Disruption of a novel regulatory locus results in decreased Bdnf expression, obesity, and type 2 diabetes in mice.
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 approximately 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.
Sha
Haibo
H
Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Xu
Jingyue
J
Tang
Jing
J
Ding
Jun
J
Gong
Jianfeng
J
Ge
Xiaomei
X
Kong
Dong
D
Gao
Xiang
X
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D002874:Chromosome Mapping; D017124:Conserved Sequence; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D005809:Genes, Regulator / Q000235:genetics*; D017930:Genes, Reporter; D006801:Humans; D006963:Hyperphagia / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D008297:Male; D008322:Mammals / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009765:Obesity / Q000097:blood / Q000235:genetics*; D013045:Species Specificity; D019076:Transgenes
D019208:Brain-Derived Neurotrophic Factor