Journal Article

A hormone complex of FABP4 and nucleoside kinases regulates islet function

Cakici, Ozgur, Robertson, Lauren T., Inouye, Karen E., Lee, Alexandra, Prentice, Kacey J., Calay, Ediz S., Hotamisligil, Gökhan S., Eguchi, Kosei, Ziegler, Anette-Gabriele, Otterbeck, Emily, Cedillo, Paulina, Engin, Feyza, Lee, Grace Y., Achenbach, Peter, Saksi, Jani

2021

Overview

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 described 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 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. Hormonal FABP4 is discovered to be a pivotal regulator of an adipose–beta-cell endocrine axis that coordinates energy status and metabolic organ function, and targeting this axis improved metabolic outcomes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/2 / 13/31 / 13/51 / 13/95 / 14/19 / 14/34 / 14/63 / 38/77 / 631/443/319/1642/137/1418 / 631/443/319/1642/137/773 / 631/45/776/1178 / 631/80/304 / 631/80/86/820 / 64 / 64/60 / 82 / 82/1 / 82/58 / 82/75 / 96 / Adenosine / Adenosine diphosphate / Adenosine kinase / Adipocytes / Adipocytes - metabolism / Amino acids / Antibodies / Beta cells / Binding proteins / Binding sites / Biological control systems / Diabetes / Diabetes mellitus (insulin dependent) / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus - metabolism / Energy balance / Fatty Acid-Binding Proteins - metabolism / Glucose / Hormones / Humanities and Social Sciences / Humans / Insulin / Insulin - metabolism / Insulin resistance / Islands of Langerhans / Islets of Langerhans - enzymology / Islets of Langerhans - physiology / Kinases / Lipolysis / Metabolic disorders / Metabolism / multidisciplinary / Nucleoside-diphosphate kinase / Nucleosides / Nucleosides - metabolism / Organs / Peptides / Phosphotransferases / Phosphotransferases - metabolism / Physiological aspects / Physiological research / Plasma / Proteins / Science / Science (multidisciplinary)