Overexpression of the Adiponectin Receptor AdipoR1 in Rat Skeletal Muscle Amplifies Local Insulin Sensitivity

Author:

Patel S. A.1,Hoehn K. L.2,Lawrence R. T.2,Sawbridge L.1,Talbot N. A.1,Tomsig J. L.2,Turner N.34,Cooney G. J.34,Whitehead J. P.5,Kraegen E. W.36,Cleasby M. E.13

Affiliation:

1. Department of Comparative Biomedical Sciences (S.A.P., L.S., N.A.T., M.E.C.), Royal Veterinary College, University of London, London NW1 0TU, United Kingdom

2. Department of Pharmacology (K.L.H., R.T.L., J.L.T.), University of Virginia Health System, Charlottesville, Virginia 22908

3. Diabetes and Obesity Research Program (N.T., G.J.C., E.W.K., M.E.C.), Garvan Institute of Medical Research, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia

4. St. Vincent's Hospital Clinical School (N.T., G.J.C.), Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia

5. Department of Metabolic Medicine (J.P.W.), Mater Medical Research Institute, South Brisbane, Queensland 4101, Australia

6. School of Medical Sciences (E.W.K.), Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia

Abstract

Abstract Adiponectin is an adipokine whose plasma levels are inversely related to degrees of insulin resistance (IR) or obesity. It enhances glucose disposal and mitochondrial substrate oxidation in skeletal muscle and its actions are mediated through binding to receptors, especially adiponectin receptor 1 (AdipoR1). However, the in vivo significance of adiponectin sensitivity and the molecular mechanisms of muscle insulin sensitization by adiponectin have not been fully established. We used in vivo electrotransfer to overexpress AdipoR1 in single muscles of rats, some of which were fed for 6 wk with chow or high-fat diet (HFD) and then subjected to hyperinsulinemic-euglycemic clamp. After 1 wk, the effects on glucose disposal, signaling, and sphingolipid metabolism were investigated in test vs. contralateral control muscles. AdipoR1 overexpression (OE) increased glucose uptake and glycogen accumulation in the basal and insulin-treated rat muscle and also in the HFD-fed rats, locally ameliorating muscle IR. These effects were associated with increased phosphorylation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3β. AdipoR1 OE also caused increased phosphorylation of p70S6 kinase, AMP-activated protein kinase, and acetyl-coA carboxylase as well as increased protein levels of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif-1 and adiponectin, peroxisome proliferator activated receptor-γ coactivator-1α, and uncoupling protein-3, indicative of increased mitochondrial biogenesis. Although neither HFD feeding nor AdipoR1 OE caused generalized changes in sphingolipids, AdipoR1 OE did reduce levels of sphingosine 1-phosphate, ceramide 18:1, ceramide 20:2, and dihydroceramide 20:0, plus mRNA levels of the ceramide synthetic enzymes serine palmitoyl transferase and sphingolipid Δ-4 desaturase, changes that are associated with increased insulin sensitivity. These data demonstrate that enhancement of local adiponectin sensitivity is sufficient to improve skeletal muscle IR.

Publisher

The Endocrine Society

Subject

Endocrinology

Reference61 articles.

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