Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity. Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo. Fatty acid binding protein 4 promotes autoimmune diabetes by recruitment and activation of pancreatic islet macrophages. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Does diabetes appear in distinct phenotypes in young people? Results of the diabetes mellitus incidence Cohort Registry (DiMelli). German new onset diabetes in the young incident cohort study: DiMelli study design and first-year results. Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes. Unconventional secretion of FABP4 by endosomes and secretory lysosomes. Calcium-dependent release of adipocyte fatty acid binding protein from human adipocytes. Schlottmann, I., Ehrhart-Bornstein, M., Wabitsch, M., Bornstein, S. Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Low-expression variant of fatty acid-binding protein 4 favors reduced manifestations of atherosclerotic disease and increased plaque stability. Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses.
Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Increased lipolysis, diminished adipose tissue insulin sensitivity, and impaired beta-cell function relative to adipose tissue insulin sensitivity in obese youth with impaired glucose tolerance. Insulin regulation of lipolysis in nondiabetic and IDDM subjects. 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. 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. 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. 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. Although circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans 4, 5, 6, 7, no mechanism of action has yet been described 8, 9, 10. Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4) 3. 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.
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