A hormone complex of FABP4 and nucleoside kinases regulates islet function

Article

关键词: ACID-BINDING PROTEIN;    P2Y(1) RECEPTOR;    ADENOSINE KINASE;    SECRETION;    ADIPOKINE;    CELLS;    CMPF;    AP2;    IDENTIFICATION;    INHIBITION;   

DOI  :  10.1038/s41586-021-04137-3

来源: SCIE

【 摘 要 】

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 homeostasis(1,2). 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 humans(4-7), no mechanism of action has yet been describe(8-10). 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 land 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.

【 授权许可】

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