Requirement of JIP1-mediated c-Jun N-terminal kinase activation for obesity-induced insulin resistance.
The c-Jun NH(2)-terminal kinase (JNK) interacting protein 1 (JIP1) has been proposed to act as a scaffold protein that mediates JNK activation. However, recent studies have implicated JIP1 in multiple biochemical processes. Physiological roles of JIP1 that are related to the JNK scaffold function of JIP1 are therefore unclear. To test the role of JIP1 in JNK activation, we created mice with a germ line point mutation in the Jip1 gene (Thr(103) replaced with Ala) that selectively blocks JIP1-mediated JNK activation. These mutant mice exhibit a severe defect in JNK activation caused by feeding of a high-fat diet. The loss of JIP1-mediated JNK activation protected the mutant mice against obesity-induced insulin resistance. We conclude that JIP1-mediated JNK activation plays a critical role in metabolic stress regulation of the JNK signaling pathway.
Morel
Caroline
C
Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Standen
Claire L
CL
Jung
Dae Young
DY
Gray
Susan
S
Ong
Helena
H
Flavell
Richard A
RA
Kim
Jason K
JK
Davis
Roger J
RJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D054392:Adipokines / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism; D004789:Enzyme Activation; D005234:Fatty Liver / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D015151:Immunoblotting; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D054392:Adipokines; D001786:Blood Glucose; D016207:Cytokines; D004041:Dietary Fats; D007328:Insulin; C490665:Mapk8ip protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases