PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin

Abstract

PM. PACAP intraperitoneal treatment suppresses appetite and food intake via PAC1 receptor in mice by inhibiting ghrelin and increasing GLP-1 and leptin. Am J Physiol Gastrointest Liver Physiol 309: G816 -G825, 2015. First published September 3, 2015 doi:10.1152/ajpgi.00190.2015.-Pituitary adenylate cyclase-activating peptide (PACAP) is expressed within the gastroenteric system, where it has profound physiological effects. PACAP was shown to regulate food intake and thermogenesis centrally; however, PACAP peripheral regulation of appetite and feeding behavior is unknown. Therefore, we studied PACAP's effect on appetite and food intake control by analyzing feeding behavior and metabolic hormones in PAC1-deficient (PAC1Ϫ/Ϫ) and age-matched wild-type (WT) mice intraperitoneally injected with PACAP 1-38 or PACAP 1-27 before the dark phase of feeding. Food intake and feeding behavior were analyzed using the BioDAQ system. Active ghrelin, glucagon-like peptide-1 (GLP-1), leptin, peptide YY, pancreatic polypeptide, and insulin were measured following PACAP 1-38 administration in fasted WT mice. PACAP 1-38/PACAP1-27 injected into WT mice significantly decreased in a dose-dependent manner cumulative food intake and reduced bout and meal feeding parameters. Conversely, PACAP 1-38 injected into PAC1Ϫ/Ϫ mice failed to significantly change food intake. Importantly, PACAP1-38 reduced plasma levels of active ghrelin compared with vehicle in WT mice. In PAC1Ϫ/Ϫ mice, fasting levels of active ghrelin, GLP-1, insulin, and leptin and postprandial levels of active ghrelin and insulin were significantly altered compared with levels in WT mice. Therefore, PAC1 is a novel regulator of appetite/satiety. PACAP 1-38/PACAP1-27 significantly reduced appetite and food intake through PAC1. In PAC1Ϫ/Ϫ mice, the regulation of anorexigenic/orexigenic hormones was abolished, whereas active ghrelin remained elevated even postprandially. PACAP significantly reduced active ghrelin in fasting conditions. These results establish a role for PACAP via PAC1 in the peripheral regulation of appetite/satiety and suggest future studies to explore a therapeutic use of PACAP or PAC1 agonists for obesity treatment.pituitary adenylate cyclase-activating peptide; PAC1 receptor; appetite; ghrelin; GLP-1; leptin PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) was originally isolated from the ovine hypothalamus and is highly conserved among vertebrates (1). PACAP, because of its protein structure, particularly in the first 27 amino acids, belongs to the secretin-glucagon superfamily of hormones, which includes vasoactive intestinal peptide (VIP), gastric inhibitory peptide, glucagon-like peptide (GLP)-1 and GLP-2, growth hormone-releasing hormone, peptide histidine methionine, peptide histidine isoleucine, and exendins (34). PACAP exists in two variant forms: PACAP 1-27 and the COOHterminally extended form PACAP 1-38 that originates from the same precursor and stimulates adenylate cyclase activity in pituitary cells (23,35). PACAP functions through its P...

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis

“…Array results need to be confirmed by individual PCR experiments, but there are some observations that we would like to note here. Thus, receptors for several anorectic peptides that were suggested, or clinically tested, as an antiobesity treatment (Cron et al, 2016;González et al, 2015;Vu et al, 2015;Li et al, 2016) seem to be upregulated in high-5HT animals (e.g. bombesin-like receptor 3: H/L = 1.45; neurotensin receptor 1: H/L = 1.55; Cntf receptor: H/L = 1.38; adenylate cyclase activating polypeptide 1 receptor type 1: H/L = 1.35; Table 1).…”

Identification by Docking Simulation and in vivo Effect of Essential Oil from Cinnamommum burmannii as Anti-obesity with Leptin Receptor in the Olfactory System of Mice Balb C

“…8 Another study by Keung et al (2011) showed that administration of exogenous leptin via ICV in obese mice (mice were given a high-fat diet) then play to lose weight and food intake, it also served to increase fatty acid oxidation, and increased tolerance glukosa. 9 In this research, immunohistochemical methods will be used to see on the metabolic activity of hormone receptors olfactory system Balb C after being given the essential oils from bark and leaves of the plant cinnamon (Cinnamomum burmannii) via inhalation. Metabolic hormone receptor activity in the olfactory system by the response observed secretion (a protein) that is produced due to the hormone-receptor binding in the hypothalamus.…”

“…Though based on a study conducted by Peters et al (2007), Keung et al (2011), and Schulz et al (2012) note that the metabolic hormone (leptin) that works directly on the hypothalamus starts the process of interaction that occurs between the lep-R in system olfaktori. [8][9][10] Given these facts , this study aims to look at the effect of inhalation of essential oil of cinnamon (Cinnamomum burmannii ) on the metabolic activity of hormone receptors Balb C mice olfactory system by the protein that is secreted in the hypothalamus using immunohistochemistry method.…”

“…8 Another study showed that administration of exogenous leptin via ICV in obese mice (mice were given a high-fat diet) then play to lose weight and food intake, also served to increase fatty acid oxidation and increased tolerance glucose. 9 The effect of weight loss and food intake also occurs in obese rats given exogenous leptin via intranasal. 10 Based on these studies it can be concluded that the effect of decreasing body weight and food intake by leptin beginning of leptin binding to its receptors on the olfactory system which then affects the activity of the hypothalamus in response to appetite and metabolism.…”

Developmental changes in the hypothalamic mRNA expression levels of PACAP and its receptor PAC1 and their sensitivity to fasting in male and female rats

“…Recently, it has been reported that hypothalamic PACAP in the VMN is a target of central leptin signaling. For example, the anorectic actions of leptin are abolished in PAC1‐deficient mice (Vu et al, 2015) and PACAP knockout mice (Tanida et al, 2013). In addition, PACAP mRNA expression in the VMN is reduced in leptin knockout mice and increased by the administration of leptin (Hawke et al, 2009).…”