Obesity is recognized as a serious worldwide threat to human health. Evidence indicates that over the course of hours and days caloric intake is closely matched to energy expenditure in normal individuals, such that body weight remains stable over time. This regulation occurs via a classical endocrine feedback loop in which the """"""""adiposity signals"""""""" insulin and leptin are secreted in proportion to body fat mass and interact with regulatory neurons found in the hypothalamic arcuate nucleus (ARC). Human obesity and the best animal model thereof, diet-induced obesity (DIO) are fundamentally different, leading to the hypothesis that acquired hypothalamic resistance to the adiporegulatory effects of insulin and leptin results in impaired body fat mass regulation. Previously we have demonstrated that the ability of both insulin and leptin to regulate feeding is dependent upon the activation of phosphatidylinositol 3-kinase (PI3K) in ARC neurons; this pathway is the major mode of insulin action in peripheral tissues and has been identified as a """"""""target"""""""" of insulin resistance via accumulation of long chain fatty acyl CoA molecules (LC-CoA). We have generated preliminary data demonstrating both behavioral (food intake) and biochemical (PI3K) hypothalamic insulin and leptin resistance in obese DIO animals and that mechanisms implicated in peripheral insulin resistance may also be responsible for central resistance. We propose:
Aim 1 : To determine the time-course of central insulin and leptin (vs peripheral) resistance in DIO.
Aim 2 : To determine if the accumulation of hypothalamic long-chain fatty acyl CoA molecules in DIO coincides with behavioral and/or biochemical resistance.
Aim 3 : To determine if insulin and leptin regulation of FOXO proteins in hypothalamus is disrupted in DIO.
Aim 4 : To determine if genetic enhancement of the hypothalamic PI3K pathway enhances insulin and leptin sensitivity and attenuates DIO.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069927-03
Application #
7095060
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Sato, Sheryl M
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$311,860
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Silver, Heidi J; Niswender, Kevin D; Kullberg, Joel et al. (2012) Comparison of Gross Body Fat-Water Magnetic Resonance Imaging at 3 Tesla to Dual-Energy X-Ray Absorptiometry in Obese Women. Obesity (Silver Spring) :
Silver, Heidi J; Niswender, Kevin D; Keil, Charles D et al. (2012) CNR1 genotype influences HDL-cholesterol response to change in dietary fat intake. PLoS One 7:e36166
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Niswender, Kevin D; Daws, Lynette C; Avison, Malcolm J et al. (2011) Insulin regulation of monoamine signaling: pathway to obesity. Neuropsychopharmacology 36:359-60
Siuta, Michael A; Robertson, Sabrina D; Kocalis, Heidi et al. (2010) Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice. PLoS Biol 8:e1000393
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Sarruf, David A; Yu, Fang; Nguyen, Hong T et al. (2009) Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 150:707-12
Niswender, Kevin D; Beech, Bettina M (2008) Obesity: increasing awareness of novel environmental factors. Diabetes 57:1786-7
Huizinga, Mary Margaret; Niswender, Kevin D; Gebretsadik, Tebeb et al. (2008) Insulin use and weight maintenance in well-controlled type 2 diabetes: a prospective cohort study. Obesity (Silver Spring) 16:1933-7
Stafford, John M; Yu, Fang; Printz, Richard et al. (2008) Central nervous system neuropeptide Y signaling modulates VLDL triglyceride secretion. Diabetes 57:1482-90

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