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Muscle-specific knock-out of NUAK family SNF1-like kinase 1 (NUAK1) prevents high fat diet-induced glucose intolerance.

Inazuka F, Sugiyama N, Tomita M, Abe T, Shioi G, Esumi H - J. Biol. Chem. (2012)

Bottom Line: Quantitative phosphoproteome analysis of soleus muscle was performed to understand the molecular mechanisms underlying the knock-out phenotype.Nuak1 mRNA was preferentially expressed in highly oxidative tissues such as brain, heart, and soleus muscle.Phosphoproteome analysis revealed that phosphorylation of IRS1 Ser-1097 was markedly decreased in NUAK1-deficient muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8561, Japan.

ABSTRACT
NUAK1 is a member of the AMP-activated protein kinase-related kinase family. Recent studies have shown that NUAK1 is involved in cellular senescence and motility in epithelial cells and fibroblasts. However, the physiological roles of NUAK1 are poorly understood because of embryonic lethality in NUAK1 mice. The purpose of this study was to elucidate the roles of NUAK1 in adult tissues. We determined the tissue distribution of NUAK1 and generated muscle-specific NUAK1 knock-out (MNUAK1KO) mice. For phenotypic analysis, whole body glucose homeostasis and muscle glucose metabolism were examined. Quantitative phosphoproteome analysis of soleus muscle was performed to understand the molecular mechanisms underlying the knock-out phenotype. Nuak1 mRNA was preferentially expressed in highly oxidative tissues such as brain, heart, and soleus muscle. On a high fat diet, MNUAK1KO mice had a lower fasting blood glucose level, greater glucose tolerance, higher insulin sensitivity, and higher concentration of muscle glycogen than control mice. Phosphoproteome analysis revealed that phosphorylation of IRS1 Ser-1097 was markedly decreased in NUAK1-deficient muscle. Consistent with this, insulin signaling was enhanced in the soleus muscle of MNUAK1KO mice, as evidenced by increased phosphorylation of IRS1 Tyr-608, AKT Thr-308, and TBC1D4 Thr-649. These observations suggest that a physiological role of NUAK1 is to suppress glucose uptake through negative regulation of insulin signaling in oxidative muscle.

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Related in: MedlinePlus

MNUAK1KO mice show improved insulin sensitivity and increased glycogen storage in skeletal muscle.A and B, rate of glucose uptake in soleus muscles isolated from 18–20-week-old control and MNUAK1KO mice fed a NC (A) or a HFD (B) without or with insulin stimulation. The data are the means ± S.E. (n = 7 for NC and 8 for HFD). C, glycogen concentration in the soleus muscle of 13–15-week-old control and MNUAK1KO mice fed a NC or HFD. The data are the means ± S.E. (n = 8). *, p < 0.05 (Student's t test).
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Figure 4: MNUAK1KO mice show improved insulin sensitivity and increased glycogen storage in skeletal muscle.A and B, rate of glucose uptake in soleus muscles isolated from 18–20-week-old control and MNUAK1KO mice fed a NC (A) or a HFD (B) without or with insulin stimulation. The data are the means ± S.E. (n = 7 for NC and 8 for HFD). C, glycogen concentration in the soleus muscle of 13–15-week-old control and MNUAK1KO mice fed a NC or HFD. The data are the means ± S.E. (n = 8). *, p < 0.05 (Student's t test).

Mentions: To determine whether the improved whole body glucose metabolism is attributed to NUAK1-deficient skeletal muscle, we measured glucose uptake into isolated soleus muscle without or with insulin. Insulin-stimulated glucose uptake was observed in the soleus muscle from both MNUAK1 and control mice fed a NC (Fig. 4A). Under HFD conditions, the effects of insulin were less pronounced in the soleus muscle from control mice, whereas NUAK1-deficient soleus muscle displayed insulin-stimulated glucose uptake comparable with that observed under NC conditions (Fig. 4B). We also measured the soleus muscle glycogen concentration in MNUAK1KO and control mice. The glycogen concentration was significantly higher in the soleus of MNUAK1KO mice under both NC and HFD conditions, indicating that NUAK1 plays a critical role in glucose storage in the soleus muscle (Fig. 4C). Taken together, our findings suggest that a muscle-specific knock-out of NUAK1 preserved insulin sensitivity under HFD conditions.


