Leptin and insulin regulate energy balance by conveying the abundance of peripheral energy stores to the brain. In addition, leptin and insulin also act in the hypothalamus to regulate systemic insulin sensitivity and glucose homeostasis, and this function of leptin and insulin appears to be independent of their effects on feeding and adiposity. Our long-term objective is to understand the signaling mechanisms by which leptin and insulin regulate various physiologic processes. We have previously demonstrated that leptin and insulin directly stimulate PI3K signaling in key leptin and insulin target neurons in the hypothalamus. While PI3K signaling is important for insulin?s metabolic effects, recent pharmacological studies indicate that the PI3K signaling pathway plays an important role in mediating leptin?s effect on glucose homeostasis. To date, genetic evidence is still lacking to establish the functional requirement of hypothalamic PI3K signaling in energy balance and glucose homeostasis in vivo. Moreover, neuronal subgroups important for this regulation have not been identified. In this proposal, we will test the hypothesis that PI3K in leptin responsive neurons is required for proper maintenance of energy balance and glucose homeostasis. We will determine whether chronic or acute PI3K knockdown in specific leptin responsive neurons leads to altered energy balance, increased systemic insulin resistance and impaired glucose homeostasis. We will also evaluate the function of PI3K and Jak-Stat3 signaling in Pomc and Agrp neurons, two key leptin and insulin target neurons in the hypothalamus. The proposed study will elucidate the functional necessity of PI3K in mediating energy balance and glucose homeostasis, and will identify the neuronal subgroups that are important for this process. It will advance our understanding of the signaling mechanisms by which leptin and insulin regulate energy balance and glucose homeostasis, and provide insight into the etiology of obesity and type 2 diabetes.

Public Health Relevance

Obesity prevalence has increased dramatically in the United States, and is a major risk factor for type 2 diabetes, cardiovascular diseases, and other health problems. Research outlined in this proposal will help better understand how leptin and insulin regulate body weight and glucose homeostasis, and will provide insight into the etiology of obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080427-05
Application #
8240072
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2008-02-01
Project End
2013-06-30
Budget Start
2012-02-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$389,371
Indirect Cost
$137,351
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Warne, James P; Xu, Allison W (2013) Metabolic transceivers: in tune with the central melanocortin system. Trends Endocrinol Metab 24:68-75
Warne, James P; Varonin, Jillian M; Nielsen, Sofie S et al. (2013) Coordinated regulation of hepatic energy stores by leptin and hypothalamic agouti-related protein. J Neurosci 33:11972-85
Newton, A Jamila; Hess, Simon; Paeger, Lars et al. (2013) AgRP innervation onto POMC neurons increases with age and is accelerated with chronic high-fat feeding in male mice. Endocrinology 154:172-83
Olofsson, Louise E; Unger, Elizabeth K; Cheung, Clement C et al. (2013) Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance. Proc Natl Acad Sci U S A 110:E697-706
Warne, James P; Alemi, Farzad; Reed, Alison S et al. (2011) Impairment of central leptin-mediated PI3K signaling manifested as hepatic steatosis independent of hyperphagia and obesity. Cell Metab 14:791-803