Journal article
Bidirectional Mendelian randomization highlights causal relationships between circulating INHBC and multiple cardiometabolic diseases and traits
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
-
-
(Preview, Accepted manuscript, pdf, 1.6MB, Terms of use)
-
(Supplementary materials, zip, 2.2MB, Terms of use)
-
- Publisher copy:
- 10.2337/db24-0168
Authors
+ British Heart Foundation
More from this funder
- Funder identifier:
- https://ror.org/02wdwnk04
- Grant:
- FS/SCRF/24/32029
- FS/16/45/32359
- Publisher:
- American Diabetes Association
- Journal:
- Diabetes More from this journal
- Volume:
- 73
- Issue:
- 12
- Pages:
- 2084-2094
- Place of publication:
- United States
- Publication date:
- 2024-09-16
- Acceptance date:
- 2024-09-05
- DOI:
- EISSN:
-
1939-327X
- ISSN:
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0012-1797
- Pmid:
-
39283655
- Language:
-
English
- Pubs id:
-
2031085
- Local pid:
-
pubs:2031085
- Source identifiers:
-
W4402580303
- Deposit date:
-
2026-02-25
- ARK identifier:
Terms of use
- Copyright holder:
- American Diabetes Association
- Copyright date:
- 2024
- Rights statement:
- © 2024 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
- Notes:
- This is the accepted manuscript version of the article. The final version is available online from American Diabetes Association at https://dx.doi.org/10.2337/db24-0168
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