As the onset of reproductive disorders occur in younger patients, correlations to the western diet (high in fats and sugars) and adolescent obesity leads us to focus on these factors’ effects on reproductive health. Early reproductive disorders such as adolescent polycystic ovarian syndrome present with insulin resistance, elevated triglycerides, and ovarian dysfunction . Thus, understanding the mechanisms that regulate whole-body metabolism is an important aspect of mitigating symptoms of reproductive disorders .
Historically, female mice were not used in reproductive and metabolic studies because they fail to present the long-term metabolic abnormalities consistent with obesity . Recent evidence has shown that ovarian hormones play an important role in this phenomenon, as removal of the ovaries prior to a high-fat diet (HFD; >40% kcal from fats) results in similar rates of weight gain as in males. Studies that assess sex hormone levels in mice on HFD follow them (12 weeks+) and have not examined acute effects of western diet on reproductive processes . The pathways linking reproductive dysfunction and HFD consumption are likely due to dietary components such as saturated fatty acids, cholesterol, and glucose metabolites . Short-term consumption of HFD may promote increased bioavailability of exogenous cholesterol and increase production of steroid hormones in females, negatively influencing reproductive physiology. Understanding the mechanisms of altered reproductive physiology due to consumption of western diet in female rodents presents an opportunity to target early therapeutic windows.
Our laboratory has shown that young female mice have acute changes in estrous cycling and serum progesterone when fed a western diet (45% kcal from fat) without significant increases in body weight or fasting glucose levels . Estrous cycling was tracked via vaginal cytology, twice per day. After 4 weeks on western diet, we observed longer follicular phases and shorter luteal phases in females on a HFD compared to normal chow despite equal cycle lengths. These changes were not observed after 8 or 12 weeks, when animals began to show more weight gain. Interestingly, serum progesterone was increased during proestrus after 4 weeks of a HFD, indicating that progesterone production may play a role in protection from weight gain and cycle changes. Other studies show impaired cycling and little to no shifts in sex hormones, particularly estradiol, but these effects were not assessed as early [4, 5]. Assessment of estrous cycling is typically conducted once and compares general cyclicity and representative cycles, which may not capture subtle shifts in cycling patterns. Ours was the first study to assess estrous cycling longitudinally across multiple months and compare time spent in each phase quantitatively.
Historically, the effects of short-term increases in caloric intake from a HFD had not been considered but can be an important factor in the etiology of reproductive disorders. Mitigating the negative effects of HFD on ovarian function is likely an essential aspect of therapeutics for infertility when developed during adolescence. Examining interactions between sex hormones, metabolism, and reproduction will aid in understanding of how these systems interact in a sex-specific fashion.
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This work was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke grant number K22NS096030 (to M.D.B.), the University of Texas System STARS program research support grant (to M.D.B.), the American Pain Society Future Leaders Grant (to M.D.B.), and the Rita Allen Foundation Grant (to M.D.B.).
The authors declare no competing interests.
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Lenert, M.E., Burton, M.D. Acute effects of a high-fat diet on estrous cycling and body weight of intact female mice. Neuropsychopharmacol. 47, 418–419 (2022). https://doi.org/10.1038/s41386-021-01164-6