Muscle-specific knock-out of NUAK family SNF1-like kinase 1 (NUAK1) prevents high fat diet-induced glucose intolerance.

Inazuka F, Sugiyama N, Tomita M, Abe T, Shioi G, Esumi H - J. Biol. Chem. (2012)

MNUAK1KO mice show improved insulin sensitivity and increased glycogen storage in skeletal muscle.A and B, rate of glucose uptake in soleus muscles isolated from 18–20-week-old control and MNUAK1KO mice fed a NC (A) or a HFD (B) without or with insulin stimulation. The data are the means ± S.E. (n = 7 for NC and 8 for HFD). C, glycogen concentration in the soleus muscle of 13–15-week-old control and MNUAK1KO mice fed a NC or HFD. The data are the means ± S.E. (n = 8). *, p < 0.05 (Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351321&req=5

Figure 4: MNUAK1KO mice show improved insulin sensitivity and increased glycogen storage in skeletal muscle.A and B, rate of glucose uptake in soleus muscles isolated from 18–20-week-old control and MNUAK1KO mice fed a NC (A) or a HFD (B) without or with insulin stimulation. The data are the means ± S.E. (n = 7 for NC and 8 for HFD). C, glycogen concentration in the soleus muscle of 13–15-week-old control and MNUAK1KO mice fed a NC or HFD. The data are the means ± S.E. (n = 8). *, p < 0.05 (Student's t test).
Mentions: To determine whether the improved whole body glucose metabolism is attributed to NUAK1-deficient skeletal muscle, we measured glucose uptake into isolated soleus muscle without or with insulin. Insulin-stimulated glucose uptake was observed in the soleus muscle from both MNUAK1 and control mice fed a NC (Fig. 4A). Under HFD conditions, the effects of insulin were less pronounced in the soleus muscle from control mice, whereas NUAK1-deficient soleus muscle displayed insulin-stimulated glucose uptake comparable with that observed under NC conditions (Fig. 4B). We also measured the soleus muscle glycogen concentration in MNUAK1KO and control mice. The glycogen concentration was significantly higher in the soleus of MNUAK1KO mice under both NC and HFD conditions, indicating that NUAK1 plays a critical role in glucose storage in the soleus muscle (Fig. 4C). Taken together, our findings suggest that a muscle-specific knock-out of NUAK1 preserved insulin sensitivity under HFD conditions.

Bottom Line: Quantitative phosphoproteome analysis of soleus muscle was performed to understand the molecular mechanisms underlying the knock-out phenotype.Nuak1 mRNA was preferentially expressed in highly oxidative tissues such as brain, heart, and soleus muscle.Phosphoproteome analysis revealed that phosphorylation of IRS1 Ser-1097 was markedly decreased in NUAK1-deficient muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-8561, Japan.

ABSTRACT
NUAK1 is a member of the AMP-activated protein kinase-related kinase family. Recent studies have shown that NUAK1 is involved in cellular senescence and motility in epithelial cells and fibroblasts. However, the physiological roles of NUAK1 are poorly understood because of embryonic lethality in NUAK1 mice. The purpose of this study was to elucidate the roles of NUAK1 in adult tissues. We determined the tissue distribution of NUAK1 and generated muscle-specific NUAK1 knock-out (MNUAK1KO) mice. For phenotypic analysis, whole body glucose homeostasis and muscle glucose metabolism were examined. Quantitative phosphoproteome analysis of soleus muscle was performed to understand the molecular mechanisms underlying the knock-out phenotype. Nuak1 mRNA was preferentially expressed in highly oxidative tissues such as brain, heart, and soleus muscle. On a high fat diet, MNUAK1KO mice had a lower fasting blood glucose level, greater glucose tolerance, higher insulin sensitivity, and higher concentration of muscle glycogen than control mice. Phosphoproteome analysis revealed that phosphorylation of IRS1 Ser-1097 was markedly decreased in NUAK1-deficient muscle. Consistent with this, insulin signaling was enhanced in the soleus muscle of MNUAK1KO mice, as evidenced by increased phosphorylation of IRS1 Tyr-608, AKT Thr-308, and TBC1D4 Thr-649. These observations suggest that a physiological role of NUAK1 is to suppress glucose uptake through negative regulation of insulin signaling in oxidative muscle.

Show MeSH
Related in: MedlinePlus