The proposed research focuses on the neuropeptide glucagon-like-peptide-1 (GLP-1) and its role in controlling for food intake and body weight. FDA-approved GLP-1 receptor (GLP-1R) agonists for the treatment of Type II Diabetes Mellitus (T2DM) produce improvements in blood glucose regulation and, in addition, produce meaningful reductions in food intake and body weight in both humans and animal models. Therefore, recent attention has been given to long-acting GLP-1R agonists as a potential treatment for obesity. It is remarkable to note, however, while nausea and/or vomiting are the major adverse events (i.e. side effect) reported in ~20-50% of T2DM patients prescribed GLP-1R agonists there is very little investigation of the mechanisms mediating the nausea/malaise and virtually no understanding of the significance of nausea/malaise in relation to GLP-1R- mediated suppression of food intake. Experiments in this proposal will examine the potential mechanisms and gastrointestinal and central nervous system (CNS) structures mediating the nausea/malaise following GLP-1R activation by examining: [1] the role of GLP-1Rs expressed on vagal afferent and CNS neurons in mediating the nausea/malaise and food intake suppression of GLP-1R agonists;[2] gastrointestinal mechanisms mediating the nausea/malaise response of GLP-1R agonists. The overall research proposed will provide a framework for development of GLP-1R-mediated treatments with reduced incidence of nausea/vomiting that can be used by a greater population of obese individuals. In addition, results may help identify potential targets for combination drug therapy to ameliorate the malaise side effects of current FDA-approved GLP-1R ligands.

Public Health Relevance

Basic science discoveries have identified specific brain chemical systems that can reduce food intake when stimulated. While currently no pharmaceutical treatment for obesity exists, drugs targeting the hormone glucagon-like-peptide-1 (GLP-1) hold promise as food intake is suppressed following their administration. Unfortunately, nausea and/or vomiting are the major side effects of these GLP-1 drugs and therefore this proposal aims to identify the potential mechanisms and gastrointestinal and brain structures mediating the nausea of these drugs, providing necessary research for development of GLP-1 treatments for obesity with reduced incidence of nausea/vomiting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
5R03DK093874-02
Application #
8438402
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2012-03-05
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$77,200
Indirect Cost
$28,950
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Mietlicki-Baase, Elizabeth G; Rupprecht, Laura E; Olivos, Diana R et al. (2013) Amylin receptor signaling in the ventral tegmental area is physiologically relevant for the control of food intake. Neuropsychopharmacology 38:1685-97