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. 2008 Aug;57(8):2046-54.
doi: 10.2337/db07-1824. Epub 2008 May 16.

Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake

Darleen A Sandoval  1 , Didier Bagnol, Stephen C Woods, David A D'Alessio, Randy J Seeley
Affiliations

Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake

Darleen A Sandoval et al. Diabetes. 2008 Aug.

Abstract

Objective: Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the central GLP-1 system regulates glucose tolerance as well.

Research design and methods: We used glucose tolerance tests and hyperinsulinemic-euglycemic clamps to assess the role of the central GLP-1 system on glucose tolerance, insulin secretion, and hepatic and peripheral insulin sensitivity. Finally, in situ hybridization was used to examine colocalization of GLP-1 receptors with neuropeptide tyrosine and pro-opiomelanocortin neurons.

Results: We found that central, but not peripheral, administration of low doses of a GLP-1 receptor antagonist caused relative hyperglycemia during a glucose tolerance test, suggesting that activation of central GLP-1 receptors regulates key processes involved in the maintenance of glucose homeostasis. Central administration of GLP-1 augmented glucose-stimulated insulin secretion, and direct administration of GLP-1 into the arcuate, but not the paraventricular, nucleus of the hypothalamus reduced hepatic glucose production. Consistent with a role for GLP-1 receptors in the arcuate, GLP-1 receptor mRNA was found to be expressed in 68.1% of arcuate neurons that expressed pro-opiomelanocortin mRNA but was not significantly coexpressed with neuropeptide tyrosine.

Conclusions: These data suggest that the arcuate GLP-1 receptors are a key component of the GLP-1 system for improving glucose homeostasis by regulating both insulin secretion and glucose production.

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Figures

FIG. 1.
FIG. 1.
Effect of blocking CNS GLP-1 receptors on glucose (A) and insulin (B) responses to an intraperitoneal glucose injection. A: Glucose response to the intraperitoneal glucose load was significantly greater at 15 and 30 min after the glucose injection with dH-EX versus saline injected into the i3vt. Integrated area under the curve (iAUC) was also significantly greater in dH-EX versus saline (inlay). B: There were no significant differences between groups in the insulin response to the glucose load. *P 0.05 vs. saline.
FIG. 2.
FIG. 2.
Insulin response to an intravenous glucose or saline bolus 5 min after i3vt GLP-1 or saline injection. A: Insulin levels were significantly greater at 4 min, and area under the curve for insulin response was significantly greater after GLP-1 (inset). B: Insulin levels did not significantly change with an intravenous saline bolus after i3vt GLP-1 and saline injections. *P < 0.05 vs. saline.
FIG. 3.
FIG. 3.
Photomicrographs illustrating the expression of GLP-1r mRNAs in NPY and POMC neurons in rat mid- and caudal ARC as detected by double in situ hybridization histochemistry. Neurons expressing GLP-1 receptor are visualized by a white, dense, silver-grain accumulation, while either NPY (A–C) or POMC (D–F) mRNAs appeared as a black precipitate in cell bodies. In the mid-ARC at low magnification (A and D), many GLP-1 receptor–expressing cells do not express NPY mRNA and are localized more laterally (A). Neurons expressing only GLP-1r are also visualized in the periventricular area posterior to both NPY and POMC neurons (A and D). A high number of POMC-expressing cells are found expressing GLP-1r mRNA characterized by strong silver-grain accumulation over the digoxigenin black precipitate and are clearly seen at higher magnification (F). In the caudal ARC (B and E), many neurons expressing the GLP-1 receptor but not NPY or POMC are found mostly in the posterior and periventricular part (B and E). C and F are photomicrographs at higher magnification of inserts represented by a black square in A and D.
FIG. 4.
FIG. 4.
Illustrations of computer-assisted anatomical mapping and three-dimensional serial section reconstruction of POMC, GLP-1 receptors, and POMC/GLP-1 receptor–expressing cells in rat retrochiasmatic and arcuate nuclei. Anatomical maps were generated by drawing colored symbols over each cell type during examination of microscopic slides under a 40× objective. Green dots or squares, cells expressing GLP-1 receptor alone. Blue dots or triangles, cells expressing POMC alone. Red dots, cells expressing both GLP-1 receptor and POMC. 3v, third ventricle; PVH, paraventricular nucleus of the hypothalamus. (Please see http://dx.doi.org/10.2337/db07-1824 for a high-quality digital representation of this figure.)
FIG. 5.
FIG. 5.
ARC and PVN cannula-placement sites. After completion of the hyperinsulinemic-euglycemic clamps, the animals were killed and toludine blue dye was injected into the cannula. The brain was then sectioned and placement was verified. Black dots represent correct cannula placement. Rats with cannulas not placed in the ARC and PVN were excluded from the analysis (n = 8).
FIG. 6.
FIG. 6.
Effect of ARC GLP-1 on peripheral glucose homeostasis during a hyperinsulinemic-euglycemic clamp. A: Glucose infusion rate during the glucose clamp was similar between the three groups. B: Glucose production was significantly reduced in ARC GLP-1 versus both saline and i3vt GLP-1 groups. C: Glucose uptake was significantly reduced in ARC and i3vt GLP-1 vs. saline. D: Glucose infusion rate during the hyperinsulinemic-eulgycemic clamp was similar between saline, ARC GLP-1, and ARC GLP-1 plus glibenclamide. E: Coinfusion of glibenclamide into the ARC prevented GLP-1–induced inhibition of glucose production. F: Coinfusion of glibenclamide into the ARC prevented GLP-1–induced inhibition of glucose uptake. *P < 0.05 vs. saline. †P < 0.05 vs. saline and i3vt. ‡P < 0.05 vs. saline and GLP-1 plus glibenclamide.
FIG. 7.
FIG. 7.
Effect of infusion of GLP-1 or saline into the PVN on glucose kinetics. A: Glucose infusion rate during the glucose clamp was similar between PVN saline and GLP-1 groups. B: Glucose production was similar between the PVN GLP-1 and saline groups. C: Glucose uptake was similar between the PVN GLP-1 and saline groups.
FIG. 8.
FIG. 8.
Effect of site-specific injections of GLP-1 on food intake. A: Cumulative food intake was similar after unilateral or bilateral (inset) ARC injection of GLP-1 or saline. B: Cumulative food intake was significantly reduced after 60 and 120 min of GLP-1 injection compared with an equal volume of saline injected directly into the PVN. *P < 0.05 vs. GLP-1.
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