New research led by a team from the Sabri Ülker Center for Metabolic Research at the Harvard T.H. Chan School of Public Health identified a new hormone named fabkin that helps regulate metabolism and may play a critical role in the development of both type 1 and type 2 diabetes.
The findings are published in the journal Nature in a paper titled, “A hormone complex of FABP4 and nucleoside kinases regulates 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,” the researchers wrote. “Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4). Although 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 functional hormone complex with adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to regulate extracellular ATP and ADP levels.”
“For many decades, we have been searching for the signal that communicates the status of energy reserves in adipocytes to generate appropriate endocrine responses, such as the insulin production from pancreatic beta cells,” said senior author Gökhan S. Hotamisligil, director of the Sabri Ülker Center. “We now have identified fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”
In the new study, the researchers demonstrated that when FABP4 is secreted from fat cells and enters the bloodstream, it binds with the enzymes NDPK and ADK to form the protein complex now identified as fabkin. In this protein complex, FABP4 modifies the activity of NDPK and ADK to regulate levels of molecules known as ATP and ADP, which are the essential units of energy in biology. The researchers discovered that surface receptors on nearby cells sense the changing ratio of ATP to ADP, triggering the cells to respond to the changing energy status. As such, fabkin is able to regulate the function of these target cells.
The study showed blood levels of fabkin were high in mice and human patients with either type 1 or type 2 diabetes. They also discovered that blocking the activity of fabkin prevented the development of both forms of diabetes in the animals.
“The discovery of fabkin required us to take a step back and reconsider our fundamental understanding of how hormones work,” said lead author Kacey Prentice, research associate in the Sabri Ülker Center and department of molecular metabolism. “I am extremely excited to find a new hormone, but even more so about seeing the long-term implications of this discovery.”
