Abstract
BackgroundOver-activity and elevated expression of glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology of insulin resistance and Type 2 diabetes. Administration of specific GSK-3 inhibitors to diabetic or obese rodent models improves glycaemic control and insulin sensitivity. However, due to the indiscriminatory nature of these inhibitors, the relative contribution of the two isoforms of GSK-3 (GSK-3α and GSK-3β) is not known. Recently, we demonstrated that an out-bred strain of mice (ICR) lacking expression of GSK-3α in all tissues displayed improved insulin sensitivity and enhanced hepatic glucose metabolism. We also found that muscle (but not liver) inactivation of GSK-3β conferred insulin and glucose sensitization in an in-bred strain of mice (C57BL/6).Methodology/Principal FindingsHere, we have employed tissue-specific deletion of GSK-3α, to examine the relative contribution of two insulin-sensitive tissues, muscle and liver, towards the insulin sensitization phenotype originally observed in the global GSK-3α KO animals. We found that mice in which GSK-3α has been inactivated in either skeletal-muscle or liver displayed no differences in glucose tolerance or insulin sensitivity compared to wild type littermates. Given the strain differences in our original analyses, we examined the insulin and glucose sensitivity of global GSK-3α KO animals bred onto a C57BL/6 background. These animals also revealed no significant differences in glucose metabolism/insulin sensitivity compared to their wild type littermates. Furthermore, deletion of hepatic GSK-3α on the out-bred, ICR background failed to reproduce the insulin sensitivity manifested by the global deletion of this isoform.Conclusions/SignificanceFrom these data we conclude that the improved insulin sensitivity and hepatic glucose homeostasis phenotype observed upon global inactivation of GSK-3α is strain-specific. We surmise that the insulin-sensitization observed in the out-bred strain of mice lacking GSK-3α is mediated by indirect means that do not require intrinsic function of GSK-3α in skeletal muscle and liver tissues.
Highlights
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine protein kinase that is encoded by two distinct genes, Glycogen Synthase Kinase-3a (GSK-3a) (52 kDa) and GSK-3b (47 kDa)
Skeletal muscle-specific GSK-3a knockout (KO) animals were generated by breeding GSK-3a floxed mice with mice expressing Cre under the control of the myosin light chain 1f (MLC1f) promoter (MLC Cre- C57BL/6B6/129 background), a gene that is predominantly expressed in fast twitch skeletal muscle fibres
GSK-3a expression is completely lost in quadricep, gastrocnemius and extensor digitorum longus (EDL) muscles, whereas there is only partial reduction of GSK-3a expression in soleus, which is primarily composed of slow twitch fibres (Figure 1A)
Summary
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine protein kinase that is encoded by two distinct genes, GSK-3a (52 kDa) and GSK-3b (47 kDa) These two isoforms are highly conserved and share ,98% sequence similarity in their catalytic domains [1]. GSK-3 is a constitutively active kinase in resting cells that becomes rapidly inactivated by phosphorylation at Ser 21 (GSK-3a) and Ser 9 (GSK-3b) in response to insulin through a phosphatidylinositol 3 (PI-3) kinase/ protein kinase B (PKB, termed Akt)-dependent manner. Both GSK-3 expression and activity are elevated in muscle and adipose tissue of diabetic humans and rodents [2,3]. We found that muscle (but not liver) inactivation of GSK-3b conferred insulin and glucose sensitization in an in-bred strain of mice (C57BL/6)
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