The marked increase in the prevalence of obesity in the Untied States over the past decade poses a serious thereat to public health. Although the circulating adiposity signals leptin and insulin can reduce food intake and body weights in animal models, obese animals and humans exhibit high levels of food intake despite elevated plasma concentrations of insulin and leptin, indicating hypothalamic resistance to these despite elevated plasma concentrations of insulin and leptin, indicating hypothalamic resistance to these factors. Our research seeks to determine the importance of the PI3K pathway to insulin and leptin signaling in crucial neuronal subgroups within the hypothalamus. We propose to identity the expression pattern of PI3K within the hypothalamus using double-labeled I3HH and IHC for NPY, POMC, and the PI3K subunits p85 and p110. We also propose to use double-labeled IHC to identify neuronal populations in which P13K activity occurs in response to insulin and leptin treatment. Finally, we will develop mice with deletions of p85 targeted to POMC and NPY neurons to determine the importance of PI3K signaling in these pathways to the regulation of body weight. Insight into this shared intracellular pathway will allow progress toward treatment of impaired leptin and insulin regulation of body weight in the obese.
| Xu, Yong; Hill, Jennifer W; Fukuda, Makoto et al. (2010) PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab 12:88-95 |
| Hill, Jennifer W; Elias, Carol F; Fukuda, Makoto et al. (2010) Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 11:286-97 |
| Hill, Jennifer W; Xu, Yong; Preitner, Frederic et al. (2009) Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology 150:4874-82 |
| Hill, Jennifer W; Williams, Kevin W; Ye, Chianping et al. (2008) Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest 118:1796-805 |
