Effects of Ketogenic Diet on Reproductive Health in Obese Mice
Abstract
Obesity negatively impacts overall health and reproduction in females and males by disrupting the hypothalamic-pituitary-gonadal axis and other physiological functions essential for fertility. The leptin-deficient obese mouse (ob/ob) is a well-established model of obesity-associated reproductive dysfunction and infertility, characterized by hyperglycemia, hypogonadism, absent estrous cycles in females and reduced sperm production in males. The ketogenic diet (KD), a high-fat, low-carbohydrate diet, has multiple metabolic effects which may be linked to reproductive function. Data on KD effects on ob/ob mouse reproduction are limited; therefore, this study was designed to evaluate the potential effects of a ketogenic diet on metabolic and reproductive parameters in obese female and male mice. Female and male ob/ob mice were fed a standard diet (SD) or ketogenic diet (KD) from five until twelve weeks of age. C57 wild type mice on SD were also included as an additional control group. At the end of the seven-week dietary intervention, mice were euthanized for collection of blood and tissues to evaluate metabolic and reproductive outcomes. Obese mice showed significantly increased body weight, adipose tissue, high blood glucose levels, and reproductive impairments. Females showed smaller uterine size and altered uterine morphology. In males, obesity reduced testes and epididymis weight, and sperm production and quality. KD did not reduce body weight or adipose tissue but significantly reduced blood glucose levels in both sexes. Interestingly, KD partially restored estrogen responsiveness in females. In males, partially restored testicular sperm production and epididymal sperm maturation, including daily sperm production (DSP) and transit time. These findings suggest that the altered metabolic profile of obese mice on a ketogenic diet may improve estrogen activity in the female uterus, and testicular sperm production and epididymal sperm maturation in males. Importantly, these improvements occurred independently from changes in body weight or the presence of leptin, as ob/ob mice on a ketogenic diet lack leptin and remained obese.
