SAT-113 Effects of an Eucaloric High-fat Diet Shown to Induce Reprometabolic Syndrome in Healthy Normal Weight Women

Abstract Disclosure: I.E. Schauer: None. K.N. Kuhn: None. K. Duffy: None. D.F. Yabroudi: None. B. Shiferaw: None. A.P. Bradford: None. N.F. Santoro: Novo Nordisk, Astellas Phama, Ansh Labs. Obesity in women is characterized by suppression of the hypothalamic-pituitary-ovarian axis resulting in subfertility, increased miscarriage, and adverse obstetrical outcomes. We termed this phenotype Reprometabolic Syndrome and have reproduced the endocrine dysfunction in normal weight (NW) women using an eucaloric high-fat diet (HFD). In this study, we examined the effects of the HFD on activity, sleep, body fat, insulin sensitivity and serum lipidomics. Methods:18 NW, healthy, eumenorrheic women (BMI 21.5 ± 1.9 kg/m2) were fed a one month, eucaloric diet containing 48% calories from fat. Measurements were obtained over 3 menstrual cycles: before, during and after the HFD. Fitbits monitored daily activity and sleep patterns, and body fat was determined by DXA. Insulin sensitivity was measured by a 2 stage, euglycemic, hyperinsulinemic clamp. Results were analyzed by linear mixed models. Serum lipidomes were determined by LC/MS using Metabolanalyst. Levels pre- and post-HFD were compared by Wilcoxon rank tests with FDR correction for multiple comparisons. Results: BMI was unchanged, and the diet had no significant impact on participants’ daily activity. Wake after sleep onset events decreased (2.56 ± 4 vs 2.00 ± 3.5, p=0.02) in response to the HFD, but sleep duration was not affected. Glucose infusion rates decreased post HFD (0.28 ± 0.1 vs 0.23 ±0.07, p=0.013) indicating development of insulin resistance. Insulin stimulated fatty acid clearance was not changed. A paradoxical but small decrease in % body fat (31.3 ± 5.6 vs 29.9 ± 5.6, p<0.01), total fat mass (18.5 ± 4.4 vs 17.7 ± 4.5 kg, p<0.01) and trunk fat (7.6 ± 2.6 vs 7.1 ± 2.6 kg, p<0.01) was observed in response to the HFD, in every participant. Visceral fat volume was also lower (308 ± 123 vs 287 ± 121, p=0.03). Lipidomics revealed HFD-induced changes in bioactive lipids implicated in regulation of metabolism, insulin sensitivity and the pathophysiology of obesity. Serum ceramides, lysophosphatidylethanolamine and lysophosphatidylinositol, potential mediators of insulin resistance, decreased following the HFD, while lysophosphatidylglycerol a regulator of glucose metabolism and insulin secretagogue, was increased. Changes in diacylglycerols and phospholipid mediators of cell signaling pathways were also observed. Conclusions: An eucaloric HFD that induced the relative hypogonadotropic hypogonadism characteristic of Reprometabolic Syndrome, resulted in insulin resistance and significant changes in bioactive lipids, despite no changes in BMI, activity or sleep duration. An unexpected decrease in body fat was observed, perhaps reflecting a counter regulatory response and metabolic flexibility in healthy women of normal weight. Further analysis of HFD dependent changes in insulin action and bioactive lipid profiles may provide mechanistic insights into the development of Reprometabolic syndrome in women with obesity. Presentation: Saturday, July 12, 2025