A hormone complex of FABP4 and nucleoside kinases regulates islet function

Nature. 2021 Dec;600(7890):720-726. doi: 10.1038/s41586-021-04137-3. Epub 2021 Dec 8.


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.

MeSH terms

  • Adipocytes / metabolism
  • Diabetes Mellitus / metabolism
  • Fatty Acid-Binding Proteins* / metabolism
  • Humans
  • Insulin / metabolism
  • Islets of Langerhans* / enzymology
  • Islets of Langerhans* / physiology
  • Lipolysis
  • Nucleosides / metabolism
  • Phosphotransferases* / metabolism


  • FABP4 protein, human
  • Fatty Acid-Binding Proteins
  • Insulin
  • Nucleosides
  • Phosphotransferases
  • nucleoside phosphotransferase