1674-P: Stearate Potentiates MIP-1a Production with TNF-a via TLR4/TBK1/IKKe /IRF3 Signal Axis: Significance for Insulin Resistance

Increased levels of plasma free fatty acids (FAs) are an important contributor to chronic inflammation, insulin resistance and other obesity-related complications. However, the molecular mechanisms by which individual FAs contribute to obesity-associated inflammation and disorders remain incompletely understood. Here we report that dietary saturated FAs specifically stearate led to a profound production of macrophage inflammatory protein (MIP)-1α (CCL3) in the presence of TNF-α in monocytes, macrophages and adipose tissues. Using pharmacologic and genetic approaches, we identified the involvement of TLR4/TBK1/IKKε/IRF3 signal axis in this production of MIP-1α in response to stearate and TNF-α. Consistent with this, cultured adipose tissues from TLR4 knockout (KO) mice revealed that stearate and TNF-α treatment did not induce MIP-1α compared with TLR2 KO or wild type (C57BL/6) mice. Moreover, C57BL/6 mice fed a high fat diet (HFD) for 16 weeks showed elevated levels of plasma fatty acids, TNF-α and MIP-1α along with insulin resistance. MIP-1α was significantly correlated with TNF-α. Our human data shows that expression of TLR4/p-IRF3 was elevated in the PBMCs of obese individuals as compared to lean. Furthermore, elevated MIP-1α expression levels in obese fat tissues were significantly correlated with TNF-α and macrophage markers.

In conclusion, these findings provide a mechanistic link between stearate and TNF-α for the overproduction of obesity associated MIP-1α, which could be used as a new target for the treatment of obesity-related chronic inflammation/insulin resistance.