Effects of obesity and gender on insulin receptor expression in liver of SHHF/Mcc-FAcp rats.

In SHHF/Mcc-FAcp rats (formerly SHR/Mcc-cp), obesity and male gender synergistically modulate hyperinsulinemia, insulin resistance and predisposition to diabetes. Our previous studies showed gender and obesity modulate hepatic cell surface insulin binding and insulin clearance additively. Hepatic insulin receptors (IR) bind insulin as a first step in insulin clearance through internalization and degradation. We hypothesize that the synergistic effects of obesity and gender on hepatic insulin binding and clearance result from interaction of these two factors on hepatic IR expression. To address IR expression in SHHF/Mcc-FAcp rats, we quantitated IR protein levels in detergent-solubilized liver homogenates by Western blotting and IR mRNA levels by a solution hybridization/RNase protection assay. Obesity reduced total hepatic IR content in males and females, 50% and 68% respectively. Male gender reduced IR protein content 24% in lean, but had no effect on IR protein content in obese rats. Neither gender nor obesity affected hepatic IR mRNA content. Thus, obesity appears to affect hepatic IR protein content and cell surface binding through post-transcriptional mechanisms; similarly, male gender in lean rats reduces IR protein levels and cell surface binding through mechanisms not involving changes in mRNA levels. In obese rats, the synergistic effects of male gender appears to involve changes in IR trafficking and consequently cell surface insulin binding and processing.