Genetic variation in the ACVR1C gene has been reported to be associated with decreased waist-to-hip ratio and risk of type 2 diabetes in humans. However, the effect of this naturally occurring variation on ALK7 function is unclear. Here we show that the human ACVR1C variant I195T, which displays the greatest effect on waist-to-hip ratio adjusted for body mass index, fails to signal in response to ALK7 ligands in a cell-based assay. This is consistent with observations in mice that impaired ALK7 signaling increases lipolysis and decreases adiposity. As further validation of ALK7 as an obesity target, we present data showing in the naturally occurring polygenic obese TSOD mouse a specific high affinity neutralizing monoclonal anti-ALK7 antibody (ALK7 mAb) dramatically decreases leptin levels, adipose macrophages and adiposity. The specificity of the ALK7 mAb is demonstrated by its lack of effect in genetically deficient ALK7 mice. These data along with the knowledge that normal Balb/c mice harbor a homozygous ALK7 nonsense mutation suggests that targeting ALK7 in humans should decrease obesity, susceptibility to diabetes and have minimal on-target negative consequences.
Y. Bu: None. M. Zhao: None. M. Fredericks: None. M. Cannell: None. Y. Dagon: None. C.A. Emdin: None. K. Okunishi: None. H. Wang: None. D. Sako: None. R. Castonguay: Employee; Self; Acceleron Pharma. R.N.V. Suragani: None. S. Kathiresan: Advisory Panel; Self; Regeneron Genetics Center. Consultant; Self; Color Genomics, Corvia Medical, Inc., Medgenome, Pfizer Inc. Stock/Shareholder; Self; Catabasis Pharmaceuticals, Maze Therapeutics, San THerapeutics, Verve Therapeutics. A. Grinberg: None. J. Knopf: Stock/Shareholder; Self; Acceleron Phama. R.S. Pearsall: Employee; Self; Acceleron Pharma, Inc. Stock/Shareholder; Self; Acceleron Pharma, Inc. R. Kumar: Employee; Self; Acceleron Pharma. T. Izumi: Research Support; Self; Acceleron Pharma.