Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control

Abstract

Alhough the glucagon-like peptide-1 (GLP-1) system is critical to energy balance control and is a target for obesity pharmacotherapies, the receptor-population-mediating effects of endogenous GLP-1 signaling are not fully understood. To address this, we developed a novel adeno-associated virus (AAV-GLP-1R) that utilizes short hairpin RNA to chronically knock down GLP-1 receptors (GLP-1R) in rats. As pharmacological studies highlight the hindbrain nucleus tractus solitarius (NTS) as a brain region important for GLP-1R-mediated effects on energy balance, AAV-GLP-1R was injected into the NTS to examine the role of endogenous NTS GLP-1R signaling in energy balance control. Chow intake and meal size were significantly increased following chronic NTS GLP-1R knockdown. In addition, NTS GLP-1R knockdown significantly increased self-administration of palatable food under both fixed and progressive ratio schedules of reinforcement. Collectively, these data demonstrate that endogenous NTS GLP-1R signaling is required for the control of food intake and motivation to feed, and provide a new strategy to investigate the importance of distinct GLP-1R populations in the control of a variety of functions.

Chronic Suppression of Glucagon-Like Peptide-1 Receptor (GLP1R) mRNA Translation in the Rat Bed Nucleus of the Stria Terminalis Reduces Anxiety-Like Behavior and Stress-Induced Hypophagia, But Prolongs Stress-Induced Elevation of Plasma Corticosterone

“…A forebrain tissue block containing the BST was mounted onto the cryostat chuck, and thin sections were examined under a fluorescence microscope (model 80i, Nikon) until GFP-expressing cells were visualized within the alBST injection site. Bilateral BST micropunches (1 mm 3 ) of GFP-labeled tissue were collected and kept frozen for subsequent qRT-PCR analysis, using previously reported primers and procedures (Alhadeff et al, 2017). Total RNA was extracted from micropunches using TRIzol (Thermo Fisher Scientific) and the RNeasy kit (Qiagen).…”

“…TaqMan gene expression kits and PCR reagents (Applied Biosystems) were used to quantify the relative levels of translatable mRNA for GLP1R (GLP1r, Rn00562406) relative to rat GAPDH mRNA (Gapdh, Rn01775763_g1). Relative mRNA expression was calculated using the comparative Ct method, as previously described (Hayes et al, 2010;Alhadeff et al, 2017). qRT-PCR data from 2 of the original 16 rats prepared for analysis (n ϭ 1/AAV injection group) were subsequently discarded due to technical errors during RNA isolation and cDNA synthesis.…”

Interoceptive modulation of neuroendocrine, emotional, and hypophagic responses to stress

“…For example, rats increase food intake when GLP-1 receptor antagonists are administered into the 4th ventricle or directly into the cNTS (Hayes et al 2009). Additionally, results from studies study utilizing viral-mediated knockdown of either PPG or GLP-1 receptor within the cNTS indicate that GLP-1 signaling is critical for both short- and long-term regulation of food intake (Barrera et al 2011; Alhadeff et al 2016). Together, these results indicate that GLP-1 signaling in the caudal brainstem (and potentially other central target sites) is necessary for normal feeding control, and also is sufficient to suppress intake.…”

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core

“…Much of the existing work on the anorectic effects of GLP-1 is heavily focused on GLP-1 signaling through metabolic control nuclei including nuclei of the hypothalamus and the nucleus of the solitary tract [28–30]. Recent work, however, has demonstrated that that GLP-1 also decreases food intake by reducing the rewarding value of food [31–34], implicating a physiological role for the peptide beyond energy balance regulation.…”