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Edited by Barbara B. Kahn, Beth Israel Deaconess Medical Center, Boston, MA, and approved October 26, 2017 (received for review May 28, 2017)
Significance
Calorie intake exceeding energy requirements is the chief culprit in the obesity epidemic affecting the United States and other countries. However, genetic factors may also contribute to the etiology of obesity. This study demonstrates that ankyrin-B (AnkB) deficiency in adipose tissue (AT) causes cell-autonomous adiposity, rendering mice more susceptible to becoming obese with age or when fed a high-fat diet and causing other metabolic complications. Loss of AnkB in AT increases glucose uptake and lipogenesis as a result of deficient clathrin-mediated GLUT4 endocytosis. We also show that AnkB mutations present in millions of Americans cause similar cellular metabolic impairments.
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.
Footnotes
↵1Present address: Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
- ↵2To whom correspondence may be addressed. Email: dlorenzo{at}email.unc.edu or benne012{at}mc.duke.edu.
Author contributions: D.N.L. and V.B. designed research; D.N.L. performed research; D.N.L. contributed new reagents/analytic tools; D.N.L. analyzed data; and D.N.L. and V.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1708865114/-/DCSupplemental.
Published under the PNAS license.
References
Obesity due to loss of ankyrin-B
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