Endocrine Abstracts

The peptides acylated and unacylated ghrelin (AG and UAG) are produced predominantly in the stomach. AG is the only known circulating orexigenic hormone with obesogenic and insulin-desensitising properties. Recent evidence suggests that UAG can inhibit these activities of AG. To investigate potential inhibitory effects of UAG and AZP-531, a UAG analogue, on AG-induced appetite and obesity we used an established rat model of diet induced obesity. Animals were fed a high-fat diet, then at 3 weeks implanted with osmotic mini-pumps containing either vehicle, AG, UAG, AG+UAG, AZP-531 or AG+AZP-531 (n=8 per group). All peptides were infused at 4 nmol/kg per h for 4 weeks. From 1 week before the start of infusion body weight and food intake were measured daily, blood sampling and assessments of feeding behaviour were made weekly. At the end of the experiment fat mass of different tissues, and body water and lean mass were measured. Tissues were also processed for mRNA analysis. The AG treated groups showed increased weight gain relative to the non-AG treated groups, but there was no significant effect of the UAG analogues. AG significantly increased total fat, but not lean or water mass. Remarkably, UAG and AZP-531 blocked AG-induced total fat accumulation, their inhibitory effects being localised to subcutaneous and retroperitoneal depots. UAG and AZP-531 also significantly suppressed AG-driven total food intake as well as aspects of AG-driven feeding behaviour, particularly speed of food intake. These activities may occur via a central mechanism since UAG and AZP-531 prevented the suppression of hypothalamic Mc4r mRNA by AG. In conclusion, UAG analogues suppress AG-induced fat accumulation and feeding behaviours, and may therefore have therapeutic potential in clinical indications where hyperphagia and altered behaviour towards food are related to high ghrelin levels such as Prader-Willi syndrome.