Potential Role of Hypothalamic and Plasma Ghrelin in the Feeding Behavior of Obese Type 2 Diabetic Rats with Intraventricular Glucagon-Like Peptide-1 Receptor Agonist Intervention

Abstract

Objective: To investigate the relationship of central and peripheral ghrelin during an exendin-4 (Ex-4) intervention to feeding in obese type 2 diabetic rodents.

Methods: Animal models of diet-induced obesity (DIO) and type 2 diabetes were developed using male Sprague-Dawley rats fed with a high-fat diet and induced into DIO-streptozotocin diabetic rats. Ex-4 or the glucagon-like peptide-1 (GLP-1) receptor agonist exendin fragment-[9-39] (Ex-9) was intracerebroventricularly (ICV) administered. Multivariate linear regression analysis was performed to investigate potential predictors of food intake after Ex-4 administration.

Results: ICV administration of Ex-4 significantly inhibited feeding and decreased weight, plasma active ghrelin, hypothalamic ghrelin, and gastric ghrelin levels. The changes in hypothalamic ghrelin and plasma ghrelin could predict the amount of 8-h average food intake. Central preadministration of Ex-9 followed by treatment with Ex-4 could inhibit the decrease in feeding at 0.5, 2, and 8 h. It could also inhibit the decrease in hypothalamic ghrelin at 0.5, 2, and 8 h, as well as in plasma and gastric ghrelin at 2 and 8 h.

Conclusions: In a GLP-1 receptor-dependent manner, central and peripheral ghrelin play a vital role in the inhibition of feeding by Ex-4 administration. Hypothalamic ghrelin, but not plasma ghrelin, may be involved in central Ex-4 inhibition of feeding in the very early feeding period.

Keywords: Appetite regulation; Glucagon-like peptide-1 receptor agonist; Hypothalamic ghrelin; Obesity; Type 2 diabetes.

Fig. 1

Study flowchart of rat group formation. STZ, streptozotocin; DIO, diet-induced obesity; Ex, exendin.

Fig. 2

Central effects of Ex-4 on food intake and body weight. A Cumulative food intake. B Average food intake. C Weight change. DIO rats were used in A and used as controls (DIO-control) in B and C. Values are means ± SEM (n = 50 for DIO-STZ Ex-4 group and n = 40 for DIO-STZ vehicle and DIO groups). * p < 0.05, ** p < 0.01 compared to DIO-STZ vehicle or Ex-4 (ICV) group; ^# p < 0.05, ^## p < 0.01 compared to DIO-control. STZ, streptozotocin; DIO, diet-induced obesity; Ex, exendin; ICV, intracerebroventricular; IP, intraperitoneal.

Fig. 3

Central effects of Ex-4 on blood glucose (A), insulin (B), blood obestatin (C), plasma ghrelin (D), hypo­thalamic ghrelin (E), and gastric ghrelin (F) levels. DIO rats were used as controls (DIO-control). Values are means ± SEM (n = 50 for DIO-STZ Ex-4 group and n = 40 for DIO-STZ vehicle and DIO groups). * p < 0.05, ** p < 0.01 compared to DIO-STZ vehicle; ^# p < 0.05, ^## p < 0.01 compared to DIO-control. STZ, streptozotocin; DIO, diet-induced obesity; Ex, exendin.

Fig. 4

Differences in blood glucose (A), insulin (B), plasma ghrelin (C), obestatin (D), hypothalamic ghrelin (E), and gastric ghrelin (F) levels between before and after ICV Ex-4 administration. DIO-STZ rats were used. Values are means ± SEM. STZ, streptozotocin; DIO, diet-induced obesity; Ex, exendin; ICV, intracerebroventricular.

Fig. 5

Central effects of Ex-9 on food intake and ghrelin levels. A Average food intake. B Plasma ghrelin. C Hypothalamic ghrelin. D Gastric ghrelin. Values are means ± SEM (n = 50 for Ex-4 group and n = 40 for Ex-9/Ex-4 and NS groups). * p < 0.05, ** p < 0.01 compared to Ex-4 group; ^# p < 0.05 compared to NS group. Ex, exendin.