Both insulin and the cell death-inducing DNA fragmentation factor-α-like 
effector (CIDE) family play important roles in apoptosis and lipid droplet 
formation. Previously, we reported that CIDEA and CIDEC are differentially 
regulated by insulin and contribute separately to insulin-induced anti-apoptosis 
and lipid droplet formation in human adipocytes. However, the upstream signals 
of CIDE proteins remain unclear. Here, we investigated the signaling molecules 
involved in insulin regulation of CIDEA and CIDEC expression. The 
phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and PI-103 blocked 
both insulin-induced downregulation of CIDEA and upregulation of CIDEC. The Akt 
inhibitor API-2 and the c-Jun N-terminal kinase (JNK) inhibitor SP600125 
selectively inhibited insulin regulation of CIDEA and CIDEC expression, 
respectively, whereas the MAPK/ERK kinase inhibitor U0126 and the p38 inhibitor 
SB203580 did not. Small interfering RNA-mediated depletion of Akt1/2 prevented 
insulin-induced downregulation of CIDEA and inhibition of apoptosis. Depletion 
of JNK2, but not JNK1, inhibited insulin-induced upregulation of CIDEC and lipid 
droplet enlargement. Furthermore, insulin increased both Akt and JNK 
phosphorylation, which was abrogated by the PI3K inhibitors. These results 
suggest that insulin regulates CIDEA and CIDEC expression via PI3K, and it 
regulates expression of each protein via Akt1/2- and JNK2-dependent pathways, 
respectively, in human adipocytes.