IGF-I attenuates FFA-induced activation of JNK1 phosphorylation and TNFα expression in human subcutaneous preadipocytes

OBJECTIVE: Free fatty acids (FFAs) are increased in visceral fat and contribute to insulin resistance through multiple mechanisms, including c-Jun N-terminal kinase (JNK) activation and expression of TNFα. Given that IGF-I-mediated proliferation is impaired in omental compared to subcutaneous (sc) preadipocytes, we investigated IGF-I anti-inflammatory action in preadipocytes from sc and omental adipose tissue. METHODS: Preadipocytes isolated from abdominal sc and omental fat of obese subjects were studied in primary culture. Cells were exposed to FFAs with or without IGF-I pretreatment followed by analysis of cytokine expression and JNK phosphorylation. Lentivirus infection was used to express a constitutively active AKT (myr-AKT) in omental preadipocytes. RESULTS: FFAs increased expression of TNFα, IL-6 and MCP-1 in sc and omental preadipocytes. IGF-I pretreatment reduced FFA-induced JNK1 phosphorylation and TNFα expression in sc but not omental preadipocytes. Treatment with the JNK1/2 inhibitor SP600125 reduced FFAinduced expression of TNFα. FFAs and MALP-2, a specific TLR2/6 ligand, but not specific ligands for TLR4 and TLR1/2, increased JNK1 phosphorylation. IGF-I completely inhibited MALP-2-stimulated phosphorylation of JNK1. Expression of myr-AKT in omental preadipocytes inhibited FFA-stimulated JNK1 phosphorylation. CONCLUSIONS: IGF-I attenuates FFA-induced JNK1 phosphorylation and TNFα expression through activation of AKT in human subcutaneous but not omental preadipocytes.