Active Diabetes, Hormones & Metabolism Cancer

Deciphering the role of ALK7 in the regulation of fat distribution and cardiometabolic disease risk

Funder BHF Charity-funded
Recipient organisation University of Oxford
Funding £1.3M
Period Oct 2024 — Sept 2029

In plain English

AI plain-English summary

Where fat sits on the body matters more for heart health than how much fat there is, and this project will investigate a newly discovered genetic switch that determines whether fat is stored safely under the skin or dangerously around the organs. People with the same total body fat can have very different risks of heart disease and type 2 diabetes, depending on whether their fat accumulates in the abdomen or the hips and thighs. Recent genetic studies have identified rare variants in two genes—*ACVR1C* and *INHBE*—that protect carriers from coronary heart disease by shifting fat storage toward healthier depots. The researcher leading this fellowship will study human volunteers carrying these protective mutations, examine how the corresponding proteins (ALK7 and activin E) control fat cell behaviour in the lab, and screen for drugs that block ALK7 activity in human fat cells. If successful, the work could deliver a drug-screening platform and candidate compounds that mimic the protective fat-distribution pattern, offering a fundamentally new way to reduce cardiometabolic risk. The project is primarily fundamental science—uncovering the molecular wiring that governs where fat goes—but the same pathway could eventually be targeted to prevent heart attacks and diabetes in the general population.

View original technical description
Fat distribution is an independent cardiometabolic risk factor but its molecular and cellular determinants remain unclear. I aim to uncover new mechanisms governing regional adiposity through human genetics and clinical investigations. As an example, GWAS have revealed that loss-of-function variants in ACVR1C and INHBE, encoding activin receptor-like kinase 7 (ALK7) and activin E (Act-E), which are expressed in adipocytes and hepatocytes respectively, are linked to favourable fat distribution and protection from coronary heart disease and/or type 2 diabetes. These findings also raise the possibility of a liver-adipose tissue, Act-E-ALK7 endocrine axis, regulating systemic metabolism. This proposal will explore the adipose and cardiometabolic phenotype of ACVR1C and INHBE loss-of-function mutation carriers; investigate the consequences of ACVR1C and INHBE loss- and gain-of-function on depot-specific human adipocyte biology; undertake a screen for pharmacological ALK7 inhibitors in human adipocytes. The fellowship will deliver (1) molecular mechanisms regulating adipocyte function, (2) an optimised drug-screening platform and potentially novel drugs to treat/prevent cardiometabolic disorders, (3) a template for future work on other gene targets regulating fat distribution. The project will additionally endow me with training in human physiological, cardiac imaging, and drug screening studies, and facilitate my transition to an international leader in adipose tissue biology.

View the original record at the funder ↗

Researchers

Constantinos Christodoulides (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Dissecting the role of Wnt signalling in the regulation of fat distribution and susceptibility to cardiometabolic disease
Coupling novel non-invasive imaging methods and new gene therapies to detect and treat type 2 diabetes
Understanding the role of lipid metabolism in heart failure
KLF14, adipose dysfunction, insulin resistance and type 2 diabetes: from genetic discovery to biological mechanisms and translation.
Identification, functional characterization and in vivo mouse CRISPR transgene modeling of novel human genome wide association variants for metabolic

Original classification

None

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.