Studies with wortmannin indicate that insulin stimulation of lipogenesis involves multiple signalling pathways

Abstract

Insulin stimulates fatty acid synthesis from glucose in adipose tissue through activation of both pyruvate dehydrogenase (PDH) and acetyl CoA carboxylase (ACC) as well as by increased glucose transport into the cell. While the activation of glucose transport is primarily due to the increase in translocation of the Glut4 glucose transporter isoform to the plasma membrane [I], stimulation of PDH and ACC is thought to involve changes in the phosphorylation states of these enzymes. Although activation of the PDH complex arises from increased dephosphorylation of the enzyme following stimulation of a specific PDH phosphatase [2], the increase in ACC activity is associated with increased phosphorylation of the enzyme by an insulin-stimulated ACC kinase. [3]. Wortmannin, a specific phosphatidyl inositol 3-kinax inhibitor, blocks the increase in glucose uptake in response to insulin in isolated rat adipocytes [4]. In agreement with this, Table 1 shows that wortmannin reduces the stimulation of glucose uptake into rat epididymal fat pads by insulin from 6.7 fold in the absence of the inhibitor to 3.5 fold in its presence. The effect on ACC activity is even more pronounced, with wortmannin completely abolishing the stimulation of ACC by insulin. In contrast to these results, wortmannin has no effect on the increase in PDH activity in fat pads treated with insulin.