Sex steroid hormones drive dimorphic responses in GDF15-deficient mouse models of cardiometabolic diseases

Growth Differentiation Factor 15 (GDF15) is recognized as a biomarker of cardiovascular disease, but its role in atherosclerosis remains unclear. Here, we investigated the role of GDF15 in atherosclerosis by crossing GDF15-deficient mice with LDLr^-/- mice. Male GDF15^-/- LDLr^-/- mice fed a Western diet developed less atherosclerotic lesions than littermate controls despite exhibiting a pro-obesogenic phenotype, whereas GDF15 deficiency did not affect metabolism or lesion development in females. Plasma GDF15 levels were higher in male LDLr^-/- mice than in females but were comparable to those measured in ovariectomized LDLr^-/- females. Importantly, ovariectomy in females induced metabolic and vascular phenotypes similar to those of GDF15^-/- LDLr^-/- males, while gonadectomy in males had no effect, emphasizing the role of female steroid hormones in GDF15-related sexual dimorphism. These findings highlight the sex-specific effects of GDF15 on metabolism and atherosclerosis, underscoring the importance of sex and hormonal status in cardiometabolic disease management.