Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL-49653

1997 ◽  
Vol 273 (5) ◽  
pp. E915-E921 ◽  
Author(s):  
Carsten Schmitz-Peiffer ◽  
Nicholas D. Oakes ◽  
Carol L. Browne ◽  
Edward W. Kraegen ◽  
Trevor J. Biden
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Muscle Protein ◽  
Skeletal Muscle Protein ◽  
Insulin Sensitizer ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance ◽  
Kinase C

We have recently shown that the reduction in insulin sensitivity of rats fed a high-fat diet is associated with the translocation of the novel protein kinase Cε(nPKCε) from cytosolic to particulate fractions in red skeletal muscle and also the downregulation of cytosolic nPKCθ. Here we have further investigated the link between insulin resistance and PKC by assessing the effects of the thiazolidinedione insulin-sensitizer BRL-49653 on PKC isoenzymes in muscle. BRL-49653 increased the recovery of nPKC isoenzymes in cytosolic fractions of red muscle from fat-fed rats, reducing their apparent activation and/or downregulation, whereas PKC in control rats was unaffected. Because BRL-49653 also improves insulin-stimulated glucose uptake in fat-fed rats and reduces muscle lipid storage, especially diglyceride content, these results strengthen the association between lipid availability, nPKC activation, and skeletal muscle insulin resistance and support the hypothesis that chronic activation of nPKC isoenzymes is involved in the generation of muscle insulin resistance in fat-fed rats.

scholarly journals Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity

Diabetes ◽  
2000 ◽  
Vol 49 (8) ◽  
pp. 1353-1358 ◽  
Author(s):  
S. I. Itani ◽  
Q. Zhou ◽  
W. J. Pories ◽  
K. G. MacDonald ◽  
G. L. Dohm
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Human Skeletal Muscle ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance ◽  
Kinase C

scholarly journals Enforced expression of protein kinase C in skeletal muscle causes physical inactivity, fatty liver and insulin resistance in the brain

2008 ◽  
Vol 14 (4) ◽  
pp. 903-913 ◽  
Author(s):  
Anita M. Hennige ◽  
Martin Heni ◽  
Jürgen Machann ◽  
Harald Staiger ◽  
Tina Sartorius ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Fatty Liver ◽  
Physical Inactivity ◽  
Kinase C ◽  
The Brain

Alterations in the Expression and Cellular Localization of Protein Kinase C Isozymes   and   Are Associated With Insulin Resistance in Skeletal Muscle of the High-Fat-Fed Rat

Diabetes ◽  
1997 ◽  
Vol 46 (2) ◽  
pp. 169-178 ◽  
Author(s):  
C. Schmitz-Peiffer ◽  
C. L. Browne ◽  
N. D. Oakes ◽  
A. Watkinson ◽  
D. J. Chisholm ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cellular Localization ◽  
High Fat ◽  
Kinase C

scholarly journals Activated protein kinase C α associates with annexin VI from skeletal muscle

1998 ◽  
Vol 330 (2) ◽  
pp. 675-681 ◽  
Author(s):  
Carsten SCHMITZ-PEIFFER ◽  
L. Carol BROWNE ◽  
H. John WALKER ◽  
J. Trevor BIDEN
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Binding Proteins ◽  
Muscle Protein ◽  
Binding Protein ◽  
Calcium Dependent ◽  
Kinase C ◽  
Annexin Vi ◽  
Overlay Assay

