IGF-I Attenuates FFA-Induced Activation of JNK1 Phosphorylation and TNF alpha 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 TNF alpha. Given that insulin-like growth factor-1 (IGF-1)-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. Design and 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 the expression of tumor necrosis factor (TNF)alpha, interleukin (IL)-6, and monocyte chemotactic protein (MCP)-1 in SC and omental preadipocytes. IGF-I pretreatment reduced FFA-induced JNK1 phosphorylation and TNF alpha expression in SC but not omental preadipocytes. Treatment with the JNK1/2 inhibitor SP600125 reduced FFA-induced expression of TNF alpha. 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 attenuated FFA-induced JNK1 phosphorylation and TNF alpha expression through activation of AKT in human subcutaneous but not omental preadipocytes.