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Junling He, Yi Ding, Natalia Nowik, Charel Jager, Muhamed N H Eeza, A Alia, Hans J Baelde, and Herman P Spaink

Leptin is a hormone which functions in the regulation of energy homeostasis via suppression of appetite. In zebrafish, there are two paralogous 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-resistance in zebrafish larvae, suggesting that the lepb plays a role in glucose homeostasis. In the current study, we characterised lepb-deficient (lepb −/−) adult zebrafish generated via a CRISPR-CAS9 gene editing approach by investigating whether the disruption of the 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 the 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 are an attractive model to perform mechanistic and therapeutic research in T2DM and its complications.