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Professor Gökhan S. Hotamışlıgil (Harvard T.H. Chan School of Public Health, Boston, USA) discussed: Foundations of Immunometabolism and Implications for Metabolic Health and Disease
Immunometabolism is an emerging field investigating the interplay between immune response and metabolic processes. In the last two decades it has become clear that overlapping and redundant inflammatory pathways play pleiotropic roles in metabolism, and that the metabolic state is a critical determinant of immune function.
The focus of this lecture was the role of fatty acid binding proteins (FABP4) in immunometabolism. FABP4 is expressed in most metabolically critical tissues, including adipose tissue, liver, pancreas, brain, and the vasculature; and more recently was shown to be expressed in immune cells too. In adipocytes, FABP4 is a metabolic effector, whereas in macrophages it acts as an immune effector. FABP4 activity is increased in obesity and type 2 diabetes; circulating FABP4 levels are also correlated with key clinical parameters, including body mass index, insulin resistance, and dyslipidaemia.
Several downstream pathways are regulated by FABP4, suggesting a potential role in chronic immunometabolic disease. The most striking evidence is from genetic models, such as FABP4 knockout mice, which under conditions of high fat feeding maintain blood glucose levels to normal plasma levels despite developing obesity. Furthermore, in the APOE mouse model fed a high fat diet, there was reduction in atherosclerosis and improved survival. This protective phenotype associated with FABP4 deficiency is maintained until end of life. These experimental findings suggest the possibility of targeting multiple components of immunometabolic disease. In pursuit of this, small molecule-mediated inhibition of FABP4 was also shown to improve glucose homeostasis in mouse models and is the focus of ongoing development (1).
This supports a role for FABP4 in maintaining glucose homeostasis which was first indicated over 15 years ago by genetic studies of individuals with mutations in the FABP4 gene, which were associated with reduced risk for diabetes, hypertriglyceridaemia, and cardiovascular disease (2). In a subsequent genome wide analysis, this gene was among the top alleles as candidates for joint presence of coronary heart disease and type 2 diabetes (3), thus providing proof of principle.
FABP4 is strongly associated with cardiometabolic risk and cardiovascular mortality. The question posed by Professor Hotamışlıgil was how does FABP4 regulate glucose homeostasis at the molecular level? Recent unpublished insights suggest that FABP4 acts as functional hormone to negatively regulate insulin secretion by complexing with nucleoside kinases (NDPK and ADK) and affecting beta cell function.
FABP4 continues to be a focus of interest, as a potential therapeutic target with overlapping roles in metabolic syndrome, diabetes, and atherosclerotic cardiovascular disease.
- Hotamisligil GS et al. Metabolic functions of FABPs–mechanisms and therapeutic implications. Nat Rev Endocrinol 2015;11:592-605.
- Tuncman G, et al. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci U S A. 2006;103:6970-5.
- Zhao W, et al. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet 2017;49:1450-1457.