UC Riverside

Infertility, affecting 1 in 8 couples globally, is influenced by various factors such as delayed motherhood, poor dietary habits, genetic disorders, environmental endocrine disruptors, and obesity. Reproduction, orchestrated by gonadotropin-releasing hormone (GnRH) neurons from the hypothalamus, involves the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary, stimulating steroidogenesis and gametogenesis in the gonads. GnRH neuron pulsatile secretion requires regulation by afferent neurons, primarily kisspeptin, and potentially GABAergic signals that activate GnRH neurons.

Genetic factors, specifically mutations in the Fragile X messenger ribonucleoprotein 1 gene (FMR1), contribute to fertility issues, particularly premature ovarian failure (POF) in women under 40. Using the Fmr1KO mouse model, we determined elevated gonadotropin hormone levels, increased GABAergic innervation of GnRH neurons, and higher sympathetic innervation in the ovaries of Fmr1KO mice. Since GABA is excitatory to GnRH neurons this may contribute to an increase in LH pulse frequency. Ovariectomy experiments revealed that the hypothalamus drives high LH, while increased FSH, is dependent on the ovaries and possibly influenced by heightened innervation.

Diet-induced obesity (DIO), affecting a third of the global population, induces hypogonadism in obese men, characterized by low testosterone and sperm count. Studying reproductive dysfunction in mice using the DIO model with a high-fat diet demonstrated lower sperm numbers and testosterone levels, aligning with observations in humans. Investigation of pituitary responsiveness to GnRH revealed comparable LH secretion in control and obese males, suggesting an unaffected pituitary response. Control mice showed an expected increase in LH after chemogenetic activation of kisspeptin neurons. Unexpectedly, activation of kisspeptin neurons caused a higher LH fold change in obese males, indicating suppressed kisspeptin neurons in DIO. Kisspeptin neurons are activated by proopiomelanocortin (POMC) neurons through α-melanocyte-secreting hormone (α-MSH) and its receptor, melanocortin 4 receptor (MC4R), and their pulse generation is synchronized by glutamate. Investigation into these components revealed a lower LH fold change response in DIO, suggesting that DIO leads to kisspeptin neuron suppression due to dysregulation in the crosstalk between the feeding and reproductive circuit. These studies uncover a mechanism contributing to reproductive dysregulation in women with FMR1 mutations and obesity-mediated hypogonadism in males.