Alba Bosquet1, Josefa Girona1, Sandra Guaita-Esteruelas1, Mercedes Heras1, Paula Saavedra-García1, Neus Martínez-Micaelo1, Lluís Masana2, Ricardo Rodríguez-Calvo3. 1. Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili (IISPV), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Universitat Rovira i Virgili, Reus, Spain. 2. Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili (IISPV), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Universitat Rovira i Virgili, Reus, Spain. Electronic address: luis.masana@urv.cat. 3. Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut d'Investigació Sanitària Pere Virgili (IISPV), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Universitat Rovira i Virgili, Reus, Spain. Electronic address: ricardo.rodriguez@ciberdem.org.
Abstract
AIMS: Fatty acid binding protein 4 (FABP4) inhibitors have been proposed as potential therapeutic approaches against insulin resistance-related inflammation and type 2 diabetes mellitus. However, the underlying molecular mechanisms by which these molecules drive these effects in skeletal muscle remain unknown. Here, we assessed whether the FABP4 inhibitor BMS309403 prevented lipid-induced endoplasmic reticulum (ER) stress-associated inflammation in skeletal muscle. MATERIALS AND METHODS: The BMS309403 treatment was assessed both in the skeletal muscle of high-fat diet (HFD)-fed mice and in palmitate-stimulated C2C12 myotubes. RESULTS: HFD feeding promoted insulin resistance, which is characterized by increased plasma levels of glucose, insulin, non-esterified fatty acids, triglycerides, resistin, and leptin and reduced plasma levels of adiponectin compared with control mice fed a standard diet. Additionally, insulin-resistant animals showed increased FABP4 plasma levels. In line with this evidence, recombinant FABP4 attenuated the insulin-induced AKT phosphorylation in C2C12 myotubes. Treatment with BMS309403 reduced lipid-induced ER stress and inflammation in both mouse skeletal muscle and C2C12 myotubes. The effects of the FABP4 inhibitor reducing lipid-induced ER stress-associated inflammation were related to the reduction of fatty acid-induced intramyocellular lipid deposits, ROS and nuclear factor-kappaB (NF-κB) nuclear translocation. Accordingly, BMS309403 reduced lipid-induced p38 MAPK phosphorylation, which is upstream of NF-κB activation. CONCLUSION: Overall, these findings indicate that BMS309403 reduces fatty acid-induced ER stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation.
AIMS: Fatty acid binding protein 4 (FABP4) inhibitors have been proposed as potential therapeutic approaches against insulin resistance-related inflammation and type 2 diabetes mellitus. However, the underlying molecular mechanisms by which these molecules drive these effects in skeletal muscle remain unknown. Here, we assessed whether the FABP4 inhibitor BMS309403 prevented lipid-induced endoplasmic reticulum (ER) stress-associated inflammation in skeletal muscle. MATERIALS AND METHODS: The BMS309403 treatment was assessed both in the skeletal muscle of high-fat diet (HFD)-fed mice and in palmitate-stimulated C2C12 myotubes. RESULTS: HFD feeding promoted insulin resistance, which is characterized by increased plasma levels of glucose, insulin, non-esterified fatty acids, triglycerides, resistin, and leptin and reduced plasma levels of adiponectin compared with control mice fed a standard diet. Additionally, insulin-resistant animals showed increased FABP4 plasma levels. In line with this evidence, recombinant FABP4 attenuated the insulin-induced AKT phosphorylation in C2C12 myotubes. Treatment with BMS309403 reduced lipid-induced ER stress and inflammation in both mouse skeletal muscle and C2C12 myotubes. The effects of the FABP4 inhibitor reducing lipid-induced ER stress-associated inflammation were related to the reduction of fatty acid-induced intramyocellular lipid deposits, ROS and nuclear factor-kappaB (NF-κB) nuclear translocation. Accordingly, BMS309403 reduced lipid-induced p38 MAPK phosphorylation, which is upstream of NF-κB activation. CONCLUSION: Overall, these findings indicate that BMS309403 reduces fatty acid-induced ER stress-associated inflammation in skeletal muscle by reducing p38 MAPK activation.
Authors: Ricardo Rodríguez-Calvo; Sara Samino; Josefa Girona; Neus Martínez-Micaelo; Pere Ràfols; María García-Altares; Sandra Guaita-Esteruelas; Alexandra Junza; Mercedes Heras; Oscar Yanes; Xavier Correig; Lluis Masana Journal: Biomolecules Date: 2020-09-03