title: High fat diet-induced TGF-β/Gbb signaling provokes insulin resistance through the tribbles expression.
abstract: 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.
authors.affiliation: Neurophysiology and Metabolism Research Group, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Neurophysiology and Metabolism Research Group, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.|Functional Genomics Dept., University of Science and Technology (UST), Daejeon 34113, Korea.
authors.forename: Moonyoung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Neurophysiology and Metabolism Research Group, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.|Functional Genomics Dept., University of Science and Technology (UST), Daejeon 34113, Korea.
authors.forename: Kyu-Sun
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Neurophysiology and Metabolism Research Group, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.|Functional Genomics Dept., University of Science and Technology (UST), Daejeon 34113, Korea.|Convergence Research Centre for Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
authors.forename: Kweon
authors.initials: K
authors.lastname: Yu
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005216:Fat Body / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; C089440:gbb protein, Drosophila; C410505:trbl protein, Drosophila; C494917:Akt1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt