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

Author:

Adam Rene C.1,Pryce Dwaine S.1,Lee Joseph S.1,Zhao Yuanqi1,Mintah Ivory J.1,Min Soo1,Halasz Gabor1ORCID,Mastaitis Jason1,Atwal Gurinder S.1,Aykul Senem1,Idone Vincent1,Economides Aris N.1ORCID,Lotta Luca A.1,Murphy Andrew J.1,Yancopoulos George D.1,Sleeman Mark W.1ORCID,Gusarova Viktoria1

Affiliation:

1. Regeneron Pharmaceuticals, Tarrytown, NY 10591

Abstract

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.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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