A hormone complex of FABP4 and nucleoside kinases regulates islet function.
A hormone complex of FABP4 and nucleoside kinases regulates islet function.
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DOI：
10.1038/s41586-021-04137-3
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发表时间：
2021-12
期刊：
影响因子：
64.8
通讯作者：
Hotamisligil GS
中科院分区：
文献类型：
--
作者：
Prentice KJ;Saksi J;Robertson LT;Lee GY;Inouye KE;Eguchi K;Lee A;Cakici O;Otterbeck E;Cedillo P;Achenbach P;Ziegler AG;Calay ES;Engin F;Hotamisligil GS
从脂肪细胞中释放能量储备是维持能量不足时期生存的关键，然而，与胰岛素抵抗和/或胰岛素不足相关的失控或慢性脂解作用会破坏代谢平衡。伴随着脂肪分解的是最近发现的一种激素--脂肪酸结合蛋白4(FABP4)的释放。虽然在临床前模型和人类中，循环FABP4水平与心脏代谢性疾病密切相关，但其作用机制尚未被描述。在这里，我们证明了激素性FABP4与腺苷激酶(ADK)和核苷二磷酸酶(NDPK)形成了一种新的功能激素复合体，以调节细胞外ATP和ADP的水平。我们确定了这种激素对β细胞的实质性影响，并考虑到β细胞功能在控制脂肪分解和糖尿病发展中的核心作用，假设激素FABP4是脂肪-β细胞内分泌轴的关键调节因子。抗体介导的这种荷尔蒙复合体的靶向改善了代谢结果，增强了β细胞功能，并保持了β细胞的完整性，以预防1型和2型糖尿病。因此，FABP4-ADK-NDPK复合体Fabtin代表了一种未知的激素和作用机制，将能量状态与代谢器官的功能结合在一起，有望成为治疗代谢性疾病的靶点。
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. Coupled to lipolysis is the release of a recently identified hormone, fatty acid-binding protein 4 (FABP4). While circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans, no mechanism of action has yet been described. Here, we show that hormonal FABP4 forms a novel functional hormone complex with Adenosine Kinase (ADK) and Nucleoside Diphosphate Kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial impact 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, Fabtin, represents a previously unknown hormone and mechanism of action integrating energy status with the function of metabolic organs, representing a promising target against metabolic disease.
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影响因子：
5
作者：
Baurand, A;Raboisson, P;Gachet, C
通讯作者：
Gachet, C
影响因子：
17.1
作者：
Burak, M. Furkan;Inouye, Karen E.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.
影响因子：
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Prentice KJ;Wendell SG;Liu Y;Eversley JA;Salvatore SR;Mohan H;Brandt SL;Adams AC;Serena Wang X;Wei D;FitzGerald GA;Durham TB;Hammond CD;Sloop KW;Skarke C;Schopfer FJ;Wheeler MB
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Wheeler MB
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46.9
作者：
Rezania, Alireza;Bruin, Jennifer E.;Kieffer, Timothy J.
通讯作者：
Kieffer, Timothy J.
影响因子：
17.1
作者：
Engin F;Yermalovich A;Nguyen T;Hummasti S;Fu W;Eizirik DL;Mathis D;Hotamisligil GS
通讯作者：
Hotamisligil GS