Local activation of the IkappaK-NF-kappaB pathway in muscle does not cause insulin resistance.
Insulin resistance of skeletal muscle is a major defect in obesity and type 2 diabetes. Insulin resistance has been associated with a chronic subclinical inflammatory state in epidemiological studies and specifically with activation of the inhibitor kappaB kinase (IkappaBK)-nuclear factor-kappaB (NF-kappaB) pathway. However, it is unclear whether this pathway plays a role in mediating insulin resistance in muscle in vivo. We separately overexpressed the p65 subunit of NF-kappaB and IkappaBKbeta in single muscles of rats using in vivo electrotransfer and compared the effects after 1 wk vs. paired contralateral control muscles. A 64% increase in p65 protein (P < 0.001) was sufficient to cause muscle fiber atrophy but had no effect on glucose disposal or glycogen storage in muscle under hyperinsulinemic-euglycemic clamp conditions. Similarly, a 650% increase in IkappaBKbeta expression (P < 0.001) caused a significant reduction in IkappaB protein but also had no effect on clamp glucose disposal after lipid infusion. In fact, IkappaBKbeta overexpression in particular caused increases in activating tyrosine phosphorylation of insulin receptor substrate-1 (24%; P = 0.02) and serine phosphorylation of Akt (23%; P < 0.001), implying a moderate increase in flux through the insulin signaling cascade. Interestingly, p65 overexpression resulted in a negative feedback reduction of 36% in Toll-like receptor (TLR)-2 (P = 0.03) but not TLR-4 mRNA. In conclusion, activation of the IkappaBKbeta-NF-kappaB pathway in muscle does not seem to be an important local mediator of insulin resistance.
Polkinghorne
Emma
E
Department of Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London, United Kingdom.
Lau
Quintin
Q
Cooney
Gregory J
GJ
Kraegen
Edward W
EW
Cleasby
Mark E
ME
D000818:Animals; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D025461:Feedback, Physiological; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D051550:I-kappa B Kinase / Q000502:physiology*; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism
D016328:NF-kappa B; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; D005947:Glucose