Homeostatic Regulation of Estrus Cycle of Young Female Mice on Western Diet

The etiology of reproductive disorders correlates with weight gain in patients, but the link between reproduction, diet, and weight has been difficult to translate in rodents. As rates of childhood obesity and reproductive disorders increase, the need to study the effects of weight and diet on adolescent females is key. Previous studies show that female mice are resistant to high-fat diet–induced weight gain, but the mechanisms are unclear. Literature also suggests that ovarian function is essential to resistance in weight gain, as an ovariectomy leads to a weight-gaining phenotype similar to male mice on a high-fat diet. However, reproductive changes that occur in adolescent mice on high-fat diet have not been assessed. Here, we show that regulation of the estrus cycle via progesterone is critical to metabolic homeostasis in female mice on a high-fat diet. Female mice were put on high-fat diet or control diet for 12 weeks starting at 4 weeks of age. Every 4 weeks, their estrus cycle was tracked and fasting glucose was measured. We found that after 4 weeks on high-fat diet, there was no difference in weight between groups, but an increase in time spent in proestrus and estrus in mice on high-fat diet and an increase in serum progesterone during proestrus. These results show that intact females modulate their estrus cycle in response to a high-fat diet as a mechanism of homeostatic regulation of body weight, protecting them from metabolic abnormalities. Understanding the mechanisms behind this protection may yield therapeutic opportunities for treatment of reproductive disorders in adolescent female patients.