Glypican-4 Enhances Insulin Signaling via Interaction With the Insulin Receptor and Serves as a Novel Adipokine

  1. C. Ronald Kahn1
  1. 1Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts
  2. 2Department of Medicine, University of Leipzig, Leipzig, Germany
  1. Corresponding author: C. Ronald Kahn, c.ronald.kahn{at}


Obesity, especially visceral obesity, is associated with insulin resistance and metabolic syndrome. We previously identified the cell surface proteoglycan glypican-4 as differentially expressed in subcutaneous versus visceral white fat depots. Here we show that glypican-4 is released from cells and adipose tissue explants of mice, and that circulating glypican-4 levels correlate with BMI and insulin sensitivity in humans. Furthermore, glypican-4 interacts with the insulin receptor, enhances insulin receptor signaling, and enhances adipocyte differentiation. Conversely, depletion of glypican-4 results in reduced activation of the insulin receptor and prevents adipocyte differentiation in vitro by inhibiting insulin-mediated C/EBPβ phosphorylation. These functions of glypican-4 are independent of its glycosylphosphatidylinositol membrane anchorage, as a nonmembrane–bound mutant of glypican-4 phenocopies the effects of native glypican-4 overexpression. In summary, glypican-4 is a novel circulating insulin sensitizing adipose-derived factor that, unlike other insulin sensitizers, acts directly on the insulin receptor to enhance signaling.


  • Received October 19, 2011.
  • Accepted March 26, 2012.

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  1. Diabetes vol. 61 no. 9 2289-2298
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