Effects of a Reprometabolic Syndrome-Inducing Eucaloric High-Fat Diet on Insulin Sensitivity, Body Composition, the Lipidome, and the Microbiome

Background: We previously demonstrated recapitulation of the relative hypogonadotropic hypogonadism of obesity, the Reprometabolic Syndrome (RMS), in women of normal BMI with a one-month high-fat, eucaloric diet (HFD). Objective: Assess effects of HFD on sleep, body composition and lifestyle and metabolic secondary outcomes and correlate insulin sensitivity changes with the RMS. Methods: A total of 18 normally cycling women aged 18–38 with BMI 18–24 kg/m2 were enrolled for a four-month study including a eucaloric HFD (48% calories from fat) for one menstrual cycle. Activity, sleep, body composition, and the lipidome were measured in all participants. Fecal microbiome was analyzed in the last nine participants, and insulin sensitivity by two-stage hyperinsulinemic euglycemic clamp was measured before and after HFD in 15 participants. Results: Relative to the pre-diet period, BMI, activity and sleep measures did not change, except for waking after sleep onset (WASO), which appeared to decrease during and post HFD. DXA revealed statistically significant decreases in total percent fat, total fat mass, visceral fat volume, and trunk fat volume. Whole-body insulin sensitivity decreased with the HFD while adipocyte insulin sensitivity was unaffected. Insulin sensitivity changes did not correlate with change in gonadotropins or response to gonadotropin releasing hormone (GnRH). Multiple significant changes in plasma lipids were observed, including increased ceramides and glucosylceramides. Microbiome analysis revealed increased microbial diversity. Conclusions: A one-month eucaloric HFD that induced RMS in normal-weight, reproductive-aged women also induced whole-body insulin resistance (IR) and multiple lipidomics changes potentially associated with IR. These changes in IR occurred despite overall stable activity, BMI and sleep, but did not correlate with the HPO axis defects. The unexpected decrease in body fat and increase in microbial diversity may be related to specific dietary elements of the HFD.