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Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

Author

Listed:
  • Qin Yang

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Timothy E. Graham

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Nimesh Mody

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Frederic Preitner

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Odile D. Peroni

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Janice M. Zabolotny

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Ko Kotani

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Loredana Quadro

    (Columbia University
    Rutgers–The State University of New Jersey)

  • Barbara B. Kahn

    (Beth Israel Deaconess Medical Center and Harvard Medical School)

Abstract

In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4-/-) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4-/- mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived ‘signal’ that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.

Suggested Citation

  • Qin Yang & Timothy E. Graham & Nimesh Mody & Frederic Preitner & Odile D. Peroni & Janice M. Zabolotny & Ko Kotani & Loredana Quadro & Barbara B. Kahn, 2005. "Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes," Nature, Nature, vol. 436(7049), pages 356-362, July.
    • Handle: RePEc:nat:nature:v:436:y:2005:i:7049:d:10.1038_nature03711
    DOI: 10.1038/nature03711
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    Cited by:

    1. Demetrios Petrakis & Loukia Vassilopoulou & Charalampos Mamoulakis & Christos Psycharakis & Aliki Anifantaki & Stavros Sifakis & Anca Oana Docea & John Tsiaoussis & Antonios Makrigiannakis & Aristides, 2017. "Endocrine Disruptors Leading to Obesity and Related Diseases," IJERPH, MDPI, vol. 14(10), pages 1-18, October.
    2. Konxhe Kulaj & Alexandra Harger & Michaela Bauer & Özüm S. Caliskan & Tilak Kumar Gupta & Dapi Menglin Chiang & Edward Milbank & Josefine Reber & Angelos Karlas & Petra Kotzbeck & David N. Sailer & Fr, 2023. "Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Lidwina Priliani & Sukma Oktavianthi & Elizabeth L Prado & Safarina G Malik & Anuraj H Shankar, 2020. "Maternal biomarker patterns for metabolism and inflammation in pregnancy are influenced by multiple micronutrient supplementation and associated with child biomarker patterns and nutritional status at," PLOS ONE, Public Library of Science, vol. 15(8), pages 1-21, August.
    4. Yu Zou & Da-Hong Wang & Noriko Sakano & Yoshie Sato & Suketaka Iwanaga & Kazuhisa Taketa & Masayuki Kubo & Kei Takemoto & Chie Masatomi & Kiyomi Inoue & Keiki Ogino, 2014. "Associations of Serum Retinol, α-Tocopherol, and γ-Tocopherol with Biomarkers among Healthy Japanese Men," IJERPH, MDPI, vol. 11(2), pages 1-14, January.
    5. Tina Rönn & Jones K. Ofori & Alexander Perfilyev & Alexander Hamilton & Karolina Pircs & Fabian Eichelmann & Sonia Garcia-Calzon & Alexandros Karagiannopoulos & Hans Stenlund & Anna Wendt & Petr Volko, 2023. "Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Cecilia Pessoa Rodrigues & Aindrila Chatterjee & Meike Wiese & Thomas Stehle & Witold Szymanski & Maria Shvedunova & Asifa Akhtar, 2021. "Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    7. Jonathan M. Dreyfuss & Yixing Yuchi & Xuehong Dong & Vissarion Efthymiou & Hui Pan & Donald C. Simonson & Ashley Vernon & Florencia Halperin & Pratik Aryal & Anish Konkar & Yinong Sebastian & Brandon , 2021. "High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    8. Federica Catalano & Francesca De Vito & Velia Cassano & Teresa Vanessa Fiorentino & Angela Sciacqua & Marta Letizia Hribal, 2022. "Circadian Clock Desynchronization and Insulin Resistance," IJERPH, MDPI, vol. 20(1), pages 1-11, December.

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