Increased food intake with oxyntomodulin analogues

AbstractOxyntomodulin analogues offer a novel treatment for obesity. However during analogue screening in a rat model increased food intake was consistently observed. To further investigate this finding, a series of representative analogues (OXM14 and OXM15) and their Glu-3 equivalents (OXM14E3 and OXM15E3) were administered to rats for 7 days and food intake and bodyweight measurements taken. To investigate the role of glucagon receptor activation glutamate (Glu/E) was substituted at amino acid position 3. GLP-1 and glucagon receptor efficacy of the oxyntomodulin analogues and their Glu-3 counterparts were measured at the rat receptors in vitro. Doses of 25nmol/kg of OXM14 and OXM15 increased food intake by up to 20%. Bodyweight was not significantly increased. Food intake was not increased with the Glu-3 peptides, indicating that a glucagon receptor mechanism may be responsible for the increase in food intake

A glucagon analogue decreases body weight in mice via signalling in the liver.

Glucagon receptor agonists show promise as components of next generation metabolic syndrome pharmacotherapies. However, the biology of glucagon action is complex, controversial, and likely context dependent. As such, a better understanding of chronic glucagon receptor (GCGR) agonism is essential to identify and mitigate potential clinical side-effects. Herein we present a novel, long-acting glucagon analogue (GCG104) with high receptor-specificity and potent in vivo action. It has allowed us to make two important observations about the biology of sustained GCGR agonism. First, it causes weight loss in mice by direct receptor signalling at the level of the liver. Second, subtle changes in GCG104-sensitivity, possibly due to interindividual variation, may be sufficient to alter its effects on metabolic parameters. Together, these findings confirm the liver as a principal target for glucagon-mediated weight loss and provide new insights into the biology of glucagon analogues

Ghrelin acylation by ghrelin-O-acyltransferase can occur in healthy part of oncologic liver in humans

INTRODUCTION: Activation of ghrelin is controlled by the enzyme Ghrelin-O-Acyl Transferase (GOAT). In humans, localization of this acylation is poorly understood. The aim of that study was to explore GOAT localization and activation in human Liver by evaluating both bioactive and non-bioactive ghrelin in the blood stream entering and leaving liver and to simultaneously evaluate GOAT mRNA expression in Liver. METHODS: Healthy part of oncologic hepatic tissue collected from nine patients undergoing hepatectomy was used to evaluate GOAT mRNA expression by quantitative real time polymerase chain reaction (RTqPCR). Simultaneously blood from portal vein, supra hepatic vein, sub clavicular vein and radial artery was also sampled to assay total and acylated ghrelin. RESULTS: Acylated ghrelin level was significantly increased in supra hepatic vein compared to portal vein level (385±42 ng/ml vs. 268±24 ng/ml, p=0.04). Supra hepatic vein to portal vein ratio for acylated ghrelin (acylation ratio) is at 1.4±0.1. Mean expression of GOAT mRNA in liver, expressed as 2-∆Ct/µg total RNA/1µl of liver tissue was at 0.042±0.021 arbitrary units. GOAT mRNA expression in liver was correlated with acylated to total ghrelin ratio in supra hepatic vein (p=0.016, R=0.75) and with acylation liver ratio (p=0.05, R=0.61). CONCLUSIONS: Blood concentration of acylated ghrelin was found significantly increased after its passage through liver suggesting acylation can occur in the liver. RTqPCR data confirmed the presence of GOAT in liver, with positive correlation between GOAT expression and acylated ghrelin liver ratio. This study strongly suggests that liver is a site of ghrelin acylation in human