Abstract
The mechanism of FFA-induced insulin resistance is not fully understood. We have searched for effector molecules(s) in FFA-induced insulin resistance. Palmitic acid (PA) but not oleic acid (OA) induced insulin resistance in L6 myotubes through C-Jun N-terminal kinase (JNK) and insulin receptor substrate 1 (IRS-1) Ser307 phosphorylation. Inhibitors of ceramide synthesis did not block insulin resistance by PA. However, inhibition of the conversion of PA to lysophosphatidylcholine (LPC) by calcium-independent phospholipase A₂ (iPLA₂) inhibitors, such as bromoenol lactone (BEL) or palmitoyl trifluoromethyl ketone (PACOCF₃), prevented insulin resistance by PA. iPLA₂ inhibitors or iPLA₂ small interfering RNA (siRNA) attenuated JNK or IRS-1 Ser307 phosphorylation by PA. PA treatment increased LPC content, which was reversed by iPLA₂ inhibitors or iPLA₂ siRNA. The intracellular DAG level was increased by iPLA₂ inhibitors, despite ameliorated insulin resistance. Pertussis toxin (PTX), which inhibits LPC action through the G-protein coupled receptor (GPCR)/Gα(i), reversed insulin resistance by PA. BEL administration ameliorated insulin resistance and diabetes in db/db mice. JNK and IRS-1Ser307 phosphorylation in the liver and muscle of db/db mice was attenuated by BEL. LPC content was increased in the liver and muscle of db/db mice, which was suppressed by BEL. These findings implicate LPC as an important lipid intermediate that links saturated fatty acids to insulin resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Proteins / pharmacology
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Cells, Cultured
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism*
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Diabetes Mellitus, Type 2 / pathology
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Disease Models, Animal
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Gene Silencing
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Glucose / metabolism
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Insulin / metabolism
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Insulin Receptor Substrate Proteins / antagonists & inhibitors
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Insulin Receptor Substrate Proteins / metabolism*
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Insulin Resistance*
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Liver / metabolism*
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Liver / pathology
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Lysophosphatidylcholines* / analysis
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Lysophosphatidylcholines* / metabolism
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Mice
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Mice, Knockout
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Muscle Fibers, Skeletal
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Naphthalenes / pharmacology
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Palmitic Acid* / metabolism
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Palmitic Acid* / pharmacology
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Pertussis Toxin / pharmacology
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Phospholipases A2, Calcium-Independent / antagonists & inhibitors
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Phospholipases A2, Calcium-Independent / metabolism*
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Phosphorylation / drug effects
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Pyrones / pharmacology
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / metabolism*
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Signal Transduction / drug effects
Substances
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Blood Proteins
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Insulin
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Insulin Receptor Substrate Proteins
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Lysophosphatidylcholines
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Naphthalenes
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PLIalpha
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Pyrones
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RNA, Small Interfering
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Receptors, G-Protein-Coupled
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Palmitic Acid
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6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one
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Pertussis Toxin
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JNK Mitogen-Activated Protein Kinases
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Phospholipases A2, Calcium-Independent
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Glucose