CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylationResearch in context
Patricia O. Benedet,
Nooshin S. Safikhan,
Maria J. Pereira,
Bryan M. Lum,
José Diego Botezelli,
Cheng-Hsiang Kuo,
Hua-Lin Wu,
Barbara P. Craddock,
W. Todd Miller,
Jan W. Eriksson,
Jessica T.Y. Yue,
Edward M. Conway
Affiliations
Patricia O. Benedet
Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada
Nooshin S. Safikhan
Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada
Maria J. Pereira
Department of Medical Sciences, Clinical Diabetology & Metabolism, Uppsala University, Sweden
Bryan M. Lum
Department of Physiology, Alberta Diabetes Institute and Group on Molecular and Cell Biology of Lipids, University of Alberta, Canada
José Diego Botezelli
Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada
Cheng-Hsiang Kuo
International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan
Hua-Lin Wu
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Barbara P. Craddock
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA
W. Todd Miller
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA; Veterans Affairs Medical Center, Northport, NY, USA
Jan W. Eriksson
Department of Medical Sciences, Clinical Diabetology & Metabolism, Uppsala University, Sweden
Jessica T.Y. Yue
Department of Physiology, Alberta Diabetes Institute and Group on Molecular and Cell Biology of Lipids, University of Alberta, Canada
Edward M. Conway
Centre for Blood Research, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Life Sciences Institute, Faculty of Medicine, University of British Columbia, Vancouver, Canada; Corresponding author. Centre for Blood Research, Life Sciences Institute, 4306-2350, Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Summary: Background: In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance. Methods: Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens. Findings: Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis. Interpretation: Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance. Funding: Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.
