Diacylglycerol kinase inhibitor R59022 attenuates conjugated linoleic acid-mediated inflammation in human adipocytes

Abstract

This article is available online at http://www.jlr.org Overweight and obesity are global health issues affecting 1.6 billion individuals worldwide ( 1 ). One potential strategy for reducing adiposity is consumption of conjugated linoleic acid (CLA), a group of conjugated octadecadienoic acid isomers derived from linoleic acid, a fatty acid (FA) that contains 18 carbons and 2 double bonds in the cis confi guration at the 9 th and 12 th carbons (i.e., cis -9, cis -12 octadecadienoic acid) ( 2 ). CLA is found in ruminant meats and dairy products, as microbes in the gastrointestinal tract of ruminant animals convert linoleic acid into different isoforms of CLA through biohydrogenation ( 2 ). This process changes the position and confi guration of the double bonds, resulting in a single bond between the two double bonds. The major isomers produced include cis -9, trans -11 (c9,t11) and trans -10, cis -12 (t10,c12) CLA. Food sources of CLA contain ‫ف‬ 80% c9,t11 CLA and 10% t10,c12 CLA, and the remaining 10% is composed of other isomers ( 2 ). CLA is also produced chemically from linoleic acid for inclusion in supplements and fortifi ed foods, yielding a composition containing ‫ف‬ 40% c9,t11 CLA, ‫ف‬ 40% t10,c12 CLA isomers, and the remaining 20% other isomers ( 2 ).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 infl ammation and insulin resistance, we hypothesized that inhibiting DGKs with R59022 would prevent t10,c12 CLA-mediated infl ammatory 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 ␥ , adiponectin, and insulin-dependent glucose transporter 4; and v ) decreased fatty acid and glucose uptake and triglyceride content. DGK was targeted for investigation based on our fi ndings that i ) DGK was highly expressed in primary human adipocytes and timedependently induced by t10,c12 CLA and that ii ) t10,c12 CLA-induced DGK expression was dose-dependently decreased with R59022. Small interfering RNA (siRNA) targeting DGK decreased t10,c12 CLA-induced DGK , 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 infl ammatory signaling in primary human adipocytes.

Maternal conjugated linoleic acid alters hepatic lipid metabolism via the AMPK signaling pathway in chick embryos

“…Given that CLA is known to regulate lipid metabolism in rodents and avians, it is necessary to evaluate the extent to which maternal CLA influences hepatic lipid metabolism in developing chick embryos. In agreement with previous studies in different animal models (Martinez et al, 2013 ; Malinska et al, 2015 ; Wang et al, 2019 ), the present results showed that maternal CLA supplementation reduced the serum TG levels and subcutaneous adipose tissue weights in chick embryos, suggesting that the maternal CLA content altered lipid metabolism and fat deposition in developmental embryos. CLA was shown to elevate the metabolic rate of fat by inhibiting fatty acid synthesis and/or accelerating fatty acid oxidation and lipolysis (Evans et al, 2002 ; Chung et al, 2005 ; Obsen et al, 2012 ).…”

Modulation of Peroxisome Proliferator-Activated Receptor gamma (PPAR γ) by Conjugated Fatty Acid in Obesity and Inflammatory Bowel Disease

“…99 Possible upstream signals of trans-10,cis-12 CLA mediated increased [Ca 2+ ] i and inflammation included phospholipase C (PLC) 102 and diacylglycerol kinases (DGKs). 103 PLC, as an upstream enzyme that produces diacylglycerol (DAG), a substrate for DGK, and inositol-3-phosphate (IP3), an inducer of calcium release from the ER, was found to play an important role in trans-10,cis-12 CLA mediated activation of [Ca 2+ ] i accumulation, inflammatory signaling, delipidation, and insulin resistance in human primary adipocytes. 102 DGKs are a family of kinases that phosphorylate DAG, resulting in the conversion of DAG into phosphatidic acid (PA).…”

“…CLA mediated inflammatory signaling, insulin resistance, and delipidation in primary human adipocytes. 103 On the basis of the studies by Shen et al and Martinez et al, the mechanism of CLAmediated inflammation and PPAR γ activity could be proposed (Figure 2). ■ MODULATION OF PPAR γ BY CLA IN IBD Inflammatory disorders including IBD, rheumatoid arthritis, atherosclerosis, metabolic syndrome, and ischemia/reperfusion injury are recognized as a major health problemd worldwide.…”

Low level of trans-10, cis-12 conjugated linoleic acid decreases adiposity and increases browning independent of inflammatory signaling in overweight Sv129 mice

“…We previously demonstrated that 10,12 CLA increased the expression of several G-coupled receptor proteins (GPR) such as GPR56 and GPRC5A [10], and activated phospholipase c [11] and diacyglycerol kinase [12], resulting in increased calcium release from endoplasmic reticulum (ER) [13] in human primary adipocytes. By chemically-blocking calcium release from the ER, 10,12 CLA-mediated activation of extracellular signal-regulated kinase (ERK)1/2 [6, 14], cJun-NH2-terminal kinase [15], and nuclear factor kappa B (NFκB) [8] were attenuated [13].…”