MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity

Abstract

The ciliopathies Bardet-Biedl Syndrome and Alström Syndrome are genetically inherited pleiotropic disorders with primary clinical features of hyperphagia and obesity. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood (Thm1 cko). Thm1 cko mice show decreased hypothalamic proopiomelanocortin expression as well as hyperphagia, obesity, metabolic disease and hepatic steatosis. In obese Thm1 cko mice, two-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied with decreased levels of blood glucose, insulin and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report of MetAP2i reducing hyperphagia and body weight, and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity.

Hyperphagia in Prader-Willi syndrome with obesity: From development to pharmacological treatment

“…Tesofensine, a serotoninnoradrenaline-dopamine monoamine reuptake inhibitor was co-administered with metoprolol (to reduce blood pressure) and showed that it could inhibit hunger feeling and food cravings by boosting the three neurotransmitters' activity. Meanwhile, Beloranib inhibits an enzyme methionine aminopeptidase 2 (MetAP2) that reduces hunger and induces weight loss (45). While JD5037, a cannabinoid-1 receptor blocker reacts on CB receptors function in inhibiting food intake and increasing satiety.…”