Abstract
Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adipose Tissue / enzymology
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Adipose Tissue / metabolism
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Adipose Tissue / physiopathology
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Animals
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Blood Glucose / metabolism
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Diabetes Mellitus, Type 2 / complications
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Diabetes Mellitus, Type 2 / enzymology
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / physiopathology
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Diet
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Disease Models, Animal
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Gene Deletion
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Homeostasis
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Hyperinsulinism / complications
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Hyperinsulinism / enzymology
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Hyperinsulinism / genetics
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Hyperinsulinism / physiopathology
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Insulin / pharmacology
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Insulin Receptor Substrate Proteins
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Insulin Resistance / genetics
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Insulin Resistance / physiology*
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Lipid Metabolism
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Mice
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Mice, Knockout
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Mice, Obese
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinase 9
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Mitogen-Activated Protein Kinases / deficiency
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Obesity / complications
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Obesity / enzymology*
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Obesity / genetics
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Obesity / physiopathology*
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Phosphoproteins / metabolism
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Phosphorylation
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Receptor, Insulin / metabolism
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Signal Transduction / drug effects
Substances
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Blood Glucose
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Insulin
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Insulin Receptor Substrate Proteins
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Irs1 protein, mouse
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Phosphoproteins
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Mitogen-Activated Protein Kinase 9
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Receptor, Insulin
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases