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Physiol. Genomics 31: 252-263, 2007. First published July 24, 2007; doi:10.1152/physiolgenomics.00093.2007
1094-8341/07 $8.00
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Received 26 April 2007; accepted in final form 8 July 2007.
Physiological Genomics 31:252-263 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society

Disruption of a novel regulatory locus results in decreased Bdnf expression, obesity, and type 2 diabetes in mice

Haibo Sha1, Jingyue Xu1, Jing Tang1, Jun Ding1, Jianfeng Gong1, Xiaomei Ge1, Dong Kong1 and Xiang Gao1,2

1 Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing
2 Model Organism Division, E-Institutes of Shanghai Universities, Shanghai, China

Mutants of brain-derived neurotrophic factor (BDNF) are associated with obesity. However, the regulatory mechanism of BDNF expression is still unclear. We developed a novel mutant mouse line, transgenic insertional mutants with obesity, named Timo, in which a potential regulatory locus of Bdnf was disrupted by transgene insertion. The insertion site was identified and lies 857 kb upstream of the Bdnf gene. The disrupted genomic locus is conserved across the mouse, rat, dog, and human genome and contains several highly conserved elements that are able to upregulate reporter gene expression in vitro. Along with downregulation of BDNF to ~30% of wild-type animals, Timo/Timo mice exhibited increased body weight and fat content with hepatic steatosis and elevated serum levels of leptin, cholesterol, and LDL cholesterol. These mutant mice also showed obesity-independent insulin resistance, hyperinsulinemia, impaired glucose tolerance, age-dependent hyperglycemia, and shortened life span. Molecular and phenotype analysis of Timo/Timo mice indicated the existence of a genome locus, lying 857 kb upstream of the Bdnf gene, that regulates BDNF expression, body weight, and glucose homeostasis.

brain-derived neurotrophic factor; gene regulation; insulin resistance






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