acid supply from adipocytes to promote fatty acid oxidation in muscle and oxygen consumption at the whole-body level. The treatment temporarily increased hepatic triglyceride levels, which resolved with long-term Ab treatment. Blocking of ALK7 signals also decreased production of its ligand, growth differentiation factor 3, by downregulating S100A8/A9 release from adipocytes and, subsequently, IL-1β release from adipose tissue macrophages. These findings support the feasibility of potential therapeutics targeting ALK7 as a treatment for obesity and diabetes. American Society for Clinical Investigation 2023-02-22 /pmc/articles/PMC9977491/ /pubmed/36626233 http://dx.doi.org/10.1172/jci.insight.161229 Text en © 2023 Zhao et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Zhao, Min
Okunishi, Katsuhide
Bu, Yun
Kikuchi, Osamu
Wang, Hao
Kitamura, Tadahiro
Izumi, Tetsuro
Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
title Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
title_full Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
title_fullStr Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
title_full_unstemmed Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
title_short Targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
title_sort targeting activin receptor–like kinase 7 ameliorates adiposity and associated metabolic disorders
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977491/
https://www.ncbi.nlm.nih.gov/pubmed/36626233
http://dx.doi.org/10.1172/jci.insight.161229
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