CDB25:0003809 INHBE — ACVR1C
Experimentally validated in Human, Mouse; Orthology-inferred in Human, Rat, Chicken, Macaque, Pig, Dog, Cow, Chimp, Horse, Marmoset, Sheep, Mouse
Title
Journal:; Year Published:
Abstract
Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice.
Proceedings of the National Academy of Sciences of the United States of America, 2023; PubMed, Mus Musculus Inhbe — Mus Musculus Acvr1c
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.
Activin E is a transforming growth factor β ligand that signals specifically through activin receptor-like kinase 7.
The Biochemical journal, 2024; PubMed, Homo sapiens INHBE — Homo sapiens ACVR1C
ABSTRACT: Activins are one of the three distinct subclasses within the greater Transforming growth factor β (TGFβ) superfamily. First discovered for their critical roles in reproductive biology, activins have since been shown to alter cellular differentiation and proliferation. At present, members of the activin subclass include activin A (ActA), ActB, ActC, ActE, and the more distant members myostatin and GDF11. While the biological roles and signaling mechanisms of most activins class members have been well-studied, the signaling potential of ActE has remained largely unknown. Here, we characterized the signaling capacity of homodimeric ActE. Molecular modeling of the ligand:receptor complexes showed that ActC and ActE shared high similarity in both the type I and type II receptor binding epitopes. ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. In mature murine adipocytes, ActE invoked a SMAD2/3 response via ALK7, like ActC. Collectively, our results establish ActE as a specific signaling ligand which activates the type I receptor, ALK7.