A model of insulin resistance in mice, born to diabetic pregnancy, is associated with alterations of transcription-related genes in pancreas and epididymal adipose tissue

Abstract

Objective. This study is conducted on a model of insulin-resistant (IR) mice born to dams which were rendered diabetic by the administration of streptozotocin. Methods. Adult IR and control offspring were selected and we determined the mRNA expression of transcription factors known to modulate pancreatic and adipose tissue activities and inflammation. Results. We observed that serum insulin increased, and the mRNA of insulin gene transcription factors, Pdx-1, Nkx6.1 and Maf-A, were upregulated in IR mice pancreas. Besides, their pancreatic functional capacity seemed to be exhausted as evidenced by low expression of pancreatic Glut2 and glucokinase mRNA. Though IR offspring exhibited reduced epididymal adipose tissue, their adipocytes seemed to be differentiated into macrophage-like cells, as they exhibited upregulated CD14 and CD68 antigens, generally expressed by macrophages. However, there was no peripheral macrophages infiltration into epididymal adipose tissue, as the expression of F4/80, a true macrophage marker, was undetectable. Furthermore, the expression of IL-6, TNF-α and TLR-2, key players of insulin resistance, was upregulated in the adipose tissue of IR offspring. Conclusion. Insulin resistant state in mice, born to diabetic pregnancy, alters the expression of function-related genes in pancreas and epididymal adipose tissue and these offspring are prone to develop metabolic syndrome.

Figure 1

(a) Oral glucose-tolerance tests (OGTT). Glycemia during OGTT (3 g/kg-body weight) was measured after a 15-h fast, every 5–10 minutes, for 120 minutes following glucose administration. (b) Intraperitoneal insulin-tolerance tests (IPITT). Glycemia during IPITT (0.5 U/kg body weight) was measured after a 4-h fast, every 5–10 minutes, for 120 minutes following insulin injection. *P < .01 significant difference between control offspring (open triangle) and hyperglycemic offspring (solid triangle). (c) Evolution of the body weight of the offspring from birth until 3 months of age. Open Square corresponds to control offspring and Solid Square to IR offspring. (d) Glycemia and body weight at 3 months. (e) Serum insulin and insulin mRNA expression in the pancreas. Glycemia, serum insulin, and its mRNA expression were determined as described in Section 2. The offspring were weighed during the study until the age of 3 months. The dams and the offspring after weaning were fed the standard laboratory chow. Values are means ± SEM, n = 12 per group of animals. AU: arbitrary units.

Figure 2

Maf-A, Nkx6-1, Pdx-1, and C/EBP-β (a), Glut2 and GK (b) mRNA expression in the pancreas of IR and control offspring. The expression of mRNA was quantitatively analyzed by employing real-time RT-PCR as described in Section 2. AU: arbitrary units. (c) Serum and hepatic triglyceride (TG) and free fatty acids (FFA) in IR and control offspring. The lipids were determined in serum and liver as described in Section 2. Values are means ± SEM, n = 12 per group of animals.

Figure 3

Relative epididymal adipose tissue weight (a) and adiponectin and leptin (b), and TNF-α and IL-6 (c) mRNA expression in epididymal adipose tissue. Relative liver weight (d) and FAT/CD36 and SREPB-1c mRNA expression in liver (e) of IR and control offspring. The liver and epididymal adipose tissue weights are expressed as milligrams (mg) of the tissue per grams (g) of body weight of mice. The expression of mRNA was quantitatively analyzed by employing real-time RT-PCR as described in Section 2. Values are means ± SEM, n = 12 per group of animals. AU: arbitrary units. The quantity of epididymal adipose tissue was positively correlated with the mRNA expression of adiponectin and leptin two obesity-related parameters; R² = coefficient of correlation between the mass of epididymal adipose tissue and the level of the expression of adipokines (adiponectin and leptin) in each group of animals.

Figure 4

The mRNA expression of CD14, CD68, F4/80, RANTES, CCR5, MCP-1, TCRα(a), and TLR-2 (b) in epididymal adipose tissue of IR and control offspring. The expression of mRNA was quantitatively analyzed by employing real-time RT-PCR as described in Section 2. Values are means ± SEM, n = 12 per group of animals. AU: arbitrary units.