Impaired insulin-receptor autophosphorylation is an early defect in fat-fed, insulin-resistant rats.

High-fat feeding results in impaired insulin signaling in skeletal muscle, but the role of the insulin receptor (IR) remains controversial. In the present study, female Fischer 344 rats were fed diets either low in fat [low fat, complex carbohydrate (LFCC)] or high in fat and sucrose (HFS). Insulin-stimulated skeletal muscle glucose transport, measured in purified sarcolemmal vesicles, was lower in rats consuming the HFS diet for 2 and 8 wk compared with LFCC controls (72.9 +/- 3.5, 67.6 +/- 3.5, and 86.1 +/- 3.5 pmol x mg(-1) x 15 s(-1), respectively; P < 0.05). Muscle IR content was unchanged in 2-wk HFS animals but was 50% lower in the 8-wk HFS group (P < 0.001). However, compared with LFCC, insulin-stimulated IR autophosphorylation was 26% lower in 2-wk HFS and 40% lower in 8-wk HFS animals (P < 0.005). Total muscle content of the proposed IR inhibitors cytokine tumor necrosis factor-alpha and membrane glycoprotein PC-1 was not significantly changed in HFS animals at either 2 or 8 wk. These results demonstrate that high-fat feeding induces insulin resistance in muscle concomitant with a diminished IR signaling capacity, although the mechanism remains unknown.