Hypothalamic Regulation of the Gonadal Axis and Roles of Leptin and Insulin in It

The hypothalamic-pituitary-gonadal (HPG, gonadal) axis is responsible for regulating reproductive functions, and its activity is regulated by numerous hormones, including leptin and insulin. Their primary targets are hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), which regulate secretion of gonadotropins and, thus, control puberty and fertility. The key function of leptin and insulin in hypothalamus is to mediate functional relationship between the energy availability and expenditure, on the one hand, and reproduction, which is determined, in part, by the activity of GnRH neurons, on the other. The effects of leptin and insulin on the GnRH neurons are typically indirect and mediated through other hypothalamic neurons, providing more specialized, multi-level regulation of their activity. The targets of leptin and insulin are various types of kisspeptin (Kiss1)-expressing neurons, as well as neurons expressing proopiomelanocortin (POMC, a precursor of anorexigenic melanocortin peptides), and the orexigenic factors - agouti-related peptide (AgRP) and neuropeptide Y (NPY). The Kiss1- and POMC-expressing neurons positively regulate GnRH-neurons, while the AgRP/NPY neurons are primarily involved in their negative regulation. The effects of leptin and insulin on the Kiss1-, POMC-, and AgRP/NPY-neurons, and consequently on the GnRH-neurons and the HPG axis, depend on physiological state of the organism, including its metabolic status, puberty, and gender. These effects are significantly altered in obesity and type 2 diabetes mellitus, thereby contributing to etiology and pathogenesis of the associated reproductive disorders. This review focuses on the current state of knowledge on the roles of insulin- and leptin-mediated regulation of the hypothalamic HPG axis in health and disease, as well as on the unresolved issues in this area. Understanding molecular basis of this regulation opens up broad prospects for the development of new pharmacological approaches to restoring reproductive function in obesity and diabetes.