Abstract
Diacylglycerol kinases (DGK) convert diacylglycerol to phosphatidic acid, which has been reported to stimulate calcium release from the endoplasmic reticulum. Based on our published data showing that trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA)-mediated intracellular calcium accumulation is linked to inflammation and insulin resistance, we hypothesized that inhibiting DGKs with R59022 would prevent t10,c12 CLA-mediated inflammatory signaling and insulin resistance in human adipocytes. Consistent with our hypothesis, R59022 attenuated t10,c12 CLA-mediated i) increased gene expression and protein secretion of interleukin (IL)-8, IL-6, and monocyte chemoattractant protein-1 (MCP-1); ii) increased activation of extracellular signal-related kinase (ERK), cJun-NH2-terminal kinase (JNK), and cJun; iii) increased intracellular calcium levels; iv) suppressed mRNA or protein levels of peroxisome proliferator activated receptor γ, adiponectin, and insulin-dependent glucose transporter 4; and v) decreased fatty acid and glucose uptake and triglyceride content. DGKη was targeted for investigation based on our findings that i) DGKη was highly expressed in primary human adipocytes and time-dependently induced by t10,c12 CLA and that ii) t10,c12 CLA-induced DGKη expression was dose-dependently decreased with R59022. Small interfering RNA (siRNA) targeting DGKη decreased t10,c12 CLA-induced DGKη, IL-8, and MCP-1 gene expression, as well as activation of JNK and cJun. Taken together, these data suggest that DGKs mediate, in part, t10,c12 CLA-induced inflammatory signaling in primary human adipocytes.
Highlights
Diacylglycerol kinases (DGK) convert diacylglycerol to phosphatidic acid, which has been reported to stimulate calcium release from the endoplasmic reticulum
We have demonstrated that activation of extracellular signal-regulated kinase (ERK) [4] and nuclear factor kappa B (NFB) play a role in t10,c12 conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance [5]
DGK-generated phosphatidic acid (PA) levels activate mammalian target of rapamycin (mTOR) and S6 kinase (S6K) in HEK 293 cells [14]; and we reported that t10,c12 CLA activated these two proteins in primary human adipocytes [15]
Summary
Diacylglycerol kinases (DGK) convert diacylglycerol to phosphatidic acid, which has been reported to stimulate calcium release from the endoplasmic reticulum. Based on our published data showing that trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA)-mediated intracellular calcium accumulation is linked to inflammation and insulin resistance, we hypothesized that inhibiting DGKs with R59022 would prevent t10,c12 CLA-mediated inflammatory signaling and insulin resistance in human adipocytes. Activated NFB [7,8,9] and ERK [10,11,12] induce markers of inflammation and antagonize peroxisome proliferator activated receptor (PPAR)␥ activity, thereby causing insulin resistance These data suggest that t10,c12 CLA mediates inflammatory signaling that antagonizes adipogenic processes in adipocytes. The upstream signals responsible for t10,c12 CLA-mediated increases in intracellular calcium levels, inflammatory signaling, insulin resistance, and reduced triglyceride (TG) content in human adipocytes are unknown
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