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Metabolism

Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance

  1. Regine Å. Jersin1,2,
  2. Divya Sri Priyanka Tallapragada1,2,
  3. André Madsen1,2,
  4. Linn Skartveit1,2,
  5. Even Fjære3,
  6. Adrian McCann4,
  7. Laurence Dyer1,2,
  8. Aron Willems1,2,
  9. Jan-Inge Bjune1,2,
  10. Mona S. Bjune1,2,
  11. Villy Våge2,5,
  12. Hans Jørgen Nielsen6,
  13. Håvard Luong Thorsen7,
  14. Bjørn Gunnar Nedrebø1,8,
  15. Christian Busch9,
  16. Vidar M. Steen10,11,
  17. Matthias Blüher12,
  18. Peter Jacobson13,
  19. Per-Arne Svensson13,
  20. Johan Fernø1,2,
  21. Mikael Rydén14,
  22. Peter Arner14,
  23. Ottar Nygård1,15,
  24. Melina Claussnitzer1,16,17,
  25. Ståle Ellingsen3,18,
  26. Lise Madsen3,19,
  27. Jørn V. Sagen1,2,20,
  28. Gunnar Mellgren1,2 and
  29. Simon N. Dankel1,2⇑
  1. 1Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
  2. 2Hormone Laboratory, Haukeland University Hospital, Bergen, Norway
  3. 3Institute of Marine Research, Bergen, Norway
  4. 4Bevital A/S, Laboratoriebygget, Bergen, Norway
  5. 5Center of Health Research, Førde Hospital Trust, Førde, Norway
  6. 6Department of Surgery, Voss Hospital, Bergen Health Trust, Voss, Norway
  7. 7Department of Surgery, Haugesund Hospital, Haugesund, Norway
  8. 8Department of Medicine, Haugesund Hospital, Haugesund, Norway
  9. 9Plastikkirurg1 AS, Bergen, Norway
  10. 10NORMENT, K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway
  11. 11Dr. E. Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
  12. 12Clinic for Endocrinology and Nephrology, Medical Research Center, Leipzig, Germany
  13. 13Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  14. 14Department of Medicine (H7), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
  15. 15Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
  16. 16Broad Institute of MIT and Harvard, Cambridge, MA
  17. 17Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
  18. 18Department of Biological Sciences, University of Bergen, Bergen, Norway
  19. 19Department of Biology, University of Copenhagen, Copenhagen, Denmark
  20. 20Bergen Stem Cell Consortium, Haukeland University Hospital, Bergen, Norway
  1. Corresponding author: Simon N. Dankel, simon.dankel{at}uib.no
Diabetes 2021 Mar; 70(3): 680-695. https://doi.org/10.2337/db20-0096
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Abstract

Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.13377155.

  • Received January 30, 2020.
  • Accepted December 14, 2020.
  • © 2021 by the American Diabetes Association
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Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
Regine Å. Jersin, Divya Sri Priyanka Tallapragada, André Madsen, Linn Skartveit, Even Fjære, Adrian McCann, Laurence Dyer, Aron Willems, Jan-Inge Bjune, Mona S. Bjune, Villy Våge, Hans Jørgen Nielsen, Håvard Luong Thorsen, Bjørn Gunnar Nedrebø, Christian Busch, Vidar M. Steen, Matthias Blüher, Peter Jacobson, Per-Arne Svensson, Johan Fernø, Mikael Rydén, Peter Arner, Ottar Nygård, Melina Claussnitzer, Ståle Ellingsen, Lise Madsen, Jørn V. Sagen, Gunnar Mellgren, Simon N. Dankel
Diabetes Mar 2021, 70 (3) 680-695; DOI: 10.2337/db20-0096

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Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
Regine Å. Jersin, Divya Sri Priyanka Tallapragada, André Madsen, Linn Skartveit, Even Fjære, Adrian McCann, Laurence Dyer, Aron Willems, Jan-Inge Bjune, Mona S. Bjune, Villy Våge, Hans Jørgen Nielsen, Håvard Luong Thorsen, Bjørn Gunnar Nedrebø, Christian Busch, Vidar M. Steen, Matthias Blüher, Peter Jacobson, Per-Arne Svensson, Johan Fernø, Mikael Rydén, Peter Arner, Ottar Nygård, Melina Claussnitzer, Ståle Ellingsen, Lise Madsen, Jørn V. Sagen, Gunnar Mellgren, Simon N. Dankel
Diabetes Mar 2021, 70 (3) 680-695; DOI: 10.2337/db20-0096
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