Activin E controls body fat distribution 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 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 negative feedback regulator of adipose lipolysis that restrains excessive fat breakdown during fasting. By suppressing ß-agonist-induced lipolysis, activin E promotes visceral fat accumulation, 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 increases fat utilization, lowers adiposity and drives gene signatures indicative of healthy adipose function. Our studies identify activin E-ACVR1C as metabolic rheostat promoting liver-adipose crosstalk to preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals. Overall design: All mice are on 100% C57BL/6NTac background. For over-expression studies on chow diet, mice were transduced with AAV8 constructs driving either GFP control or mInhbe expression in livers (where Inhbe is endogenously expressed). n=10 for control and Inhbe over-expression groups.  For loss of function, we have phenotyped WT vs Inhbe KO mice on chow vs. high fat diet (4 groups in total). Due to limited availability of KO animals, we have n=8 for all groups, except n=7 for Inhbe KO on chow diet. We have the same treatment groups for both subcutaneous adipose and epididymal adipose tissues.