title: Overexpression of Akt1 enhances adipogenesis and leads to lipoma formation in zebrafish.
abstract: BACKGROUND
  Obesity is a complex, multifactorial disorder influenced by the interaction of genetic, epigenetic, and environmental factors. Obesity increases the risk of contracting many chronic diseases or metabolic syndrome. Researchers have established several mammalian models of obesity to study its underlying mechanism. However, a lower vertebrate model for conveniently performing drug screening against obesity remains elusive. The specific aim of this study was to create a zebrafish obesity model by over expressing the insulin signaling hub of the Akt1 gene.
  
  
  RESULTS
  Skin oncogenic transformation screening shows that a stable zebrafish transgenic of Tg(krt4Hsa.myrAkt1)(cy18) displays severely obese phenotypes at the adult stage. In Tg(krt4:Hsa.myrAkt1)(cy18), the expression of exogenous human constitutively active Akt1 (myrAkt1) can activate endogenous downstream targets of mTOR, GSK-3α/β, and 70S6K. During the embryonic to larval transitory phase, the specific over expression of myrAkt1 in skin can promote hypertrophic and hyperplastic growth. From 21 hour post-fertilization (hpf) onwards, myrAkt1 transgene was ectopically expressed in several mesenchymal derived tissues. This may be the result of the integration position effect. Tg(krt4:Hsa.myrAkt1)(cy18) caused a rapid increase of body weight, hyperplastic growth of adipocytes, abnormal accumulation of fat tissues, and blood glucose intolerance at the adult stage. Real-time RT-PCR analysis showed the majority of key genes on regulating adipogenesis, adipocytokine, and inflammation are highly upregulated in Tg(krt4:Hsa.myrAkt1)(cy18). In contrast, the myogenesis- and skeletogenesis-related gene transcripts are significantly downregulated in Tg(krt4:Hsa.myrAkt1)(cy18), suggesting that excess adipocyte differentiation occurs at the expense of other mesenchymal derived tissues.
  
  
  CONCLUSIONS
  Collectively, the findings of this study provide direct evidence that Akt1 signaling plays an important role in balancing normal levels of fat tissue in vivo. The obese zebrafish examined in this study could be a new powerful model to screen novel drugs for the treatment of human obesity.
authors.affiliation: Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li, Taiwan.
authors.forename: Che-Yu
authors.initials: CY
authors.lastname: Chu
authors.forename: Chi-Fang
authors.initials: CF
authors.lastname: Chen
authors.forename: R Samuel
authors.initials: RS
authors.lastname: Rajendran
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Shen
authors.forename: Te-Hao
authors.initials: TH
authors.lastname: Chen
authors.forename: Chueh-Chuan
authors.initials: CC
authors.lastname: Yen
authors.forename: Chih-Kuang
authors.initials: CK
authors.lastname: Chuang
authors.forename: Dar-Shong
authors.initials: DS
authors.lastname: Lin
authors.forename: Chung-Der
authors.initials: CD
authors.lastname: Hsiao
mesh_terms: D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics*; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D018149:Glucose Intolerance / Q000235:genetics; D008067:Lipoma / Q000209:etiology / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish
chemical_list: D051057:Proto-Oncogene Proteins c-akt