Mechanism of lipid induced insulin resistance: Activated PKCε is a key regulator

► This work describes the molecular mechanism of lipid induced insulin resistance. ► Fatty acid (FA) downregulates insulin receptor expression in insulin target cells. ► FA phosphorylates PKCε (pPKCε) that adversely affects insulin receptor (IR). ► pPKCε impairs HMGA1, the transcription regulator of IR gene. ► Reduced IR expression due to FA abrogates insulin sensitivity.