EFFECTS OF OBESITY AND GENDER ON INSULIN-RECEPTOR EXPRESSION IN LIVEROF SHHF MCC-FA(CP) RATS/

In SHHF/Mcc-FA(c)P rats (formerly SHR/Mcc-cp), obesity and male gender synergistically modulate hyperinsulinemia, insulin resistance and pre disposition to diabetes, Our previous studies showed gender and obesit y modulate hepatic cell surface insulin binding and insulin clearance additively, Hepatic insulin receptors (RR) bind insulin as a first ste p in insulin clearance through internalization and degradation, We hyp othesize that the synergistic effects of obesity and gender on hepatic insulin binding and clearance result from interaction of these two fa ctors on hepatic IR expression, To address TR expression in SHHF/Mcc-F A(c)P 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 I R content In males and females, 50% and 68% respectively, Male gender reduced IR protein content 24% in lean, but had no effect on IR protei n content in obese rats, Neither gender nor obesity affected hepatic I R mRNA content, Thus, obesity appears to affect hepatic IR protein con tent and cell surface binding through posttranscriptional mechanisms; similarly, male gender in lean rats reduces IR protein levels and cell surface binding through mechanisms not involving changes in mRNA leve ls, In obese rats, the synergistic effects of male gender appears to i nvolve changes in IR trafficking and consequently cell surface insulin binding and processing.