Acute Effects of Glucagon-Like Peptide-1 on Hypothalamic Neuropeptide and AMP Activated Kinase Expression in Fasted Rats

Abstract

Abstract. Intracerebroventricular (icv) administration of glucagon-like peptide-1 (GLP-1) inhibits food intake and induces c-fos expression in the hypothalamus. However, the effects of GLP-1 on hypothalamic neuronal activity or neuropeptide mRNA expression are unknown. In this study, we examined the effects of GLP-1 on fasting-induced changes in the expression of hypothalamic orexigenic and anorexigenic neuropeptide. Food intake was significantly inhibited after icv injection of GLP-1 in 48 h fasted rats. Hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) mRNAs were significantly increased by fasting, whereas icv GLP-1 treatment significantly attenuated these fasting-induced increases. Both proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) mRNA levels were decreased by fasting, while GLP-1 treatment attenuated fasting-induced decreases in POMC and CART expression. We also determined the mRNA levels of AMP-activated kinase (AMPK) and found that fasting resulted in a significant stimulation of hypothalamic AMPKα2 mRNA. Fasting-induced increase in AMPKα2 mRNA was almost completely prevented by GLP-1 treatment. Analysis of phosphorylated AMPKα and acetyl CoA carboxylase showed similar results. Taken together, our observation suggests that the decreased food intake by GLP-1 is caused by preventing the fasting-induced increase in hypothalamic NPY and AgRP and the fasting-induced decrease in hypothalamic POMC and CART. Our results also suggest that the food intake lowering effect of GLP-1 is caused by reversing the fasting-induced increase in hypothalamic AMPK activity. Therefore we conclude that the anorectic effect of GLP-1 seems to be mediated by, at least in part, by the hypothalamus. GLUCAGON-LIKE peptide-1 (GLP-1) is synthesized from proglucagon-derived peptides in intestinal endocrine L cells and in selected neurons in the brain stem and hypothalamus [1]. The majority of circulating biologically active GLP-1 is found in the GLP-1-(7-36) amide form, with lesser amounts of the bioactive GLP-1-(7-37) form also detectable. The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. There has been extensive interest in understanding the role of GLP-1 in the control of satiety and food intake. Intracerebroventricular (icv) administration of GLP-1 or exendin-4 inhibited food intake and body weight in the rat [2][3][4]. These satietyrelated effects have also been observed in human studies with prandial subcutaneous injections of GLP-1 to obese subjects [5]. Blockade of central nervous system (CNS) GLP-1 action using icv infusion of GLP-1 receptor antagonist exendin (9-39) increased food intake and promoted weight gain in rats, suggesting the involvement of GLP-1 receptor in satiety [3]. Despite a large body of evidence demonstrates that GLP-1 is a potent inhibitor of food intake, the precise mechanism

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

“…In that respect, Baumgartner et al (8) observed that the induction of c-fos in the NTS, AP, and CeA was related to the eating inhibitory activity of GLP-1 when it was infused into the hepatic portal vein. Central administration of GLP-1 has also been found to stimulate catabolic neurons in the ARC (43). It is noteworthy that aversive doses of Ex-4 appear to cause a pattern of c-fos induction fairly similar to that seen following nonaversive doses, which let us suppose that the strength of the stimulation (rather than its mere presence) in certain regions might dictate the aversive response.…”

AMPK as a mediator of hormonal signalling

“…In addition, a number of these hormones have been shown to influence AMPK activity. In the short term, anorectic agents such as glucose, GLP-1 and oxyntomodulin decrease hypothalamic AMPK activity (Andersson et al 2004, Minokoshi et al 2004, Seo et al 2008, leading to reduction in food intake during satiation, while orexigenic agents such as ghrelin lead to AMPK activation and increased food intake (Andersson et al 2004, Kola et al 2005. In the long term, the circulating anorectic insulin and leptin determine the energy and adiposity profile.…”

“…Ghrelin is known to activate neurons in the NTS (Date et al 2006). GLP-1 (7-36) amide, an anorectic hormone, acts both in the hypothalamus and the NTS (Goldstone et al 2000, Seo et al 2008, Hayes et al 2009b). …”

“…Hypothalamic GLP-1 peptide content is decreased during fasting. Fasting-induced increase in hypothalamic AMPK activity is inhibited by GLP-1 and this could be the mechanism of its anorectic effects (Seo et al 2008). It has been shown that the anorectic effects of leptin are at least partly via GLP-1.…”

GLP-1, the Gut-Brain, and Brain-Periphery Axes

“…Furthermore, icv infusion of GLP-1 in fasted rodents increases the synthesis of anorexigenic peptides (POMC and cocaine-and amphetamine-regulated transcript (CART)) both in arcuate and paraventricular nuclei [94]. In these brain locations, the peptide decreases the synthesis of orexigenic peptides (neuropeptide Y (NPY) and agouti-related peptide (AgRP)).…”