Bidirectional Mendelian Randomization Highlights Causal Relationships Between Circulating INHBC and Multiple Cardiometabolic Diseases and Traits

Diabetes, vol. 73, pp. 2084–2094

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.

Authors 9

1. Nellie Y. Loh

   University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism

   Affiliation as printed

   1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K

2. Daniel B. Rosoff

   National Institutes of Health · University of Bristol · University of Oxford · National Institute on Alcohol Abuse and Alcoholism · Oxford Centre for Diabetes, Endocrinology and Metabolism · MRC Integrative Epidemiology Unit

   Affiliation as printed

   1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K

   2National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD

   3MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K

3. Rebecca Claire Richmond

   University of Bristol · University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism · MRC Integrative Epidemiology Unit

   Affiliation as printed

   1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K

   3MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K

4. Raymond Noordam Aachen 4Department of Internal Medicine Section of Gerontology and Geriatrics

   Leiden University Medical Center

   Affiliation as printed

   4Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

5. George Davey Smith

   University of Bristol · MRC Integrative Epidemiology Unit

   Affiliation as printed

   3MRC Integrative Epidemiology Unit, University of Bristol, Bristol, U.K

6. David Ray

   John Radcliffe Hospital · University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism

   Affiliation as printed

   1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K

   5NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K

7. Fredrik Karpe

   John Radcliffe Hospital · University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism

   Affiliation as printed

   1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K

   5NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K

8. Falk W. Lohoff

   National Institutes of Health · National Institute on Alcohol Abuse and Alcoholism

   Affiliation as printed

   2National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD

9. Constantinos Christodoulides corresponding

   John Radcliffe Hospital · University of Oxford · Oxford Centre for Diabetes, Endocrinology and Metabolism

   Affiliation as printed

   1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K

   5NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K