title: Glypican-4 enhances insulin signaling via interaction with the insulin receptor and serves as a novel adipokine.
abstract: 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.
authors: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA.
authors: Siegfried
authors: S
authors: Ussar
authors: Olivier
authors: O
authors: Bezy
authors: Matthias
authors: M
authors: Blüher
authors: C Ronald
authors: CR
authors: Kahn
mesh_terms: D017667:Adipocytes; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D053673:Glypicans / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism; D051379:Mice; D011972:Receptor, Insulin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D053673:Glypicans; D011972:Receptor, Insulin