Jennifer W. Hill - US grants

[unreadable] DESCRIPTION (provided by applicant): The dramatic increases in childhood and adolescent obesity in the U.S. have serious consequences for the health of the next generation. Along with its well-known health risks, childhood obesity impairs reproductive health and development. Indeed, early onset of obesity in girls, particularly during adolescence, favors the development of menses irregularities, chronic anovulation, infertility, and PCOS in adulthood. While the primary cause of this relationship is uncertain, central resistance to insulin and leptin, circulating markers of adiposity, appears to inhibit the reproductive axis. The key sites of communication between the metabolic and reproductive systems, however, remain unclear. This proposal is designed to advance our long-term goal of elucidating the molecular and genetic determinants of metabolic infertility. We hypothesize that leptin and insulin act directly on hypothalamic POMC and NPY/AgRP neurons that provide input to GnRH neurons. This hypothesis rests on findings that altered activity of POMC and NPY/AgRP neurons in response to leptin and insulin appear to depend on the phosphatidylinositol 3-kinase (PI3K) intracellular signaling pathway. In addition, previous studies have shown that brain-specific leptin receptor and insulin receptor knockouts have dramatic effects on the reproductive axis, but preventing leptin receptor signaling through non-PI3K pathways does not impair fertility. Thus, our studies will determine if insulin and leptin signaling through PI3K is required for normal (1) energy homeostasis and (2) reproductive functioning and in POMC neurons and/or in NPY/AgRP neurons. To accomplish these goals, we will genetically target the critical neurons using the cre/lox system. Specifically, we will examine the metabolic and reproductive phenotype of mice lacking insulin and leptin receptors or functional PI3K only in POMC neurons and only in NPY/AgRP neurons. We will then use electrophysiology and a novel method of visualizing Akt signaling in vitro to determine the impact of PI3K deletion on neuronal function. Collectively, these data may provide a new target for therapeutic advances in the treatment and prevention of obesity-related infertility. [unreadable] Project Narrative: With a background in the diverse fields of reproduction and metabolism, Dr. Hill is uniquely qualified to undertake these studies. The novel genetic approaches assembled during her post-doctoral fellowship will be powerful tools for investigating the understudied area of interacting hypothalamic metabolic and reproductive pathways. By providing a vehicle for her transition to research independence, this proposal lays the groundwork for a research program focused on reproductive health and the discovery of new approaches for treating nutritional and obesity-related infertility. [unreadable] [unreadable] [unreadable]

A fundamental gap exists in our understanding of how polycystic ovarian syndrome (PCOS) develops. This knowledge is essential to preventing PCOS and co-morbidities such as type 2 diabetes and cardiovascular disease. PCOS patients exhibit a low-grade inflammatory state, which may be triggered by hyperinsulinemia, obesity, or other factors. The proposal's central hypothesis is that low-grade, chronic inflammation associated with PCOS causes ovarian dysfunction. This hypothesis has been formulated from preliminary data produced in the applicant's laboratory and will be tested by pursuing three specific aims: 1) Determine whether inflammation precedes ovarian dysfunction in a potential mouse model of PCOS. 2) Determine whether genetic inhibition of inflammation can prevent the development of PCOS symptoms. 3) Determine whether pharmacological inhibition of inflammation can prevent the development of PCOS symptoms. Under the first aim, a new mouse model of PCOS developed by the applicants will be used to examine the age-dependent onset of androgen excess and inflammation. Under the second aim, mouse strains lacking an inflammatory response will be used to test whether chronic immune system activation leads to PCOS. Finally, the third aim will test whether pharmacological inhibition of a key inflammatory pathway inhibits or treats PCOS. The proposed studies will be the first direct test of whether inflammation plays an essential role in PCOS development using an animal model. The results have the potential to shift current research and clinical practice paradigms by identifying a causative factor in PCOS development and testing a novel pharmacological treatment for the disorder. The findings from this research may help to identify women at risk for PCOS and prevent its development and co-morbidities, thus reducing healthcare costs and extending lives.

? DESCRIPTION (provided by applicant): Erectile dysfunction (ED) is a frequent complication of type 2 diabetes that impairs quality of life for up to 75% of men with diabetes. ED strongly correlates with insulin resistance, obesity, and the metabolic syndrome. The long-term goal of this research is to elucidate the poorly understood pathogenesis of ED in diabetic and pre- diabetic states. The brain serves a key role in healthy erectile function by initiating sexual desie and by controlling autonomic erectile responses. Melanocortin pathways, consisting of POMC neurons that produce a- MSH and downstream MC3 and 4 receptor (MC4R)-containing neurons, are critical for these processes. However, therapeutics targeting MC receptors have the disadvantage of altering blood pressure and heart rate. The objective of this proposal is to determine if reduced endogenous a-MSH production can lead to ED and to identify the neuronal circuitry to which POMC neurons project to uniquely control erectile function. MC4Rs are found on oxytocin neurons to which POMC neurons project, and administration of a-MSH, MC4R agonists, or oxytocin increases sexual motivation, elicits sexual behaviors, and causes penile erection in mice and humans. The central hypothesis is that insulin and leptin resistance in POMC neurons promotes ED by reducing aMSH production and oxytocin signaling. This hypothesis has been formulated on the basis of strong preliminary data produced in the applicants' laboratories and will be tested with three specific aims: 1) Determine whether impaired insulin and leptin signaling in POMC neurons alters erectile function, 2) Determine whether restoring neuronal insulin and leptin sensitivity and a-MSH production improves sexual performance, and 3) Determine whether downstream oxytocin circuitry mediates the effects of a-MSH on erectile function. Under the first aim, novel cell type-specific tools will be used to allow acute neuronal manipulation to examine the role of POMC-specific insulin and leptin resistance in ED in a unique mouse model of prediabetes. In the second aim, the applicants will then determine whether reactivating hypothalamic leptin and insulin pathways restores normal sexual function and offers a potential treatment strategy in cases of central insulin and leptin resistance caused by diet-induced obesity. Under the third aim, the applicants will determine whether downstream oxytocin circuitry mediates the effects of a-MSH on erectile function using pharmacogenetics to examine whether this pathway is necessary and sufficient. A well-established cre-dependent viral tracer will then be employed to map downstream circuitry. The rationale for these studies is that they will be the first to address whether diabetes is accompanied by defective melanocortin signaling that may cause or exacerbate ED. The rising number of men with obesity and type 2 diabetes makes this research highly significant. Given the involvement of melanocortin pathways in regulating blood pressure, obesity, and glycemic control, the proposed research has the potential to guide the development of novel and effective therapies devoid of side effects that improve both the quality of life and overall health of these patients.