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.

体脂分布是心血管疾病与代谢性疾病的可遗传风险因子。在人类中，罕见的抑制素βE（Inhibin beta E，INHBE，激活素E（activin E））功能丧失型变异体与较低的腰臀比及2型糖尿病的保护效应相关。在禁食状态与肥胖个体中，肝脏脂肪酸感知通路可促进INHBE的表达，但目前尚不明确该肝分泌因子（hepatokine）激活素E如何调控机体体态与能量代谢。本研究揭示激活素E是脂肪脂解的负反馈调控因子，可在禁食过程中抑制过度的脂肪分解。通过抑制β肾上腺素能受体激动剂诱导的脂解过程，激活素E可促进小鼠内脏脂肪堆积、脂肪细胞肥大，并加重脂肪组织功能异常。从机制层面而言，本研究证实激活素E通过ACVR1C对脂肪组织发挥调控作用：激活SMAD2/3信号通路，并抑制PPARG的靶基因表达。反之，敲除激活素E或ACVR1C可提升脂肪利用效率、降低体脂质量，并诱导体现健康脂肪组织功能的基因表达特征。本研究证实激活素E-ACVR1C轴可作为代谢调谐因子，在长期禁食过程中促进肝脏-脂肪组织串扰以维持脂肪总量，而该机制在肥胖个体中属于适应不良的病理状态。

实验整体设计：所有实验小鼠均为纯合C57BL/6NTac背景。针对普通饲料喂养条件下的过表达实验，我们通过AAV8载体分别向小鼠肝脏（Inhbe的内源表达位点）递送GFP对照载体或mInhbe过表达载体；对照组与Inhbe过表达组的样本量均为n=10。在功能缺失实验中，我们对普通饲料与高脂饲料喂养的野生型（WT）与Inhbe基因敲除（KO）小鼠进行表型分析，共分为4组。由于基因敲除动物的繁育数量有限，除普通饲料喂养的Inhbe KO组样本量为n=7外，其余各组样本量均为n=8。本研究对皮下脂肪组织与附睾脂肪组织均采用相同的实验分组处理。