Insulin Resistance in Striated Muscle-specific Integrin Receptor β1-deficient Mice

Abstract

Integrin receptor plays key roles in mediating both inside-out and outside-in signaling between cells and the extracellular matrix. We have observed that the tissue-specific loss of the integrin ␤1 subunit in striated muscle results in a near complete loss of integrin ␤1 subunit protein expression concomitant with a loss of talin and to a lesser extent, a reduction in F-actin content. Muscle-specific integrin ␤1-deficient mice had no significant difference in food intake, weight gain, fasting glucose, and insulin levels with their littermate controls. However, dynamic analysis of glucose homeostasis using euglycemic-hyperinsulinemic clamps demonstrated a 44 and 48% reduction of insulinstimulated glucose infusion rate and glucose clearance, respectively. The whole body insulin resistance resulted from a specific inhibition of skeletal muscle glucose uptake and glycogen synthesis without any significant effect on the insulin suppression of hepatic glucose output or insulin-stimulated glucose uptake in adipose tissue. The reduction in skeletal muscle insulin responsiveness occurred without any change in GLUT4 protein expression levels but was associated with an impairment of the insulin-stimulated protein kinase B/Akt serine 473 phosphorylation but not threonine 308. The inhibition of insulin-stimulated serine 473 phosphorylation occurred concomitantly with a decrease in integrin-linked kinase expression but with no change in the mTOR⅐Rictor⅐LST8 complex (mTORC2). These data demonstrate an in vivo crucial role of integrin ␤1 signaling events in mediating cross-talk to that of insulin action.

Integrin α1-null Mice Exhibit Improved Fatty Liver When Fed a High Fat Diet Despite Severe Hepatic Insulin Resistance

“…In contrast, we found that activation of this pathway was down-regulated in HF-fed itga1 Ϫ/Ϫ mice compared with HF-fed itga1 ϩ/ϩ mice, indicating that the absence of integrin ␣1 dampens MAPK signaling despite hepatic insulin resistance, and JNK activation is not responsible for the observed decrease in IRS1 Tyr phosphorylation in HF-fed itga1 Ϫ/Ϫ mice. There is considerable cross-talk between the insulin and integrin signaling cascades (9,(11)(12)(13). A potential mediator of this cross-talk is the integrin-specific signaling molecule FAK.…”

“…The integrin signaling molecule focal adhesion kinase (FAK) has been shown to directly bind to IRS1 and lead to IRS1 tyrosine phosphorylation in intact cells (14). Finally, the loss of the integrin ␤1 subunit in striated muscle leads to insulin resistance and decreased muscle glucose uptake (12).…”

“…Upon ligand binding, integrins transduce signals across the plasma membrane to facilitate outside-in cell signaling (10). Several studies have suggested a role for integrins in the promotion of insulin action (9,(11)(12)(13)(14). Integrin ␣5␤1 binding to its ligand fibronectin enhances insulin-stimulated tyrosine phosphorylation of both the insulin receptor and IRS1 (13).…”

Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice

“…Akt is phosphorylated at two sites, T 308 and S 473 ( 16,17 ). The Akt2-T 308 site is phosphorylated by the insulin-regulated PI3 kinase-PDK1 pathway, whereas the Akt2-S 473 site is phosphorylated by several kinases, including mammalian target of rapamycin complex 2 (mTORC2), integrinlinked kinase, MAP kinase-activated protein kinase-2, p38 MAP kinase, protein kinase C, NIMA-related kinase-6, double-stranded DNA-dependent protein kinase, and ataxia telangiectasia-mutated gene products (18)(19)(20)(21)(22)(23)(24). Recently, mTORC2 was identified as a key regulator of Akt-S 473 and FoxO1 phosphorylation, establishing a link between the mTOR pathway and GNG (25)(26)(27).…”

“…Elovl5 elongates specifi c C [16][17][18][19][20] MUFAs and PUFAs ( 1, 4, 5 ), including palmitoleic acid (16:1,n-7), linoleic acid (18:2,n-6), ␥ -linolenic acid (18:3,n-6), arachidonic acid (20:4,n-6) and n-3 PUFA, stearidonic acid (18:4,n-3) and eicosapentaenoic acid (20:5,n-3). The corresponding Elovl5 elongation products are 18:1,n-7 ( cis -vaccenic acid), 11, 14-eicosadienoic acid p70S6K phosphorylation and blocked the Elovl5-stimulated increase in Akt2-S 473 and FoxO1-S 256 phosphorylation (see supplementary Fig.…”