FABP4 and Nucleoside Kinases Regulate Islet Function

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. Recently identified hormone FABP4 is released from adipocytes and has been strongly associated with cardiometabolic diseases in both preclinical models and humans. Despite its association with disease, the mechanism of action of FABP4 has yet to be described. Here, the authors 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. This complex has a substantial effect on beta cells, which are critical for controlling lipolysis and developing diabetes. We postulate that 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, preventing both type 1 and type 2 diabetes. 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, offering a promising target against metabolic disease.