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Hyperglycemia, hyperlipidemia, and insulin resistance are hallmarks of obesity-induced type 2 diabetes, which is often caused by a high-fat diet (HFD). However, the molecular mechanisms underlying HFD-induced insulin resistance have not been elucidated in detail. In this study, we established a  Drosophila  model to investigate the molecular mechanisms of HFD-induced diabetes. HFD model flies recapitulate mammalian diabetic phenotypes including elevated triglyceride and circulating glucose levels, as well as insulin resistance. Expression of  glass bottom boat  ( gbb ), a  Drosophila  homolog of mammalian  transforming growth factor -β ( TGF-β ), is elevated under HFD conditions. Furthermore, overexpression of  gbb  in the fat body produced obese and insulin-resistant phenotypes similar to those of HFD-fed flies, whereas inhibition of Gbb signaling significantly ameliorated HFD-induced metabolic phenotypes. We also discovered that  tribbles , a negative regulator of AKT, is a target gene of  Gbb  signaling in the fat body. Overexpression of  tribbles  in flies in the fat body phenocopied the metabolic defects associated with HFD conditions or Gbb overexpression, whereas  tribbles  knockdown rescued these metabolic phenotypes. These results indicate that HFD-induced TGF-β/Gbb signaling provokes insulin resistance by increasing  tribbles  expression.

High fat diet-induced TGF-β/Gbb signaling provokes insulin resistance through the tribbles expression