Role of glucagon-like peptide-1 signaling in mediating sensory-specific satiety

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PROJECT SUMMARY/ABSTRACT Despite its critical role in meal cessation, the neuroendocrine mechanisms underlying sensory-specific satiety (SSS) are largely unknown. SSS is the transient reduction in motivation and pleasantness for a recently consumed food. While this selective decrease in hedonic value suppresses consumption of the same food, in leads to a comparative increase in the reward value of uneaten palatable foods. As a result, a variety of readily available alternative foods can drive overconsumption. Given the variety of highly caloric foods pervasive in the modern environment, it is important to understand the mechanisms by which SSS regulates food intake. To this end, we propose to use our novel rat model of SSS to investigate the neural action of one satiation signal, glucagon-like peptide-1 (GLP-1). Indeed, our preliminary data indicate GLP-1 receptors (GLP-1Rs) in the hindbrain are critical for the SSS-induced decline in consumption of the same food. Moreover, hindbrain GLP- 1Rs are sufficient to prevent the overconsumption of an available alternative food. These data show hindbrain GLP-1 signaling is important for decreased consumption of the same food. In contrast, the effects of GLP-1 signaling is muted during the comparative increased intake of an alternative available food. However, these data unearth additional questions regarding the neural underpinnings of SSS. Notably, the neural population(s) mediating this GLP-1 signaling are unknown. An integrator of peripheral signals, the nucleus tractus solitarius (NTS) of the caudal brainstem is well-positioned to host the GLP-1 signaling involved in SSS. Not only does the NTS contain GLP-1R-expressing cells, but it also holds preproglucagon (PPG) neurons that synthesize GLP-1. Therefore, in Aim I, we propose to investigate the role of these two distinct NTS neural populations in controlling SSS. Furthermore, it is unclear how the effects of GLP-1 signaling are muted to enable the increased intake of an alternative food. Two subcortical structures, the bed nucleus of the stria terminalis (BNST) and the central amygdala (CeA) are functionally and anatomically suited to modulate GLP-1 signaling. Both regions mediate aspects of ingestive behavior and reward, and each region projects directly to PPG NTS neurons. Thus, in Aim II we will characterize the role of BNST/CeA → PPG projections during increased intake of an alternative food. Considering the ever-growing prevalence of obesity in the United States, understanding how neuroendocrine signals mediate the impact of recent food experiences on consumption is an important step in the development of approaches for treating diseases of maladaptive ingestive behavior. To this end, our experiments will investigate central GLP-1-mediated mechanisms by which SSS modulates food intake.