Peripheral and hypothalamic metabolic responses to diet-induced obesity in male and female CD-1 mice

Abstract Obesity, a chronic condition influenced by ultra-processed foods, has emerged as a global health crisis. To encompass human genetic diversity and metabolic sex differences, this research assessed peripheral and central metabolic responses to a high-fat, high-sucrose diet (HF-HSD) in outbred CD1 mice of both sexes. Male and female mice were fed either a standard diet or an HF-HSD (44% fat, 40% sucrose) for 17 weeks. Body weight gain was similar between sexes on the HF-HSD, despite higher caloric intake in males. Both sexes accumulated adipose tissue; however, females exhibited a higher adiposity index and greater visceral fat accumulation. Conversely, males displayed more severe metabolic deterioration, with higher serum glucose, insulin, HOMA-IR, and an adverse lipid profile (elevated cholesterol, triglycerides, and LDL; lower HDL). Leptin increased in both sexes, whereas adiponectin significantly decreased only in HF-HSD females. Histological evaluation of the liver showed macrovesicular hepatic steatosis in females, which was more prominent than the micro/macrovesicular pattern observed in males. Centrally, the HF-HSD induced marked hypothalamic oxidative stress, evidenced by elevated TBARS and NO and reduced SOD and CAT activities, affecting both sexes similarly. In conclusion, the HF-HSD CD1 mouse model effectively recapitulates key features of diet-induced obesity, revealing that although female sex hormones confer peripheral metabolic protection, they do not prevent diet-induced central hypothalamic oxidative damage. This robust outbred platform offers direct translational relevance to global food health crises by modeling the genetic diversity of human populations.