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. 2011 Nov;301(5):R1479-85.
doi: 10.1152/ajpregu.00356.2011. Epub 2011 Aug 17.

The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

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The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

Matthew R Hayes et al. Am J Physiol Regul Integr Comp Physiol. 2011 Nov.

Abstract

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9-39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7-36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.

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Figures

Fig. 1.
Fig. 1.
Representative images of the common hepatic branch of the vagus (CHB). A: an intact CHB prior to surgical ablation (arrows). B: visual verification of a surgically ablated CHB (arrows).
Fig. 2.
Fig. 2.
Percent change in blood glucose (mg/dl) following ingestion of an oral glucose load (2 g/kg; time 0) when combined with saline or exendin-(9–39) (Ex-9; 0.5 mg/kg ip) compared with pre-oral glucose tolerance test and pre-injection blood glucose levels. A: blockade of glucagon-like peptide-1 receptor (GLP-1R) by Ex-9 significantly increased blood glucose at times 0, 20, 40 min in CHB ablation (CHBX) and control rats. B: Ex-9 significantly increased blood glucose in control rats at time 0 and 20 min but failed to alter blood glucose values in subdiaphramatic vagal deafferentation (SDA) rats. *P < 0.05 from within-subject saline condition.
Fig. 3.
Fig. 3.
Cumulative 25% glucose intake following intraperitoneal injection of GLP-1(7–36) or saline. A: GLP-1 produced a comparable magnitude of glucose intake suppression at all time points for CHBX and control rats. B: GLP-1 significantly suppressed glucose intake of control rats at all time points, but failed to significantly suppress glucose intake of SDA rats except at 20 min. *P < 0.05 from within-subject saline condition.

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