Alteration of JNK-1 signaling in skeletal muscle fails to affect glucose homeostasis and obesity-associated insulin resistance in mice.
Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNK(C)). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNK(C) mice were crossed to Mck-Cre mice yielding JNK(SM-C) mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNK(SM-C) mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance.
Max Planck Institute for Neurological Research, Institute for Genetics, University of Cologne and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), Cologne, Germany.
Martin
M
Pal
Claudia M
CM
Wunderlich
Gabriele
G
Spohn
Hella S
HS
Brönneke
Marc
M
Schmidt-Supprian
F Thomas
FT
Wunderlich
D000818:Animals; D015153:Blotting, Western; D001823:Body Composition; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D022661:RNA, Untranslated; D020133:Reverse Transcriptase Polymerase Chain Reaction
C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D011506:Proteins; D016755:Proto-Oncogene Proteins c-jun; D022661:RNA, Untranslated; D048055:Mitogen-Activated Protein Kinase 8; D005947:Glucose