ENU mutagenesis identifies mice with morbid obesity and severe hyperinsulinemia caused by a novel mutation in leptin

Chen Jee Hong, Pei Jane Tsai, Chih Ya Cheng, Chuan Kai Chou, Huei Fen Jheng, You Chung Chuang, Chia Ning Yang, Ya Tzu Lin, Chih Wei Hsu, Irene H. Cheng, Shiow Yi Chen, Shih Jen Tsai, Ying Jay Liou, Yau Sheng Tsai

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Background: Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals. Methodology/Principal Findings: To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-Nnitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin145E/145E mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin145E/145E mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin145E/145E mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region. Conclusions/Significance: Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.

Original languageEnglish
Article numbere15333
JournalPloS one
Volume5
Issue number12
DOIs
Publication statusPublished - 2010

All Science Journal Classification (ASJC) codes

  • General

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