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Prentice, K.J.* ; Saksi, J.* ; Robertson, L.T.* ; Lee, G.Y.* ; Inouye, K.E.* ; Eguchi, K.* ; Lee, A.* ; Cakici, O.* ; Otterbeck, E.* ; Cedillo, P.* ; Achenbach, P. ; Ziegler, A.-G. ; Calay, E.S.* ; Engin, F.* ; Hotamisligil, G.S.*

A hormone complex of FABP4 and nucleoside kinases regulates islet function.

Nature 600, 720–726 (2021)
Postprint DOI
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Acid-binding Protein; P2y(1) Receptor; Adenosine Kinase; Secretion; Adipokine; Cells; Cmpf; Ap2; Identification; Inhibition
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 600, Heft: 7890, Seiten: 720–726 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Förderungen NIH
JDRF
Otto A. Malm Foundation
Finnish Foundation for Cardiovascular research
Sigrid Juselius Foundation
JDRF postdoctoral fellowship
Juvenile Diabetes Research Foundation (JDRF)
National Institutes of Health