The proposed research of this R01 application focuses on the neuropeptide glucagon-like peptide-1 (GLP-1) and its physiological role in controlling for food intake and body weight through distributed action in the central nervous system (CNS). This application supports the view that the central GLP-1 system is a master regulator of many physiological and behavioral processes involved in glycemic and food intake control. Given the growing worldwide prevalence of type II diabetes mellitus (T2DM) and obesity, it is not surprising that multiple GLP-1-based pharmaceutics are FDA approved. As anti-obesity agents however, current GLP-1-based drugs have limited efficacy. On average they produce ~5% weight loss through mechanisms resulting in inhibitory actions on food intake. This proposal advocates for the perspective that to achieve greater anti-obesity efficacy it will be necessary for basic research to decipher: (a) the specific CNS nuclei and mechanism(s) mediating GLP-1's effects on energy balance, (b) the interactions between GLP-1 receptor (GLP-1R) signaling and within-meal gastrointestinal satiation signals that also contribute to food intake control, as well as (c) what impact obesity itself has on the endogenous CNS GLP-1 system in regards to energy balance regulation. To this end, this application proposes a novel set of experiments to test the hypothesis that the distributed neuroanatomical projections of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) simultaneously activate GLP-1 receptors at multiple energy balance relevant nuclei resulting in the amplification of the neural processing of other satiation signals processed at these sites. Further, given that obesity can down-regulate neuroendocrine systems involved in energy balance regulation, we will evaluate whether the obese state negatively impacts the role of the central GLP-1 system to amplify satiety signaling. The following specific aims are examined: [1] To examine the hypothesis that the central GLP-1 system functions as a behavioral end-break for ongoing meal taking through simultaneous activation of anatomically distributed GLP-1R-expressing energy balance relevant nuclei; and [2] To examine the hypothesis that obesity down-regulates the endogenous central GLP-1 system thereby promoting the feeding behaviors that sustain the obese state.
Project summary: Relevance to public health. This project will investigate the mechanisms and brain structures mediating the food intake suppressive effects of the hormone glucagon-like peptide-1 (GLP-1) in an attempt to advance knowledge regarding other potential hormone / brain chemical systems that can be simultaneously targeted with GLP-1 to treat obesity. We will also examine what effect the obese state has on the central GLP-1 system to the control of meal taking and motivated behaviors geared towards food reward. These basic science discoveries will be instrumental in the development of future pharmacotherapies used to treat obesity and associated diseases.
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