This proposal aims to identify genetic variants that underlie susceptibility or resistance to developing diabetes and diabetic complications. We have developed a tractable genetic model system using inbred mouse strains carrying a mutation of the leptin receptor. The interaction between the obesity/diabetes syndrome caused by the leptin receptor deficiency and the specific genetic constitution of the inbred strain determines diabetes susceptibility or resistance. Genetic selection of specific chromosomal regions of the mouse genome has identified regions on mouse Chromosome 5 that is responsible for diabetes susceptibility. The region has been reduced to a 15 million base pair region containing ~200 identified genes. This proposal has three aims: 1. Define a critical interval of 100-300 kbp for Modb1. 2. Identify allelic variants that produce nonsynonymous coding sequence variants or expression differences between the C57BL/6 and FVB alleles. 3. Evaluate the impact of Modb1 alleles on beta cell regeneration/proliferation after induction of beta cell apoptosis.
|Marcelin, Geneviève; Jo, Young-Hwan; Li, Xiaosong et al. (2014) Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism. Mol Metab 3:19-28|
|Luo, Na; Marcelin, Genevieve; Liu, Shun Mei et al. (2011) Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency. Endocrinology 152:883-9|
|Reid, Brendan N; Ables, Gene P; Otlivanchik, Oleg A et al. (2008) Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J Biol Chem 283:13087-99|
|Luo, Na; Liu, Shun Mei; Liu, Hong et al. (2006) Allelic variation on chromosome 5 controls beta-cell mass expansion during hyperglycemia in leptin receptor-deficient diabetes mice. Endocrinology 147:2287-95|
|Wang, Zhuowei; Jiang, Tao; Li, Jinping et al. (2005) Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 54:2328-35|