Apolipoprotein E (apoE) is produced abundantly in the liver and brain. It plays important roles in the metabolism and redistribution of lipids. In the brain, apoE has been implicated in development, regeneration, and neuroprotection. Recently, we have identified a novel function of apoE, i.e. centrally administered apoE potently suppresses food intake and body weight without eliciting signs of toxicity, and blocking the action of endogenous brain apoE with its specific antibody increases food intake. Mice with a targeted deletion of the apoE gene consume more food and weigh more than wild-type mice. These results imply that apoE plays an essential role in the control of food intake and body weight. Thus, we speculate that insufficient apoE production may render an animal vulnerable to the development of obesity. Our long-term goal is to identify pharmacological targets for suppressing appetite as a means of preventing and treating obesity. The objective of this specific application is to identify the mechanism(s) mediating apoE's effect in the control of food intake and body weight. The first specific aim will assess the hypothesis that increased food consumption in obese animals is due in part to reduced apoE signaling in the hypothalamus, a central area regulating energy homeostasis. The second specific aim will evaluate the hypothesis that hypothalamic apoE exerts its anorectic function by influencing catabolic regulatory neuropeptides and/or their receptors. The third specific aim will identify the mechanisms that mediate apoE's anorectic action by determining apoE-relevant receptor(s) and signal transduction pathways. The proposed work is innovative because it assesses a novel physiological function of apoE in the brain. In addition, it takes advantage of the rich research environment in the University of Cincinnati Obesity and Lipid Research Centers and employs available experimental methods and several unique animal models. Moreover, outcomes of this research will have a positive impact on the field of obesity research because the fundamental new knowledge is expected to facilitate the development of preventive and therapeutic interventions to address the epidemic of obesity and, consequently, to decrease health care costs in the United States.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070992-05
Application #
8029565
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Hyde, James F
Project Start
2007-01-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$276,451
Indirect Cost
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
May, Aaron A; Bedel, Nicholas D; Shen, Ling et al. (2016) Estrogen and insulin transport through the blood-brain barrier. Physiol Behav 163:312-21
Shen, Ling; Wang, David Q-H; Lo, Chunmin C et al. (2015) Gut vagal afferents are necessary for the eating-suppressive effect of intraperitoneally administered ginsenoside Rb1 in rats. Physiol Behav 152:62-7
Shen, Ling; Liu, Yin; Wang, David Q H et al. (2014) Estradiol stimulates apolipoprotein A-IV gene expression in the nucleus of the solitary tract through estrogen receptor-α. Endocrinology 155:3882-90
Shen, Ling; Xiong, Ye; Wang, David Q-H et al. (2013) Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats. J Lipid Res 54:1430-8
Yoshimichi, Go; Lo, Chunmin C; Tamashiro, Kellie L K et al. (2012) Effect of peripheral administration of cholecystokinin on food intake in apolipoprotein AIV knockout mice. Am J Physiol Gastrointest Liver Physiol 302:G1336-42
Liu, Min; Kuhel, David G; Shen, Ling et al. (2012) Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice. Am J Physiol Regul Integr Comp Physiol 303:R903-8
Shen, Ling; Hillebrand, Allix; Wang, David Q-H et al. (2012) Isolation and primary culture of rat hepatic cells. J Vis Exp :
Liu, Min; Shen, Ling; Begg, Denovan P et al. (2012) Insulin increases central apolipoprotein E levels as revealed by an improved technique for collection of cerebrospinal fluid from rats. J Neurosci Methods 209:106-12
Shen, Ling; Wang, David Q-H; Tso, Patrick et al. (2011) Apolipoprotein E reduces food intake via PI3K/Akt signaling pathway in the hypothalamus. Physiol Behav 105:124-8
Lo, Chun-Min; Obici, Silvana; Dong, H Henry et al. (2011) Impaired insulin secretion and enhanced insulin sensitivity in cholecystokinin-deficient mice. Diabetes 60:2000-7

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