Sex‐Specific Temporal Differences in Glucose Homeostasis in CD‐1 Mice Fed Diets with Distinct Fatty Acid Profiles

Abstract

Sexual dimorphism in energy metabolism and glucose homeostasis is well documented. The extent to which specific nutrients differentially impact the sexes is less clear. We examined the sex‐specific effects of dietary fat type on somatic growth and metabolic responses over 9 months. Sixty male and female outbred CD‐1 mice (n = 10/group) were fed isoenergetic high‐fat diets (40% kcal fat) containing either (1) 100% American diet fat (Control, CON group, reflecting the average fatty acid profile consumed in the United States that has been linked to dysmetabolism, increased inflammation, and type 2 diabetes), (2) 70% CON fat + 30% butter oil (BO group), and (3) 70% CON fat + 30% fish oil (FO group) for 9 months. Standard physiological measurements and glucose homeostatic assays (i.e., intraperitoneal insulin and glucose tolerance tests, ITT and GTT, respectively) were performed at regular intervals (3, 6, and 9 months). There were no differences in feed intake after 9 months among the diet groups in males and females. The BO diet, however, resulted in a higher weight gain in both male and female mice compared to their respective CON group. Fed blood glucose levels did not differ among the diet groups in both sexes at 3 and 6 months, but by 9 months, both male and female FO mice tended to have the lowest blood glucose concentrations compared to CON mice (P=0.067). GTT demonstrated that in both sexes at 3 months, the BO groups exhibited reduced glucose tolerance compared to their CON groups (P<0.05) but by 6 months there were no longer differences among the diet groups. Furthermore, ITT showed that male mice exhibited reduced insulin sensitivity in the BO group compared to the CON group at 3 months (P<0.05), whereas female BO mice displayed a greater insulin sensitivity compared to the FO group (P<0.05). By 6 months, there were no differences in insulin sensitivity between the female diet groups, while male mice fed FO showed enhanced insulin sensitivity compared to the CON and BO groups (P<0.05). By 9 months, male and female BO mice had reduced insulin sensitivity compared to the FO mice (P<0.05). While the FO diet generally improved metabolic outcomes in both sexes, from the outset, the BO diet led to higher weight gain and worsened glucose tolerance and insulin resistance by the end of the study. Nonetheless, at the 3‐month time‐point, male and female mice on the BO diet exhibited transiently disparate responses to ITT. Hence, in the backdrop of a diet rich in American diet fats, dairy‐ vs. marine‐derived lipids impact metabolic outcomes in a temporally distinct, sex‐specific manner.