Enforced expression of protein kinase C in skeletal muscle causes physical inactivity, fatty liver and insulin resistance in the brain.
Among the multitude of dysregulated signalling mechanisms that comprise insulin resistance in divergent organs, the primary events in the development of type 2 diabetes are not well established. As protein kinase C (PKC) activation is consistently present in skeletal muscle of obese and insulin resistant subjects, we generated a transgenic mouse model that overexpresses constitutively active PKC-beta(2) in skeletal muscle to test whether activation of PKC is sufficient to cause an aversive whole-body phenotype. Upon this genetic modification, increased serine phosphorylation in Irs1 was observed and followed by impaired (3)H-deoxy-glucose uptake and muscle glycogen content, and transgenic mice exhibited insulin and glucose intolerance as they age. Muscle histochemistry revealed an increase in lipid deposition (intramyocellular lipids), and transgenic mice displayed impaired expression of transcriptional regulators of genes involved in fatty acid oxidation (peroxisome proliferator-activated receptor-gamma, PGC-1beta, acyl-CoA oxidase) and lipolysis (hormone-sensitive lipase). In this regard, muscle of transgenic mice exhibited a reduced capacity to oxidize palmitate and contained less mitochondria as determined by citrate synthase activity. Moreover, the phenotype included a profound decrease in the daily running distance, intra-abdominal and hepatic fat accumulation and impaired insulin action in the brain. Together, our data suggest that activation of a classical PKC in skeletal muscle as present in the pre-diabetic state is sufficient to cause disturbances in whole-body glucose and lipid metabolism followed by profound alterations in oxidative capacity, ectopic fat deposition and physical activity.
Hennige
Anita M
AM
University of Tuebingen, Department of Internal Medicine, Tübingen, Germany.
Heni
Martin
M
Machann
Jürgen
J
Staiger
Harald
H
Sartorius
Tina
T
Hoene
Miriam
M
Lehmann
Rainer
R
Weigert
Cora
C
Peter
Andreas
A
Bornemann
Antje
A
Kroeber
Stefan
S
Pujol
Anna
A
Franckhauser
Sylvie
S
Bosch
Fatima
F
Schick
Fritz
F
Lammers
Reiner
R
Häring
Hans-Ulrich
HU
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009928:Organ Specificity; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics
D007328:Insulin; D011493:Protein Kinase C; D064546:Protein Kinase C beta