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

Otilia Neacsu, Kelly Cleveland, Haiyan Xu, Tamara T Tchkonia, James L Kirkland, Charlotte M Boney
Obesity 2013, 21 (9): 1843-9

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 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)α, interleukin (IL)-6, and monocyte chemotactic protein (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 FFA-induced 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 attenuated FFA-induced JNK1 phosphorylation and TNFα expression through activation of AKT in human subcutaneous but not omental preadipocytes.

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