Inherited Metabolic Memory of High‐Fat Diet Impairs Testicular Fatty Acid Content and Sperm Parameters

Scope Exposure to a high‐fat diet (HFD) from early‐life is associated with a testicular metabolic signature link to abnormal sperm parameters up to two generations after exposure in mice. Hereby, this study describes a testicular lipid signature associate with “inherited metabolic memory” of exposure to HFD, persisting up to two generations in mice. Methods and Results Diet‐challenged mice (n = 36) are randomly fed after weaning with standard chow (CTRL); HFD for 200 days or transient HFD (HFDt) (60 days of HFD + 140 days of standard chow). Subsequent generations (36 mice per generation) are fed with chow diet. Mice are euthanized 200 days post‐weaning. Glucose homeostasis, serum hormones, testicular bioenergetics, and antioxidant enzyme activity are evaluated. Testicular lipid‐related metabolites and fatty acids are characterized by 1H‐NMR and GC‐MS. Sons of HFD display impaired choline metabolism, mitochondrial activity, and antioxidant defenses, while grandsons show a shift in testicular ω3/ω6 ratio towards a pro‐inflammatory environment. Grandsons of HFDt raise 3‐hydroxybutyrate levels with possible implications to testicular insulin resistance. Sperm counts decrease in grandsons of HFD‐exposed mice, regardless of the duration of exposure. Conclusion HFD‐induced “inherited metabolic memory” alters testicular fatty acid metabolism with consequences to sperm parameters up to two generations. Ancestral exposure to high‐fat diet affects testicular lipid composition and function up to two generations. Sons of HFD mice have abnormal testicular choline metabolism, mitochondrial activity, and antioxidant activity. Grandsons of HFD have ω3/ω6 ratio favorable to pro‐inflammatory environment, whereas grandsons of HFDt have elevated 3‐hydroxybutyrate. Both grandsons of HFD and HFDt have lower sperm counts than grandsons of CTRL.