Cell-autonomous Adiposity Through Increased Cell Surface GLUT4 Due to ankyrin-B Deficiency

Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12743-12748. doi: 10.1073/pnas.1708865114. Epub 2017 Nov 13.

Abstract

Obesity typically is linked to caloric imbalance as a result of overnutrition. Here we propose a cell-autonomous mechanism for adiposity as a result of persistent cell surface glucose transporter type 4 (GLUT4) in adipocytes resulting from impaired function of ankyrin-B (AnkB) in coupling GLUT4 to clathrin-mediated endocytosis. Adipose tissue-specific AnkB-KO mice develop obesity and progressive pancreatic islet dysfunction with age or high-fat diet (HFD). AnkB-deficient adipocytes exhibit increased lipid accumulation associated with increased glucose uptake and impaired endocytosis of GLUT4. AnkB binds directly to GLUT4 and clathrin and promotes their association in adipocytes. AnkB variants that fail to restore normal lipid accumulation and GLUT4 localization in adipocytes are present in 1.3% of European Americans and 8.4% of African Americans, and are candidates to contribute to obesity susceptibility in humans.

Keywords: Glut4; ankyrin-B; clathrin; membrane transport; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Adiposity / genetics*
  • African Continental Ancestry Group
  • Animals
  • Ankyrins / chemistry
  • Ankyrins / genetics*
  • Ankyrins / metabolism
  • Biological Transport
  • Clathrin / genetics
  • Clathrin / metabolism
  • Diet, High-Fat / adverse effects
  • Endocytosis
  • European Continental Ancestry Group
  • Gene Expression Regulation
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / genetics*
  • Glucose Transporter Type 4 / metabolism
  • Humans
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Models, Molecular
  • Mutation
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology
  • Protein Binding
  • Protein Structure, Secondary
  • Signal Transduction

Substances

  • Ank2 protein, mouse
  • Ankyrins
  • Clathrin
  • Glucose Transporter Type 4
  • Slc2a4 protein, mouse
  • Glucose