title: Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation.
abstract: Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Holzer
authors.forename: Eek-Joong
authors.initials: EJ
authors.lastname: Park
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Helen
authors.initials: H
authors.lastname: Tran
authors.forename: Monica
authors.initials: M
authors.lastname: Chen
authors.forename: Crystal
authors.initials: C
authors.lastname: Choi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Solinas
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D017667:Adipocytes / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D007333:Insulin Resistance; D007425:Intracellular Membranes / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D016392:Proto-Oncogene Proteins pp60(c-src); D048031:JNK Mitogen-Activated Protein Kinases