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

<b><i>Objective:</i></b> To investigate the relationship of central and peripheral ghrelin during an exendin-4 (Ex-4) intervention to feeding in obese type 2 diabetic rodents. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusions:</i></b> 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.

The Mechanism of the Gut-Brain Axis in Regulating Food Intake

“…Intracerebroventricular injection of Exendin-4 (Ex-4), a GLP-1R-specific agonist, significantly reduced food intake and decreased body weight as well as hypothalamic and gastric ghrelin levels in rats [61], consistent with Hong et al, finding that Ex-4 inhibits Ghrelin secretion via the Mammalian target of Rapamycin (mTOR) signaling pathway [62]. GLP-1 analogues were found to increase POMC neurons' activity in a time-dependent manner after intraperitoneal and subcutaneous injections in mice [63].…”