High-Fat Diet and Metabolic Diseases: A Comparative Analysis of Sex-Dependent Responses and Mechanisms.

Sex differences in metabolic disorders and susceptibility to chronic diseases induced by a high-fat diet (HFD) exhibit significant dimorphic characteristics. A long-standing male-centric bias in medical research and healthcare, predominantly focused on male physiological traits, has hindered the precise treatment of metabolic diseases in female patients. A comprehensive understanding of sex differences in metabolic health and their underlying mechanisms is crucial for advancing personalized health promotion and precision medicine. This review systematically elucidates sex-specific manifestations in high-fat diet-associated metabolic disorders: males predominantly develop visceral adiposity, insulin resistance, and dyslipidemia, accompanied by a significantly elevated risk of cardiovascular and metabolic syndromes. Premenopausal females maintain metabolic homeostasis through the estrogen-mediated optimization of glucose and lipid metabolism and oxidative stress buffering mechanisms, whereas postmenopausal-phase females experience dramatic metabolic vulnerability due to z loss of protective barriers. Furthermore, we emphasize multidimensional mechanistic interpretations of metabolic sexual dimorphism from perspectives including sex chromosome complement, sex hormone signaling pathways, epigenetic regulation, gut microbiota composition, and neuroendocrine dimorphism. This work provides critical theoretical foundations for rectifying unisex research paradigms and optimizing sex-specific early warning systems and precision therapeutic strategies for metabolic disorders.