Leptin deficiency affects glucose homeostasis and results in adiposity in zebrafish

in Journal of Endocrinology
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  • 1 J He, Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
  • 2 Y Ding, Department of Animal Sciences and Health, Institute of Biology , Leiden University, Leiden, Netherlands
  • 3 N Nowik, Department of Animal Sciences and Health, Institute of Biology , Leiden University, Leiden, Netherlands
  • 4 C Jager, Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
  • 5 M H. Eeza, Institute of Medical Physics and Biophysics, Leipzig University, Leipzig, Germany
  • 6 A Alia, Leiden Institute of Chemistry, Leiden University, Leiden, 2300 RA, Netherlands
  • 7 H Baelde, Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
  • 8 H Spaink, Department of Animal Sciences and Health, Institute of Biology, Leiden University, Leiden, Netherlands

Correspondence: Herman P Spaink, Email: h.p.spaink@biology.leidenuniv.nl
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Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogues genes encoding leptin, called lepa and lepb. In a gene expression study, we found that the lepb gene, not the lepa gene, was significantly downregulated under the state of insulin-resistant in zebrafish larvae, suggesting that the lepb plays a role in insulin homeostasis. In the current study, we characterised lepb-deficient (lepb-/-) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the deletion of lepb gene would result in the development of type 2 diabetes mellitus (T2DM) and diabetic complications. We observed that lepb-/- adult zebrafish had an increase in body weight, length and visceral fat accumulation, compared to age-matched control zebrafish. In addition, lepb-/- zebrafish had significantly higher blood glucose levels compared to control zebrafish. These data collectively indicate that lepb-/- adult zebrafish display the features of T2DM. Furthermore, we showed that lepb-/- adult zebrafish had glomerular hypertrophy and thickening of glomerular basement membrane, compared to control zebrafish, suggesting that lepb-/- adult zebrafish develop early signs of diabetic nephropathy. In conclusion, our results demonstrate that lepb regulates glucose homeostasis and adiposity in zebrafish, and suggest that lepb-/- mutant zebrafish are a promising model to investigate the role of leptin in the development of T2DM and an attractive model to perform mechanistic and therapeutic research in T2DM and its complications.

 

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