Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle - PubMed (original) (raw)

Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle

Shaikh Mizanoor Rahman et al. Proc Natl Acad Sci U S A. 2003.

Abstract

We have shown previously that mice with a targeted disruption in the stearoyl-CoA desaturase 1 gene (SCD1-/-) have increased insulin sensitivity compared with control mice. Here we show that the SCD1-/- mice have increased insulin signaling in muscle. The basal tyrosine phosphorylation of the insulin receptor and insulin receptor substrates 1 and 2 are elevated. The tyrosine phosphorylation of insulin-like growth factor-1 receptor was similar between SCD1+/+ and SCD1-/- mice. The association of insulin receptor substrates 1 and 2 with alphap85 subunit of phosphatidylinositol 3-kinase as well as the phosphorylation of Akt-Ser-473 and Akt-Thr-308 are also elevated in the SCD1-/- mice. Interestingly, the mRNA levels, protein mass, and activity of the protein-tyrosine phosphatase-1B implicated in the attenuation of the insulin signal are reduced in the SCD1-/- mice, whereas the levels of the leukocyte antigen-related protein phosphatase are similar between two groups of mice. The content of glucose transporter 4 in the plasma membrane and basal as well as insulin-mediated glucose uptake are increased in the SCD1-/- mice. In addition, the muscle glycogen content and the activities of glycogen synthase and phosphorylase are increased in the SCD1-/- mice. We hypothesize that loss of SCD1 function induces increased insulin signaling at least in part by a reduction in the expression of protein-tyrosine phosphatase 1B. SCD1 could be a therapeutic target in the treatment of diabetes.

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Figures

Fig. 1.

Immunoblots and densitometric quantification of IR, IGF-1R, IRS-1, and IRS-2 phosphorylation status and protein levels in muscle of SCD1+/+ and _SCD1_-/- mice. Tyrosine-phosphorylated forms are indicated by -P. (A) IR-P and IGF-1R-P and protein levels. (B) IRS-1-P and protein. (C) IRS-2-P and protein. *, P < 0.01; **, P < 0.005; ***, P < 0.0005 vs. controls.

Fig. 2.

Association of IRS-1 and IRS-2 with the αp85 subunit of PI3-kinase and αp85 abundance in muscle. (A) Association of IRS-1 with αp85. (B) Association of IRS-2 with αp85. (C) The p85 protein level. Data are means ± SD. *, P < 0.05; **, P < 0.01 vs. controls.

Fig. 3.

mRNA, protein, and activity of PTP-1B in muscle of SCD1+/+ and _SCD1_-/- mice. (A) PTP-1B mRNA levels. (B) PTP-1B and LAR protein levels along with combined densitometric analysis. (C) PTP-1B activity. *, P < 0.001 vs. controls.

Fig. 4.

Akt/PKB serine and threonine phosphorylation in muscle of SCD1+/+ and _SCD1_-/- mice. (A) Representative immunoblot. (B and C) Densitometric quantification. *, P < 0.005 vs. controls.

Fig. 5.

Expression and quantification of GLUT4 and glucose uptake in muscle of _SCD1_-/- and SCD1+/+ mice. (A) Representative immunoblot of GLUT4 protein expression along with combined densitometric analysis. (B) Glucose uptake measured in vivo in soleus and gastrocnemius (Gastroc) muscles. (C) Basal and insulin-stimulated glucose uptake in isolated soleus muscle from control and _SCD1_-/- mice. *, P < 0.05; **, P < 0.01; ***, P < 0.0001 vs. controls.

Fig. 6.

Enzyme activities in muscle of _SCD1_-/- and SCD1+/+ mice. (A) Glycogen synthase activities in muscle, in the presence and absence of glucose 6-phosphate. (B) Glycogen phosphorylase activities in the presence and absence of AMP. *, P < 0.05 vs. controls.

Fig. 7.

Muscle glycogen content and light microscopy of muscle tissue stained with PAS. (A) Chemical determination of glycogen in muscle. *, P < 0.001 vs. controls. (B and C) Muscle from control mice (B) and _SCD1_-/- mice (C) stained with PAS. The arrows point to the red glycogen granules. (×600.)

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Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle - PubMed (original) (raw)