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

Abstract

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 LDLrmice. Male GDF15LDLrmice 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 LDLrmice than in females but were comparable to those measured in ovariectomized LDLrfemales. Importantly, ovariectomy in females induced metabolic and vascular phenotypes similar to those of GDF15LDLrmales, 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.