Obesity and related metabolic disorders have become a tremendous public health problem. This proposal Investigates the neural circuitry that Integrates input from the adiposity hormone leptin and the gut-derived satiety signals cholecystokinin (CCK) and glucagon-like peptlde-1 (GLP-1), and the physiological relevance ofthe interactions between these signals for the control of food Intake and body weight. Available data support the hypothesis that the adiposity hormone leptin reduces food Intake in part by enhancing satiety responses to gastrointestinal signals, Includingj CCK. We have recently determined that leptin Interacts In a sirnilar rrianrier with GLP-1, but our data suggest that the leptin-CCK and leptin-GLP-1 interactions are mediated through different neuronal pathways, Here, we propose to Identify and compare brain areas In which leptin detection Is sufficient to enhance the responses to GLP-1 and CCK, using site-speclfic microinjections and gene therapy In normal rats and rats that lack leptin receptors due to genetic mutation. Next, we will Investigate whether leptin reduces food Intake and enhances the satiety response to gastrointestinal nutrients in part by modulating rats'sensitivity to endogenously released GLP-1 or CCK. Finally, we will determine whether altered sensitivity to GLP-i or CCK plays a role in the pathogenesis of diet-Induced obesity when rats are maintained on a high-fat diet, which produces leptin resistance, together, these studies will help to clarify how changes In body fat stores lead to compensatory adjustments in meal size, as well as how defects In this process may lead to obesity and metabolic disorders, and thus have the potential to significantly advance our understanding ofthe neural control of feeding and body weight.

Public Health Relevance

This research focuses on how the brain detects stored energy in fat along with the presence of nutrients In the gutj and then integrates that Information to determine how much food to eat. Our studies will improve our understanding of the neural circuitry that regulates food intake and body weight, and will help identify biological factors that contribute to the development and maintenance of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
5R00DK078779-05
Application #
8119759
Study Section
Special Emphasis Panel (NSS)
Program Officer
Yanovski, Susan Z
Project Start
2007-09-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$246,509
Indirect Cost
Name
Florida State University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
790877419
City
Tallahassee
State
FL
Country
United States
Zip Code
32306
Kay, Kristen; Parise, Eric M; Lilly, Nicole et al. (2014) Hindbrain orexin 1 receptors influence palatable food intake, operant responding for food, and food-conditioned place preference in rats. Psychopharmacology (Berl) 231:419-27
Williams, Diana L (2014) Neural integration of satiation and food reward: role of GLP-1 and orexin pathways. Physiol Behav 136:194-9
Dossat, Amanda M; Diaz, Ryan; Gallo, Lindsay et al. (2013) Nucleus accumbens GLP-1 receptors influence meal size and palatability. Am J Physiol Endocrinol Metab 304:E1314-20
Mullis, Kiersten; Kay, Kristen; Williams, Diana L (2013) Oxytocin action in the ventral tegmental area affects sucrose intake. Brain Res 1513:85-91
Parise, Eric M; Lilly, Nicole; Kay, Kristen et al. (2011) Evidence for the role of hindbrain orexin-1 receptors in the control of meal size. Am J Physiol Regul Integr Comp Physiol 301:R1692-9
Williams, Diana L; Hyvarinen, Nina; Lilly, Nicole et al. (2011) Maintenance on a high-fat diet impairs the anorexic response to glucagon-like-peptide-1 receptor activation. Physiol Behav 103:557-64
Dossat, Amanda M; Lilly, Nicole; Kay, Kristen et al. (2011) Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake. J Neurosci 31:14453-7
Williams, Diana L; Schwartz, Michael W (2011) Neuroanatomy of body weight control: lessons learned from leptin. J Clin Invest 121:2152-5
Williams, Diana L (2010) Expecting to eat: glucagon-like peptide-1 and the anticipation of meals. Endocrinology 151:445-7
Williams, Diana L (2009) Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis. Endocrinology 150:2997-3001