Inhibition of malonyl-CoA decarboxylase reduces the inflammatory response associated with insulin resistance

• Published in: American journal of physiology: endocrinology and metabolism 2012-12, Vol.303 (12), p.E1459-E1468
• Main Authors: Samokhvalov, Victor, Ussher, John R, Fillmore, Natasha, Armstrong, Ian K G, Keung, Wendy, Moroz, Daniel, Lopaschuk, David G, Seubert, John, Lopaschuk, Gary D
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological Transport - drug effects; Carboxy-Lyases - antagonists & inhibitors; Carboxy-Lyases - metabolism; Cardiomyocytes; Cardiotonic Agents - pharmacology; Cells, Cultured; Ceramides - metabolism; Enzyme Inhibitors - pharmacology; Fatty acids; Glucose; Glucose - metabolism; Insulin Resistance; Lipid Metabolism - drug effects; Macrophage Activation - drug effects; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - immunology; Myocytes, Cardiac - metabolism; Oxidation; Phenylurea Compounds - pharmacology; Phosphorylation; Phosphorylation - drug effects; Protein Processing, Post-Translational - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rodents
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00018.2012

We previously showed that genetic inactivation of malonyl-CoA decarboxylase (MCD), which regulates fatty acid oxidation, protects mice against high-fat diet-induced insulin resistance. Development of insulin resistance has been associated with activation of the inflammatory response. Therefore, we hypothesized that the protective effect of MCD inhibition might be caused by a favorable effect on the inflammatory response. We examined if pharmacological inhibition of MCD protects neonatal cardiomyocytes and peritoneal macrophages against inflammatory-induced metabolic perturbations. Cardiomyocytes and macrophages were treated with LPS to induce an inflammatory response, in the presence or absence of an MCD inhibitor (CBM-301106, 10 μM). Inhibition of MCD attenuated the LPS-induced inflammatory response in cardiomyocytes and macrophages. MCD inhibition also prevented LPS impairment of insulin-stimulated glucose uptake in cardiomyocytes and increased phosphorylation of Akt. Additionally, inhibition of MCD strongly diminished LPS-induced activation of palmitate oxidation. We also found that treatment with an MCD inhibitor prevented LPS-induced collapse of total cellular antioxidant capacity. Interestingly, treatment with LPS or an MCD inhibitor did not alter intracellular triacylglycerol content. Furthermore, inhibition of MCD prevented LPS-induced increases in the level of ceramide in cardiomyocytes and macrophages while also ameliorating LPS-initiated decreases in PPAR binding. This suggests that the anti-inflammatory effect of MCD inhibition is mediated via accumulation of long-chain acyl-CoA, which in turn stimulates PPAR binding. Our results also demonstrate that pharmacological inhibition of MCD is a novel and promising approach to treat insulin resistance and its associated metabolic complications.