The Harvard research team demonstrated that the newly found hormone, fabkin, targets the pancreas’ insulin-producing beta cells and is a driving element in the development of diabetes. After using an antibody to deactivate fabkin, the mice did not develop diabetes. Additionally, obese, diabetic mice were administered the antibody and their health was restored. (Image: Pancreatic beta-islet cells (shown in green))
According to a study conducted by the Harvard T.H. Chan School of Public Health’s Sabri Ülker Center for Metabolic Research, a recently discovered hormone, called fabkin helps regulate metabolic activity and may play a key role in the development of both type 1 and type 2 diabetes.
The researchers discovered that fabkin levels in mice and human patients with type 1 and type 2 diabetes were unusually high. The researchers discovered that inhibiting the action of fabkin in the rats prevented the development of both types of diabetes. According to the researchers, Fabkin has a similar role in humans, and the hormone complex might be a suitable therapeutic target.
Author Gökhan S. Hotamisligil stated, “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. We now have identified fabkin as a novel hormone that controls this critical function through a very unusual molecular mechanism.”
Insulin and leptin are two hormones that have a role in metabolic control. As is the case with typical hormones, fabkin is not a single molecule with a single identified receptor. Instead, fabkin is made up of a multiprotein complex that includes fatty acid binding protein 4 (FABP4), adenosine kinase (ADK), and nucleoside diphosphate kinase (NDK) (NDPK). The researchers discovered that fabkin modulates energy signals outside of cells through a series of tests. These signals subsequently govern target cell activity via a set of receptors. When it comes to diabetes, fabkin regulates the activity of beta cells in the pancreas, which produce insulin.
Hotamisligil and his team found more than a decade ago that a protein called FABP4 is produced from fat cells during lipolysis, which is the breakdown of lipids held within fat cells, usually in reaction to fasting. Since then, research has found links between circulating FABP4 and metabolic diseases like obesity, diabetes, heart disease, and cancer. Nevertheless, the method of action was unknown.
According to the recently published study, FABP4 is produced from fat cells and enters the bloodstream, where it combines with the enzymes NDPK and ADK to create the protein complex known as fabkin. FABP4 regulates the quantities of molecules known as ATP and ADP, which are the essential units of energy in life, via modifying the activity of NDPK and ADK in this protein complex. The researchers observed that neighboring cells’ surface receptors detect changes in the ratio of ATP to ADP, causing the cells to respond to the altered energy state. As a result, fabkin can control how these target cells operate.
The researchers found that fabkin targets the pancreas’ insulin-producing beta cells, and that the hormone is a driving factor in the development of diabetes. The mice did not acquire diabetes when the researchers employed an antibody to deactivate fabkin. When obese, diabetic mice were given the antibody, they regained their health.
The study was published in Nature, on December 8th, 2021.
Abstract. 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 humans4,5,6,7, no mechanism of action has yet been described8,9,10. 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.
Kacey J. Prentice, Jani Saksi, Lauren T. Robertson, Grace Y. Lee, Karen E. Inouye, Kosei Eguchi, Alexandra Lee, Ozgur Cakici, Emily Otterbeck, Paulina Cedillo, Peter Achenbach, Anette-Gabriele Ziegler, Ediz S. Calay, Feyza Engin, Gökhan S. Hotamisligil. A hormone complex of FABP4 and nucleoside kinases regulates islet function. Nature, 2021; DOI: 10.1038/s41586-021-04137-3
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