Response to Comment on: Kumar et al. Fat Cell–Specific Ablation of Rictor in Mice Impairs Insulin-Regulated Fat Cell and Whole-Body Glucose and Lipid Metabolism. Diabetes 2010;59:1397–1406

  1. Thurl E. Harris4
  1. 1Department of Molecular Physiology and Biophysics and the Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee; the
  2. 2Department of Medicine, Division of Endocrinology, University of Virginia Health System, Charlottesville, Virginia; the
  3. 3Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts; and the
  4. 4Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia
  1. Corresponding author: Anil Kumar, anil.k.laxman{at}vanderbilt.edu.

We appreciate Dr. Erol's (1) interest in our article describing the phenotype of fat cell–specific rictor knockout (FRic−/−) mice (2). Dr. Erol suggested that RBP4 may play a role in the development of insulin resistance in FRic−/− mice. RBP4 is an adipokine, whose elevated expression in, and secretion from, adipocytes correlates with the development of insulin resistance in various animal models including the fat cell–specific GLUT4 knockout (G4A−/−) mice (3). Elevated circulating levels of RBP4 have also been demonstrated in insulin-resistant obese subjects and type 2 diabetic patients (4). Although a role for adipocyte-RBP4 as a regulator of whole-body insulin sensitivity is suggested, little is known about the regulation of the expression and secretion of RBP4 in adipocytes.

We agree that loss of adipocyte GLUT4 in G4A−/− mice (3) and decreased GLUT4 expression in insulin-resistant human subjects (3,4) are associated with an increase in expression and secretion of RBP4. However, it is not known whether the adipocyte-RBP4 response is caused by the reduction in total GLUT4 levels or because of the resulting decrease in insulin-stimulated glucose influx. We did not measure whether RBP4 was altered in FRic−/− mice. However, we do not think that RBP4 is the cause of the systemic insulin resistance that was observed in FRic−/− mice. Insulin-stimulated glucose uptake is impaired in FRic−/− adipocytes because of changes in insulin signaling and defective GLUT4 translocation to the plasma membrane in the absence of rictor (2). Total GLUT4 levels are not changed in the FRic−/− adipocytes (2). The decrease in basal glucose uptake in FRic−/− adipocytes (2) does not support Dr. Erol's model whereby decreased insulin-stimulated glucose uptake induces increased basal glucose uptake. In FRic−/− mice, loss of rictor expression does not only lead to impaired GLUT4 translocation to the plasma membrane, but multiple other defects (2). Most importantly, FRic−/− mice show dysregulation of lipolysis and increased circulating nonesterified fatty acid (2), a condition not observed in G4A−/− mice (5). Because it is very well known that an increase in circulating nonesterified fatty acid is sufficient to cause insulin resistance (6), this finding alone is sufficient to explain the insulin resistance observed in the FRic−/− mice.

ACKNOWLEDGMENTS

No potential conflicts of interest relevant to this article were reported.

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REFERENCES

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