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. Adnan Erol
  1. From the Erol Project Development House for the Disorders of Energy Metabolism, Silivri-Istanbul, Turkey
  1. Corresponding author: Adnan Erol, eroladnan{at}

In their article, Kumar et al. (1) demonstrated the importance of mTORC2 for the insulin-induced glucose transport and lipolysis in adipocytes. They also discussed the mechanisms of the fat-cell–specific deletion of rictor and alterations in the insulin signaling pathway, leading to systemic insulin resistance. They suggested that the increased serum nonesterified fatty acid levels in FRic−/− mice are the mediators for the impairment of the whole-body insulin sensitivity (1). Previously, Cybulski et al. (2) showed that adipose mTORC2 negatively regulates IGF-1 and insulin production by liver and pancreas, respectively, and thereby controls systemic growth and metabolism. These researchers also had a query for the mTORC2-regulated factor(s) that could be signaling from adipose tissue to the other insulin sensitive tissues.

In adipocytes, mTORC2 phosphorylates Akt Serine473, leading to increased phosphorylation of and inhibition of AS160, and thereby stimulates the GLUT4 exocytosis (3). The signaling defects in FRic−/− adipocytes impair insulin-stimulated GLUT translocation to the plasma membrane and decrease glucose transport (1). On the other hand, adipocytes, as a glucose sensor, may detect the absence of glucose uptake by GLUT4 and, in response, secrete adipokine retinol binding protein (RBP) 4 that impairs systemic insulin sensitivity (4). RBP4, in turn, may increase the amount of GLUT4 at the plasma membrane and increase glucose basal uptake (5), suggesting the existence of a common regulatory pathway for both GLUT4 and RBP4. Thus, RBP4 might be a mechanistic link by which downregulation of GLUT4 in FRic−/− adipocytes contribute to the development of systemic insulin resistance. Increased release of RBP4 from the FRic−/− adipocytes could be an important mediator of whole-body insulin sensitivity besides increased nonesterified fatty acid level. Thereby, it is tempting to speculate that AS160, under the control of mTORC2, might be a positive regulator of RBP4 activity in adipocytes. Taken together, evaluation of RBP4 in FRic−/− fat cells by the authors could verify the link between mTORC2 kinase activity and RBP4.


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