Abstract
BackgroundObesity 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.Methodology/Principal Findings 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.Conclusion/SignificanceCollectively, 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.
Highlights
Obesity has become a worldwide health problem in recent decades
Human genes were placed under the control of zebrafish skin-specific keratin4 promoter and injected expressional vectors into one-cell stage zebrafish embryos
The injected embryos were raised to adult and the stable transgenic fish were screened by outcrossing with wild-types
Summary
Obesity has become a worldwide health problem in recent decades. According to the International Obesity Task Force (IOTF), the worldwide overweight population exceeds 1.7 billion. The potential risks of obesity or metabolic syndrome will affect human health and life quality. Evidence collected from recent studies indicates that obesity involves complex physiological disorders and is influenced by the interaction of genetic, epigenetic, and environmental factors [6,7,8]. Current methods of probing adipogenesis, obesity-related chronic diseases and metabolic syndrome largely rely on conventional in vitro cell culture and in vivo animal models. Researchers have successfully developed several animal models in nematodes [12,13], flies [14,15] and rodents [16,17] to probe adipogenesis and the disease mechanism of human obesity in vivo. Multifactorial disorder influenced by the interaction of genetic, epigenetic, and environmental factors. The specific aim of this study was to create a zebrafish obesity model by over expressing the insulin signaling hub of the Akt gene
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