Abstract
Exendin-4 (EX-4), a glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to reduce food intake and to increase proopiomelanocortin (POMC) gene expression in the hypothalamus. In this study, we examined the potential neural mechanisms by which these effects occur. Male Sprague Dawley rats were implanted with a cannula in the third ventricle of the brain through which an inhibitor of phosphatidylinositol-3 kinase (PI3K) (wortmannin) was administered, and EX-4 or vehicle was administered via intraperitoneal (IP) injection. The activity of PI3K/protein kinase B (AKT) and insulin receptor substrate-1 (IRS-1) in the hypothalamic arcuate was determined. We found that EX-4 treatment significantly decreased food intake and body weight. However, there were almost no changes in food intake and body weight when wortmannin injection (into the third ventricle) occurred prior to EX-4 IP injection. EX-4 not only increased the activity of PI3K/AKT, but it also increased IRS-1 activity. These results show that EX-4 likely suppresses food intake due to its ability to enhance insulin signaling.
Highlights
The glucagon-like peptide-1 (GLP-1) system was recently established as a target for type 2 diabetes (T2D) and obesity treatment[1,2,3], as it improves blood glucose regulation, reduces food intake, and helps to manage body weight[4, 5]
A previous study showed that EX-4 affects food intake and energy expenditure by activating GLP-1R27
Our results revealed that an insulin-IRS1-phosphatidylinositol-3 kinase (PI3K)/AKT-dependent pathway is involved in the mechanism through which GLP-1 receptor (GLP-1R) in the arcuate nucleus (ARC) mediates food intake suppression
Summary
The glucagon-like peptide-1 (GLP-1) system was recently established as a target for type 2 diabetes (T2D) and obesity treatment[1,2,3], as it improves blood glucose regulation, reduces food intake, and helps to manage body weight[4, 5]. Food intake and energy expenditure is mediated in part by neuropeptides expressed in neurons within nuclei of the mediobasal hypothalamus[15, 16] Orexigenic neuropeptides, such as neuropeptide Y (NPY) and agouti-related protein (AgRP), increase food intake and body weight, while α-melanocyte-stimulating hormone (α-MSH), a product of proopiomelanocortin (POMC), is an anorexigneic neuropeptide that reduces food intake. Our previous study suggested that GLP-1R agonist exendin-4 (EX-4) reduced food intake and body weight by altering POMC gene expression in the hypothalamus of rats[8]. PI3K/AKT signaling is both the direct and indirect upstream target of POMC gene expression[24,25,26] These data suggest that the intake suppressive effects of GLP-1R require PI3K/AKT signaling regulation. We found that the effects of ICV wortmannin on EX-4-induced reduced food intake occurred by increasing ARC PI3K signaling
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