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

Tana S Pottorf,Bryan F Burkey,Pamela V Tran,David J Cho,Micaella P Fagan,James E Vath

doi:10.1172/jci.insight.134278

Tana S Pottorf, Bryan F Burkey + Show 4 more

Open Access

https://doi.org/10.1172/jci.insight.134278

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Abstract

The ciliopathies Bardet-Biedl syndrome and Alström syndrome are genetically inherited pleiotropic disorders with hyperphagia and obesity as primary clinical features. 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 conditional knockout (cko) mice showed decreased hypothalamic proopiomelanocortin expression as well as hyperphagia, obesity, metabolic disease, and hepatic steatosis. In obese Thm1-cko mice, 2-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied by 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 to our knowledge 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.

Highlights

Obesity and associated insulin resistance increase risk for potentially fatal chronic diseases, including cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver disease
In Thm1-cko mice, Methionine aminopeptidase 2 inhibitors (MetAP2i) treatment caused a –17.1% body weight reduction compared with –5.0% for vehicle (Figure 1D and Supplemental Figure 1E). These data show that MetAP2i counters the hyperphagia and increased body weight induced by deletion of Thm1
We provide the first evidence to our knowledge that methionine aminopeptidase 2 (MetAP2) inhibition reduces food intake and body weight and substantially improves metabolic parameters in a ciliary model of obesity

Summary

Introduction

Obesity and associated insulin resistance increase risk for potentially fatal chronic diseases, including cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver disease. In preclinical and clinical studies, inhibition of methionine aminopeptidase 2 (MetAP2) has shown promising results. MetAP2 belongs to a family of metalloproteases, which cleaves the N-terminal methionine of nascent proteins. This posttranslational modification induces subcellular localization changes and activation of the targeted protein [2]. Studies showed that fumagillin and its analogs have antiobesity effects, resulting in decreased body weight and adiposity and increased insulin sensitivity in high-fat diet–induced obese mice and rats [10, 11] as well as in genetic ob/ob mutant mice [12]. The effectiveness of MetAP2i in various obesity models raises the possibility that inhibiting MetAP2 may counter other forms of obesity

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