AI Article Synopsis
- - Human studies suggest that activin C (Act-C) and its related components play a significant role in regulating fat distribution and metabolic health, indicating an interaction between liver and fat tissues.
- - Research showed that higher levels of circulating INHBC, a precursor to Act-C, are linked to lower body fat and increased risks for heart disease and fatty liver, while obesity and inflammation can raise INHBC levels.
- - The mechanisms involve Act-C's activation of a specific pathway in fat cells, which suppresses fat breakdown and may position INHBC as a potential target for treating conditions like atherogenic dyslipidemia and coronary artery disease.
Article Abstract
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 whether Act-C is an ALK7 ligand in human adipocytes. We used Mendelian randomization and in vitro studies in immortalized human abdominal and gluteal adipocytes. Circulating INHBC was causally linked to reduced lower-body fat, dyslipidemia, and increased risks of coronary artery disease (CAD) and nonalcoholic 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579406 | PMC |
| http://dx.doi.org/10.2337/db24-0168 | DOI Listing |
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