A central role for JNK in obesity and insulin resistance.
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.
Hirosumi
Jiro
J
Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA.
Tuncman
Gürol
G
Chang
Lufen
L
Görgün
Cem Z
CZ
Uysal
K Teoman
KT
Maeda
Kazuhisa
K
Karin
Michael
M
Hotamisligil
Gökhan S
GS
D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D004032:Diet; D004195:Disease Models, Animal; D017353:Gene Deletion; D006706:Homeostasis; D006946:Hyperinsulinism / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D048056:Mitogen-Activated Protein Kinase 9; D011972:Receptor, Insulin; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases