Fig. 2.

Lack of ACC2 improves insulin signaling in animal tissues. Obese tissues lead to insulin resistance. High acyl-CoA activates PKC Ø, resulting in a cascade of serine and threonine kinases and increasing serine and threonine phosphorylation of insulin receptor substrates, IRS-1 and IRS-2. These substrates generate IRS-Ser-p Thr-p, which decreases the activity of PI 3 kinase, down-regulates AKT, and decreases the translocation of GLUT4 to the plasma membrane, leading to a decrease in glucose uptake (black arrows). As a result of ACC2 deletion (red X), tissues continuously oxidize FA in the mitochondria; this leads to a decrease of FA levels, the down-regulation of PKC Ø, a decrease in the Ser-p Thr-p of IRS1 and IRS2, an increase in IRS-Tyr-p, and the up-regulation of insulin signaling, thereby increasing glucose uptake and lowering the plasma blood glucose level.