Influence of diet on visceral adipose remodeling in NONcNZO10 mice with polygenic susceptibility for type 2 diabetes

Visceral adipose tissue (VAT) is a source of inflammatory cytokines that in obese subjects may contribute to low-level systemic inflammation and development of metabolic syndrome. Expansion of VAT involves adipocyte hyperplasia and hypertrophy and requires breakdown of the extracellular matrix (ECM) and increased vascular outgrowth. To investigate changes of gene expression associated with VAT expansion and the role of combined genetics and diet we implemented gene microarray analyses of VAT in NONcNZO10 (NZ10) and control SWR/J mice subjected to control chow (CD) or a diet of high protein and fish oil (HPO). NZ10 mice on CD showed increased body weight, hyperglycemia and hyperinsulinemia at 25 weeks whereas those on HPO diet retained normal insulin levels and were normoglycemic. Two-way ANOVA revealed a significant interaction between diet and strain on blood glucose, serum insulin and percent fat but not for body weight. Microarray heat-maps revealed a remarkable combined effect of genetics and diet on genes that regulate ECM as well as angiogenic genes. RT-PCR confirmed markedly increased expression of Matrix Metalloproteinases (MMPs) -2, -3, -11, and -12, VEGF-A and C, Von Willebrand Factor (VWF) and PPARγ selectively in the NZ10/CD group. MMP-7 was significantly decreased. Protein levels of MMP-2, 3 and 9 were significantly increased in the VA of NZ10 mice fed CD while those of MMP-7 were down-regulated. Microarrays also revealed diet-dependent 2–4-fold increased expression of all 4 Tissue inhibitor of Metalloproteinases (TIMP) isoforms in NZ10 mice. Two-way ANOVA confirmed strongly interactive roles of diet and genetics on fat deposition and progression of T2D in this polygenic mouse model.