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Constitutively Active CaMKKα Stimulates Skeletal Muscle Glucose Uptake in Insulin Resistant Mice In Vivo.
|Title||Constitutively Active CaMKKα Stimulates Skeletal Muscle Glucose Uptake in Insulin Resistant Mice In Vivo.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Hinkley MJ, Ferey JL, Brault JJ, Smith CAS, Gilliam LAA, Witczak CA|
|Date Published||2013 Oct 7|
In insulin-sensitive skeletal muscle, expression of constitutively active Ca(2+)/calmodulin-dependent protein kinase kinase α (caCaMKKα) stimulates glucose uptake independent of insulin signaling (i.e. Akt and Akt-dependent TBC1D1/TBC1D4 phosphorylation). Our objectives were to determine if caCaMKKα could stimulate glucose uptake additively with insulin in insulin-sensitive muscle, in the basal state in insulin-resistant muscle, and if so to determine whether the effects were associated with altered TBC1D1/TBC1D4 phosphorylation. Mice were fed a control or high (60%kcal) fat diet for 12-wks to induce insulin resistance. Muscles were transfected with empty vector or caCaMKKα plasmids using in vivo electroporation. After 2-wks, caCaMKKα protein was robustly expressed. In insulin-sensitive muscle, caCaMKKα increased basal in vivo [(3)H]-2-deoxyglucose uptake ∼2-fold, insulin increased glucose uptake ∼2-fold, and caCaMKKα+insulin increased glucose uptake ∼4-fold. caCaMKKα did not increase basal TBC1D1 (Ser(237), Thr(590), Ser(660), pan-Thr/Ser) or TBC1D4 (Ser(588), Thr(642), pan-Thr/Ser) phosphorylation. In insulin-resistant muscle, caCaMKKα increased basal glucose uptake ∼2-fold, and attenuated high fat diet-induced basal TBC1D1 (Thr(590), pan-Thr/Ser) and TBC1D4 (Ser(588), Thr(642), pan-Thr/Ser) phosphorylation. In cell-free assays, CaMKKα increased TBC1D1 (Thr(590), pan-Thr/Ser) and TBC1D4 (Ser(588), pan-Thr/Ser) phosphorylation. Collectively, these results demonstrate that caCaMKKα stimulates glucose uptake additively with insulin, and in insulin-resistant muscle; and alters the phosphorylation of TBC1D1/TBC1D4.