<b>Bidirectional Mendelian randomization highlights causal relationships between circulating INHBC and multiple cardiometabolic diseases and traits.</b>

<p dir="ltr"><b>Abstract</b></p><p dir="ltr">Human genetic and transgenic mouse studies have highlighted a potential liver-adipose tissue endocrine axis, involving activin C (Act-C) and/or Act-E and ALK7, influencing fat distribution and systemic metabolism. We investigated the bidirectional effects between circulating INHBC, which homodimerizes into Act-C, and adiposity traits, insulin resistance, inflammation, and cardiometabolic disease risk. Additionally, we examined if Act-C is an ALK7 ligand in human adipocytes. We used<b> </b>Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidaemia, and increased risks of coronary artery disease (CAD) and non-alcoholic fatty liver disease (NAFLD). Conversely, upper-body fat distribution, obesity, hypertriglyceridemia, subclinical inflammation, and type 2 diabetes positively impacted plasma INHBC levels. Mechanistically, an atherogenic lipid profile may partly explain the INHBC-CAD link, while inflammation and hypertriglyceridemia may partly explain how adiposity traits affect circulating INHBC. Phenome-wide Mendelian randomization showed weak causal relationships between higher plasma INHBC and impaired kidney function and higher gout risk. In human adipocytes, recombinant Act-C activated SMAD2/3 signaling via ALK7 and suppressed lipolysis. In summary, INHBC influences systemic metabolism by activating ALK7 in adipose tissue and may serve as a drug target for atherogenic dyslipidemia, CAD, and NAFLD.</p><p><br></p><p><br></p><p dir="ltr"><b>Article Highlights</b></p><p dir="ltr">· <i>We explored the bidirectional relationships between circulating INHBC and cardiometabolic traits and diseases, and investigated whether activin C, an INHBC homodimer, acts as an ALK7 ligand in human adipocytes.</i></p><p><br></p><p dir="ltr">· <i>Elevated circulating INHBC was linked to dyslipidemia, increased coronary artery disease and non-alcoholic fatty liver disease risk. Conversely, upper-body obesity, hypertriglyceridemia, inflammation, and diabetes increased circulating INHBC, potentially creating a vicious cycle. Activin C</i><i> </i><i>activated ALK7 signaling in adipocytes and suppressed lipolysis.</i></p><p><br></p><p dir="ltr">· <i>INHBC is a novel hepatokine influencing systemic metabolism and a potential drug target for cardiometabolic diseases.</i></p>