We have previously detected a number of protein kinase C (PKC) α-binding proteins in skeletal muscle cytosol by blot overlay assay, and now identify the major, 69 kDa binding protein as annexin VI by immunoblotting and overlay assay of hydroxyapatite chromatography fractions. Annexin VI was also detected in immunoprecipitates of PKC α. Annexin VI and PKC α are both calcium-dependent phospholipid-binding proteins, and detection of the interaction was dependent on the presence of calcium and phosphatidylserine (PS). The association probably involves specific protein-protein interactions rather than mere bridging by lipid molecules: firstly, detection of PKC α-annexin VI complexes by overlay assay was not diminished when PS concentrations were increased over a 10-fold range, while that of other PKC α-binding protein complexes was reduced or abolished; secondly, the presence in the overlay assay of a PKC pseudosubstrate peptide, analogous to a PKC sequence previously found to be involved in PKC binding activity, reduced complex formation; thirdly, we were also able to detect annexin VI interaction with PKC β by overlay of skeletal muscle cytosol, but not with PKC ϴ, the major novel PKC in this tissue, suggesting sequences specific to calcium-dependent PKC isoenzymes are involved. While other annexin isoforms may be PKC substrates or inhibitors, annexin VI phosphorylation by PKC α could not be detected after co-purification, while phosphorylation of subsequently-added histone IIIS was readily observed. Annexin VI is a major skeletal muscle protein and our data are consistent with a role for this isoform in the control of calcium-dependent PKC.

scholarly journals The molecular mechanism linking muscle fat accumulation to insulin resistance

2004 ◽  
Vol 63 (2) ◽  
pp. 375-380 ◽  
Author(s):  
Matthew W. Hulver ◽  
G. Lynis Dohm
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Insulin Signalling ◽  
Fatty Acyl ◽  
Normal Fatty Acid ◽  
Kinase C

Skeletal muscle insulin resistance is a co-morbidity of obesity and a risk factor for the development of type 2 diabetes mellitus. Insulin resistance is associated with the accumulation of intramyocellular lipids. Intramyocellular triacylglycerols do not appear to be the cause of insulin resistance but are more likely to be a marker of other lipid intermediates such as fatty acyl-CoA, ceramides or diacylglycerols. Fatty acyl-CoA, ceramides and diacylglycerols are known to directly alter various aspects of the insulin signalling cascade. Insulin signalling is inhibited by the phosphorylation of serine and threonine residues at the levels of the insulin receptor and insulin receptor substrate 1. Protein kinase C is responsible for the phosphorylation of the serine and threonine residues. Fatty acyl-CoA and diacylglycerols are known to activate protein kinase C. The cause of the intramyocellular accumulation of fatty acyl-CoA and diacylglycerols is unclear at this time. Reduced fatty acid oxidation does not appear to be responsible, as fatty acyl-CoA accumulates in skeletal muscle with a normal fatty acid oxidative capacity. Other potential mechanisms include oversupply of lipids to muscle and/or up regulated fatty acid transport.

Atypical protein kinase C in insulin action and insulin resistance

2005 ◽  
Vol 33 (2) ◽  
pp. 350-353 ◽  
Author(s):  
R.V. Farese ◽  
M.P. Sajan ◽  
M.L. Standaert
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Lipid Synthesis ◽  
Type Ii ◽  
Atypical Protein Kinase C ◽  
Atypical Protein Kinase ◽  
Insulin Resistant ◽  
Kinase C

It now seems clear that aPKC (atypical protein kinase C) isoforms are required for insulin-stimulated glucose transport in muscle and adipocytes. Moreover, there are marked defects in the activation of aPKCs under a variety of insulin-resistant conditions in humans, monkeys and rodents. In humans, defects in aPKC in muscle are seen in Type II diabetes and its precursors, obesity, the obesity-associated polycystic ovary syndrome and impaired glucose tolerance. These defects in muscle aPKC activation are due to both impaired activation of insulin receptor substrate-1-dependent PI3K (phosphoinositide 3-kinase) and the direct activation of aPKCs by the lipid product of PI3K, PI-3,4,5-(PO4)3. Although it is still uncertain which underlying defect comes first, the resultant defect in aPKC activation in muscle most certainly contributes significantly to the development of skeletal muscle insulin resistance. Of further note, unlike the seemingly ubiquitous presence of defective aPKC activation in skeletal muscle in insulin-resistant states, the activation of aPKC is normal or increased in livers of Type II diabetic and obese rodents. The maintenance of aPKC activation in the liver may explain how insulin-dependent lipid synthesis is maintained in these states, as aPKCs function mainly in the activation of enzymes important for lipid synthesis. Thus increased activation of liver aPKC in hyperinsulinaemic states may contribute significantly to the development of hyperlipidaemia in insulin-resistant states.

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