doi: 10.1038/npp.2016.246. Epub 2016 Oct 26.
Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control
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- PMID:27782127
- PMCID: PMC5436110
- DOI: 10.1038/npp.2016.246
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Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control
Amber L Alhadeff et al. Neuropsychopharmacology.2017 Jun.
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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.
Figures
(a) rtPCR fromin vitro studies demonstrated ~88% knockdown of GLP-1R expression in rat R19 neurons overexpressing the GLP-1R following 3-day transfection with AAV-GLP-1R compared with AAV-CONTROL. (b) Representative real-time PCR (rtPCR) reveals ~66% suppression of GLP-1R mRNA in micropunched NTS tissue in AAV-GLP-1R-vs AAV-CONTROL-treated rats. (c) Representative image of GFP tagged-AAV-CONTROL injection placement in the NTS. (d) Representative image of GFP tagged-AAV-GLP-1R injection placement in the NTS. AP, area postrema. Data expressed as means±SEM, *p<0.05.
(a) Average daily chow intake for NTS AAV-GLP-1R and AAV-CONTROL rats. (b) Cumulative chow intake (from day of virus injection) in NTS AAV-GLP-1R and AAV-CONTROL rats. Data expressed as means±SEM,+p<0.10, *p<0.05.
(a) Average daily body weight for NTS AAV-GLP-1R and AAV-CONTROL rats. (b) Cumulative body weight gain (from day of virus injection) in NTS AAV-GLP-1R and AAV-CONTROL rats. Data expressed as means±SEM,+p<0.10.
Average (3-day) cumulative food intake in NTS AAV-GLP-1R and AAV-CONTROL rats, dark cycle begins at 0 h. Data expressed as means±SEM,+p<0.10, *p<0.05.
(a) Average (3-day) meal size in NTS AAV-GLP-1R and AAV-CONTROL rats, dark cycle begins at 0 h. (b) Average (3-day) meal number in NTS AAV-GLP-1R and AAV-CONTROL rats. Data expressed as means±SEM,+p<0.06, *p<0.05.
Relative NTS GLP-1R mRNA expression negatively correlates with (a) FR-1 operant responding (p=NS), (b) FR-3 operant responding and (c) FR-5 operant responding. In addition, relative NTS GLP-1R mRNA expression negatively correlates with (d) number of lever presses and (e) number of reinforcers earned on a progressive ratio schedule of reinforcement.
Number of lever presses (a) and reinforcers earned (b) in AAV-GLP-1R and AAV-CONTROL rats under an FR-5 schedule of reinforcement. Number of lever presses (c) and reinforcers earned (d) in AAV-GLP-1R and AAV-CONTROL rats under PR schedule of reinforcement. Data expressed as means±SEM,+p⩽0.1, *p<0.05.
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