A hormone complex of FABP4 and nucleoside kinases regulates islet function

Kacey J. Prentice, Jani Saksi, Lauren T. Robertson, Grace Y. Lee, Karen E. Inouye, Kosei Eguchi, Alexandra Lee, Ozgur Cakici, Emily Otterbeck, Paulina Cedillo, Peter Achenbach, Anette-Gabriele Ziegler, Ediz S. Calay, Feyza Engin and Gökhan S. Hotamisligil ()
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Kacey J. Prentice: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Jani Saksi: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Lauren T. Robertson: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Grace Y. Lee: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Karen E. Inouye: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Kosei Eguchi: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Alexandra Lee: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Ozgur Cakici: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Emily Otterbeck: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Paulina Cedillo: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Peter Achenbach: German Research Center for Environmental Health
Anette-Gabriele Ziegler: German Research Center for Environmental Health
Ediz S. Calay: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Feyza Engin: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism
Gökhan S. Hotamisligil: Sabri Ülker Center for Metabolic Research, Harvard T. H. Chan School of Public Health, Department of Molecular Metabolism

Nature, 2021, vol. 600, issue 7890, 720-726

Abstract: Abstract The liberation of energy stores from adipocytes is critical to support survival in times of energy deficit; however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency disrupts metabolic homeostasis1,2. Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4)3. Although circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans4–7, no mechanism of action has yet been described8–10. Here we show that hormonal FABP4 forms a functional hormone complex with adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial effect of this hormone on beta cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose–beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves metabolic outcomes, enhances beta-cell function and preserves beta-cell integrity to prevent both type 1 and type 2 diabetes. Thus, the FABP4–ADK–NDPK complex, Fabkin, represents a previously unknown hormone and mechanism of action that integrates energy status with the function of metabolic organs, and represents a promising target against metabolic disease.

Date: 2021
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DOI: 10.1038/s41586-021-04137-3

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