Acute elevation of circulating fatty acids impairs downstream insulin signalling in rat skeletal muscle in vivo independent of effects on stress signalling

作者：Frangioudakis Georgia; Cooney Gregory J^*

来源：Journal of Endocrinology, 2008, 197(2): 277-285.

DOI：10.1677/JOE-07-0623

The aim of this study was to examine the effect of an acute, physiological increase in plasma free fatty acid (FFA) on initial signalling events in rat red quadriceps muscle (RQ). Male Wistar rats received a 7% glycerol (GLYC) or 7% Intralipid/heparin (LIP) infusion for 3 h, after which they were either killed or infused with insulin at a rate of 0.5 U/kg per h for 5 min, before R-Q collection. Plasma FFAs were elevated to similar to 2 mM in the LIP rats only. Insulin-stimulated insulin receptor (IR) Tyrl 162/Tyrl 163 phosphorylation and IR Substrate (IRS)-1 Tyr-612 phosphorylation were increased at least twofold over basal in GLYC rats with insulin and this increase was not significantly impaired in the LIP rats. However, there was no insulin-stimulated protein kinase B (PKB) Ser473 or glycogen synthase kinase (GSK)-3 beta Set-9 phosphorylation in the LIP rats, compared with at least a twofold increase over basal in GLYC rats for both proteins. c-Jun N-terminal kinase, inhibitor of K kinase and inhibitor of nuclear factor-kappa B phosphorylation and total protein expression, as well as Ser307-IR-S-1 phosphorylation, were not altered by lipid infusion compared with GLYC infusion. These data indicate that acute, physiological elevation in FFA has a greater impact on insulin signalling downstream of lR and IRS-1, at the level of PKB and GSK-3, and that under these conditions stress signalling pathways are not significantly stimulated. Decreased PKB and GSK-3 phosphorylation in RQ may therefore be primary determinants of the reduced insulin action observed in situations of acute FFA oversupply.

• 出版日期2008-5
• 单位河北医科大学