The sex dependent effects of a high fat diet on metabolic health in middle age mice

The intake of a diet high in saturated fats (HFD) increases the risk of developing adverse health effects affecting the cardiovascular and metabolic systems, by inducing physiological changes, such as increase of reactive oxygen species, increase of proinflammatory cytokines, and overactivation of peroxisomal beta-oxidation. These changes disrupt glucose and metabolic homeostasis, causing metabolic dysregulation. However, the onset of the HFD may alter the development of metabolic dysregulation in a sex dependent way; therefore, we sought to determine whether these relationships vary by sex. 29 C57BL-6J mice (16 male and 13 female) were fed either a normal chow diet (18% kcal from fat) or a HFD (60% kcal from fat) from 6 months of age until 10 months of age. During the duration of the experiment, body weight and food consumption were measured weekly. At an age of 9 months (middle age), a glucose tolerance test (GTT), and body composition assessment (Echo MRI) were measured. At 10 months of age, mice were euthanized; blood plasma and liver samples were collected at this time to assess metabolic health. Plasma metabolic panel (ELISA) and liver oxidative stress (rtPCR) were analyzed. Both HFD male and female groups saw an increase in body weight. The HFD female group had a significantly greater increase in body weight after 8 weeks on a HFD that was maintained for the remainder of the study. HFD in females increased percent body fat (p<0.001) and decreased lean body mass (p<0.001). Both HFD male and female mice had an increase in time to process a bolus of glucose during GTT, indicating glucose intolerance, with males showing greater glucose intolerance than HFD female mice (p<0.001). Sex differences were also noted in the plasma metabolic panel, and in the liver mRNA expression of oxidative markers. These findings suggest that there are sex differences in the development of metabolic dysregulation with a high fat diet occurring in midlife. R01 NS117754 T32 AG052375 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.