Neuroendocrine regulation of the hypothalamus-pituitary-gonad (HPG) axis

Research in this laboratory investigates the interplay between metabolism and reproductive physiology. Poor nutrition and obesity are linked to multiple hormonal and reproductive disorders. For example, in girls, obesity is associated with earlier pubertal onset, which is in turn associated with increased risk of breast cancer, cardiovascular disease, asthma, and type 2 diabetes. Obesity also exacerbates the reproductive and metabolic abnormalities accompanying polycystic ovarian syndrome (PCOS), the most common reproductive disorder among women of reproductive age. Thus, to alleviate the health burden accompanying obesity, it is imperative to achieve a better understanding of the mechanisms underlying the metabolic control of HPG axis function. Only then can we potentially devise therapies that reduce the risk of metabolic-related disorders such as early puberty and PCOS. The goal of our studies is to understand how hypothalamic neurons integrate hormonal and metabolic signals to maximize reproductive and metabolic fitness. Specifically, we seek to elucidate the molecular mechanisms by which sex steroid hormones and metabolic signals relay information about nutritional status to the gonadotropin releasing hormone (GnRH) network. Our research centers on the hypothesis that PI3K is a key integrator of metabolic and neural signals regulating GnRH / luteinizing hormone (LH) release (Fig. 1). For example, GnRH and kisspeptin-expressing neurons are pivotal for the onset and maintenance of fertility, and their activity is influenced by gonadal hormones and by metabolic cues. Using a combination of transgenic animal models, neuroimaging and molecular biology techniques, our laboratory has demonstrated that PI3K signaling in GnRH and kisspeptin neurons participates in the control of gonadotropin release and neuropeptide gene expression in a sexually dimorphic fashion. Ongoing studies in my lab include: 1) Investigating the impact of metabolic stress on gonadotropin release in mice with impaired PI3K signaling in kisspeptin neurons, 2) Testing the hypothesis that PI3K mediates estradiol effects on metabolism and reproduction, and 3) Investigating whether estradiol regulation of autophagy, a PI3K-regulated cellular process, participates in the control of metabolism and reproduction.