Caudal Brainstem Processing Is Sufficient for Behavioral, Sympathetic, and Parasympathetic Responses Driven by Peripheral and Hindbrain Glucagon-Like-Peptide-1 Receptor Stimulation

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Abstract
The effects of peripheral glucagon like peptide-1 receptor (GLP-1R) stimulation on feeding, gastric emptying, and energetic responses involve vagal transmission and central nervous system processing. Despite a lack of studies aimed at determining which central nervous system regions are critical for the GLP-1R response production, hypothalamic/forebrain processing is regarded as essential for these effects. Here the contribution of the caudal brainstem to the control of food intake, core temperature, heart rate, and gastric emptying responses generated by peripheral delivery of the GLP-1R agonist, exendin-4 (Ex-4), was assessed by comparing responses of chronic supracollicular decerebrate (CD) rats to those of pair-fed intact control rats. Responses driven by hindbrain intracerebroventricular (fourth icv) delivery of Ex-4 were also evaluated. Intraperitoneal Ex-4 (1.2 and 3.0 μg/kg) suppressed glucose intake in both CD rats (5.0 ± 1.2 and 4.4 ± 1.1 ml ingested) and controls (9.4 ± 1.5 and 7.7 ± 0.8 ml ingested), compared with intakes after vehicle injections (13.1 ± 2.5 and 13.2 ± 1.7 ml ingested, respectively). Hindbrain ventricular Ex-4 (0.3 μg) also suppressed food intake in CD rats (4.7 ± 0.6 ml ingested) and controls (11.0 ± 2.9 ml ingested), compared with vehicle intakes (9.3 ± 2.1 and 19.3 ± 4.3 ml ingested, respectively). Intraperitoneal Ex-4 (0.12, 1.2, 2.4 μg/kg) reduced gastric emptying rates in a dose-related manner similarly for both CD and control rats. Hypothermia followed ip and fourth icv Ex-4 in awake, behaving controls (0.6 and 1.0 C average suppression) and CD rats (1.5 and 2.5 C average suppression). Intraperitoneal Ex-4 triggered tachycardia in both control and CD rats. Results demonstrate that caudal brainstem processing is sufficient for mediating the suppression of intake, core temperature, and gastric emptying rates as well as tachycardia triggered by peripheral GLP-1R activation and also hindbrain-delivered ligand. Contrary to the literature, hypothalamic/forebrain processing and forebrain-caudal brainstem communication is not required for the observed responses.