{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:06:21Z","timestamp":1791947181622,"version":"4.3.4"},"reference-count":40,"publisher":"American Diabetes Association","issue":"12","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/16\/45\/32359"],"award-info":[{"award-number":["FS\/16\/45\/32359"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/SCRF\/24\/32029"],"award-info":[{"award-number":["FS\/SCRF\/24\/32029"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>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\u00a0vitro 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Article Highlights<\/jats:title>\n               <\/jats:sec>","DOI":"10.2337\/db24-0168","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T15:37:55Z","timestamp":1726501075000},"page":"2084-2094","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":14,"title":["Bidirectional Mendelian Randomization Highlights Causal Relationships Between Circulating INHBC and Multiple Cardiometabolic Diseases and Traits"],"prefix":"10.2337","volume":"73","author":[{"given":"Nellie Y.","family":"Loh","sequence":"first","affiliation":[{"name":"1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of 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U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7801-809X","authenticated-orcid":false,"given":"Raymond","family":"Noordam","sequence":"additional","affiliation":[{"name":"4Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George Davey","family":"Smith","sequence":"additional","affiliation":[{"name":"3MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ray","sequence":"additional","affiliation":[{"name":"1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K."},{"name":"5NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2751-1770","authenticated-orcid":false,"given":"Fredrik","family":"Karpe","sequence":"additional","affiliation":[{"name":"1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K."},{"name":"5NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Falk W.","family":"Lohoff","sequence":"additional","affiliation":[{"name":"2National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5154-0785","authenticated-orcid":false,"given":"Constantinos","family":"Christodoulides","sequence":"additional","affiliation":[{"name":"1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 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