Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice.
The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirus-mediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor gamma coactivator 1 beta, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice.
Yang
Ruojing
R
Department of Metabolic Disease Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA. ruojingyang@yahoo.com
Wilcox
Denise M
DM
Haasch
Deanna L
DL
Jung
Paul M
PM
Nguyen
Phong T
PT
Voorbach
Martin J
MJ
Doktor
Stella
S
Brodjian
Sevan
S
Bush
Eugene N
EN
Lin
Emily
E
Jacobson
Peer B
PB
Collins
Christine A
CA
Landschulz
Katherine T
KT
Trevillyan
James M
JM
Rondinone
Cristina M
CM
Surowy
Terry K
TK
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D017931:DNA Primers / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
D017931:DNA Primers; D007328:Insulin; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D048055:Mitogen-Activated Protein Kinase 8; D005947:Glucose