UC Riverside

The increase of obesity among US men and women of age 20-39 has resulted in social and economic consequences. Obese individuals are at increased risk of developing reproductive issues. Obese women present with menstrual irregularities, pregnancy complications, and infertility due to anovulation, while obese men present with low testosterone and sperm count. Mammalian reproduction is regulated by the hypothalamic-pituitary-gonadal axis. Gonadotropin releasing hormone (GnRH) neurons, scattered in the preoptic area of the hypothalamus, synthesize and secrete GnRH to act on the anterior pituitary to stimulate the synthesis and secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from gonadotrope cells. LH and FSH then act on the gonads to promote steroidogenesis and gametogenesis.

Nutritional status exerts their effects on reproduction by modulating GnRH levels. Previous studies have reported that metabolic pathways do not directly act on GnRH neurons. Pro-inflammatory cytokines, tumor necrosis factor (TNF-α), interleukin (IL)-6 and IL-1β, which are elevated in circulation and in the central nervous system (CNS), including the hypothalamus, of obese individuals, have been implicated in altering GnRH levels in rodents challenged with lipopolysaccharide, but how these cytokines mediate their effects is unknown and controversial. Thus, we investigated mechanisms by which inflammatory signals influence GnRH neurons and GnRH gene expression to provide insight into the etiology of obesity-induced infertility.

Our studies conducted in C57BL/6J mice demonstrated sex differences in the response to diet induced obesity with respect to inflammation and hypothalamic function. We proposed neuro-immune mechanisms of obesity induced impairment of reproduction whereby neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens.

We also investigated direct effects of neuroinflammation-induced cytokines on GnRH gene expression by examining signaling pathways and mechanisms in male mice and in GnRH expressing cell line, GT1-7 cells. We identified an additional mechanism of obesity induced impairment of reproduction where LIF directly repressed GnRH mRNA via cFOS, that is induced in GnRH and other neurons that are proximal to fenestrated capillaries of diet-induced obese male mice.