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Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice

Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (INHBE, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes INHBE express...

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Autores principales: Adam, Rene C., Pryce, Dwaine S., Lee, Joseph S., Zhao, Yuanqi, Mintah, Ivory J., Min, Soo, Halasz, Gabor, Mastaitis, Jason, Atwal, Gurinder S., Aykul, Senem, Idone, Vincent, Economides, Aris N., Lotta, Luca A., Murphy, Andrew J., Yancopoulos, George D., Sleeman, Mark W., Gusarova, Viktoria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410708/
https://www.ncbi.nlm.nih.gov/pubmed/37523551
http://dx.doi.org/10.1073/pnas.2309967120
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author Adam, Rene C.
Pryce, Dwaine S.
Lee, Joseph S.
Zhao, Yuanqi
Mintah, Ivory J.
Min, Soo
Halasz, Gabor
Mastaitis, Jason
Atwal, Gurinder S.
Aykul, Senem
Idone, Vincent
Economides, Aris N.
Lotta, Luca A.
Murphy, Andrew J.
Yancopoulos, George D.
Sleeman, Mark W.
Gusarova, Viktoria
author_facet Adam, Rene C.
Pryce, Dwaine S.
Lee, Joseph S.
Zhao, Yuanqi
Mintah, Ivory J.
Min, Soo
Halasz, Gabor
Mastaitis, Jason
Atwal, Gurinder S.
Aykul, Senem
Idone, Vincent
Economides, Aris N.
Lotta, Luca A.
Murphy, Andrew J.
Yancopoulos, George D.
Sleeman, Mark W.
Gusarova, Viktoria
author_sort Adam, Rene C.
collection PubMed
description Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (INHBE, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes INHBE expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing β-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E–ACVR1C as a metabolic rheostat promoting liver–adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals.
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spelling pubmed-104107082023-08-10 Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice Adam, Rene C. Pryce, Dwaine S. Lee, Joseph S. Zhao, Yuanqi Mintah, Ivory J. Min, Soo Halasz, Gabor Mastaitis, Jason Atwal, Gurinder S. Aykul, Senem Idone, Vincent Economides, Aris N. Lotta, Luca A. Murphy, Andrew J. Yancopoulos, George D. Sleeman, Mark W. Gusarova, Viktoria Proc Natl Acad Sci U S A Biological Sciences Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (INHBE, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes INHBE expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing β-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E–ACVR1C as a metabolic rheostat promoting liver–adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals. National Academy of Sciences 2023-07-31 2023-08-08 /pmc/articles/PMC10410708/ /pubmed/37523551 http://dx.doi.org/10.1073/pnas.2309967120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Adam, Rene C.
Pryce, Dwaine S.
Lee, Joseph S.
Zhao, Yuanqi
Mintah, Ivory J.
Min, Soo
Halasz, Gabor
Mastaitis, Jason
Atwal, Gurinder S.
Aykul, Senem
Idone, Vincent
Economides, Aris N.
Lotta, Luca A.
Murphy, Andrew J.
Yancopoulos, George D.
Sleeman, Mark W.
Gusarova, Viktoria
Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice
title Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice
title_full Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice
title_fullStr Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice
title_full_unstemmed Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice
title_short Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice
title_sort activin e–acvr1c cross talk controls energy storage via suppression of adipose lipolysis in mice
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410708/
https://www.ncbi.nlm.nih.gov/pubmed/37523551
http://dx.doi.org/10.1073/pnas.2309967120
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