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. 2009 Dec;58(12):2820-7.
doi: 10.2337/db09-0281. Epub 2009 Sep 9.

Differences in the central anorectic effects of glucagon-like peptide-1 and exendin-4 in rats

Jason G Barrera  1 , David A D'Alessio, Daniel J Drucker, Stephen C Woods, Randy J Seeley
Affiliations

Differences in the central anorectic effects of glucagon-like peptide-1 and exendin-4 in rats

Jason G Barrera et al. Diabetes. 2009 Dec.

Abstract

Objective: Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting GLP-1 receptor (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of GLP-1 and Ex4, but it is possible that the two peptides control feeding via distinct mechanisms.

Research design and methods: In this study, the anorectic effects of intracerebroventricular GLP-1 and Ex4, and the sensitivity of these effects to GLP-1r antagonism, were compared in rats. In addition, the GLP-1r dependence of the anorectic effect of intracerebroventricular Ex4 was assessed in GLP-1r(-/-) mice.

Results: Intracerebroventricular Ex4 was 100-fold more potent than GLP-1 at reducing food intake, and this effect was insensitive to GLP-1r antagonism. However, GLP-1r antagonists completely blocked the anorectic effect of intraperitoneal Ex4. Despite the insensitivity of intracerebroventricular Ex4 to GLP-1r antagonism, intracerebroventricular Ex4 failed to reduce food intake in GLP-1r(-/-) mice.

Conclusions: These data suggest that although GLP-1rs are required for the actions of Ex4, there appear to be key differences in how GLP-1 and Ex4 interact with central nervous system GLP-1r and in how Ex4 interacts with GLP-1r in the brain versus the periphery. A better understanding of these unique differences may lead to expansion and/or improvement of GLP-1-based therapies for type 2 diabetes and obesity.

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Figures

FIG. 1.
FIG. 1.
Comparison of anorectic effects of intracerebroventricular GLP-1 and Ex4. A and B: Dose-response curves for intracerebroventricular GLP-1 (A) and Ex4 (B). Cumulative 4-h food intake is shown. C: Time course of anorectic effects of intracerebroventricular GLP-1 (3.0 nmol) and Ex4 (0.03 nmol) over 24 h. □, Saline; ▨, GLP-1 (3.0 nmol/l); formula image, Ex4 (0.03 nmol/l). D: Preference ratios for 0.1% saccharin versus total fluid intake during the 4-h two-bottle access to saccharin and water. Saccharin was previously paired with intracerebroventricular saline, intracerebroventricular GLP-1 (3.0 nmol), intracerebroventricular Ex4 (0.03 nmol), or intraperitoneal LiCl (0.15 mol/l administered at 2.0% body wt). Dotted line represents preference ratio for saline-treated rats. Data are represented as means ± SE. *P < 0.05 vs. saline. #P < 0.05 vs. GLP-1.
FIG. 2.
FIG. 2.
Effect of GLP-1r antagonists on anorexia induced by intracerebroventricular GLP-1 and Ex4. A and B: Rats were pretreated with intracerebroventricular dHEx (10 μg) followed by intracerebroventricular GLP-1 (10 μg) (A) or Ex4 (0.1 μg) (B). C and D: Rats were pretreated with intracerebroventricular Ex9 (100 μg) followed by intracerebroventricular GLP-1 (10 μg) (C) or Ex4 (0.1 μg) (D). Cumulative 4-h food intake is shown. Data are represented as means ± SE. *P < 0.05 vs. Sal/Sal. #P < 0.05 vs. Sal/GLP-1.
FIG. 3.
FIG. 3.
Effect of dHEx on c-Fos immunoreactivity induced by intracerebroventricular GLP-1 and Ex4. Quantification of c-Fos–positive nuclei in the PVN (A), NTS (B), and CeA (C) of rats that were treated with intracerebroventricular saline or dHEx (10 μg) followed by intracerebroventricular saline, GLP-1 (10 μg), or Ex4 (0.1 μg) and killed 2 h later. Data are represented as means ± SE. *P < 0.05 vs. Sal/Sal. #P < 0.05 vs. Sal/GLP-1.
FIG. 4.
FIG. 4.
Effect of dHEx (100 nmol/l) on insulin secretion induced by GLP-1 (1.0 nmol/l) and Ex4 (0.01 and 1.0 nmol/l) in the presence of glucose (200 mg%). Data are represented as means ± SE. *P < 0.05 vs. glucose. #P < 0.05 vs. glucose + GLP-1 (1.0 nmol/l) or glucose + Ex4 (1.0 nmol/l). □, Saline; ■, 100 nmol/l dHEx.
FIG. 5.
FIG. 5.
Effect of intraperitoneal dHEx (1.0 mg/kg) on anorexia induced by intraperitoneal Ex4 (10.0 μg/kg). Cumulative 4-h food intake is shown. Data are represented as means ± SE. *P < 0.05 vs. Sal/Sal. #P < 0.05 vs. Sal/Ex4.
FIG. 6.
FIG. 6.
Effect of intracerebroventricular Ex4 in wild-type and GLP-1r−/− mice. A and B: Wild-type mice received intracerebroventricular saline (□) or Ex4 (1.0 μg) (■). Food intake (A) and body weight change (B) were measured over 96 h. C and D: GLP-1r−/− mice received intracerebroventricular saline or Ex4 (1.0 μg). Food intake (C) and body weight change (D) were measured over 24 h. Data are represented as means ± SE. *P < 0.05 vs. saline.
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