CD59 drives diet-induced obesity and glucose intolerance, insulin resistance, and metabolic dysfunction-associated steatotic liver disease.

CD59 is known as a membrane-bound regulator of the complement system that prevents the formation of the membrane attack complex on host cells. Here we report the metabolic consequences of CD59a knockout (KO) in mice fed a high-fat diet (HFD). Mice lacking CD59a were protected from the development of insulin resistance, glucose intolerance, hyperinsulinemia, obesity, and fatty liver. Mutants fed an HFD had elevated adiponectin levels and reduced leptin levels in plasma. Data from metabolic cages suggested decreased appetite and an increase in voluntary wheel activity in mutants. Liver transcriptome analysis showed a marked decrease of inflammatory and fibrotic pathways in CD59a KO mice on an HFD, and plasma and liver metabolomics were remarkably similar, indicating close correspondence between systemic and hepatic metabolic profiles. In conclusion, we uncover a noncanonical role of CD59a in the development of diet-induced insulin resistance, hyperinsulinemia, glucose intolerance, and obesity.