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  • br Introduction The replacement of a regular


    Introduction The replacement of a regular intake of healthy oils and fibres for a diet based substantially on high fat- and high sugar-content foods has had profound consequences for public health. These changes in the way that the populations of high income, particularly Western countries, manage their dietary habits have undoubtedly triggered what is now considered an epidemic of obesity that has consequently resulted in an increase in serious, chronic conditions associated with dysfunctions of energy balance, including type 2 diabetes and cardiovascular diseases [1], [2]. Furthermore, it is now widely accepted that low grade chronic inflammation associated with obesity may be directly connected to other inflammatory related pathologies such as asthma, colitis and, potentially, some forms of cancer, including colon cancer [3], [4], [5], [6], [7], [8], [9]. These effects have triggered a major increase in interest with regard to the role of metabolite sensing and how this may affect physiology in health and disease, with concepts including the interface between the metabolic and immune systems, i.e. immuno-metabolism, coming to the front of scientific discussions [9], [10]. There has been particular interest in free fatty Pefloxacin receptor (FFA) sensing and its association with the mode of signalling of a number of recently de-orphanised G protein-coupled receptors (GPCRs) [11]. This is a fast moving and exciting area of research focusing the interest of pharmacologists, chemists, immunologists and physiologists in an interdisciplinary manner. FFAs, including health boosting omega-3 fatty acid containing oils, are therefore no longer considered only as metabolic intermediaries but also as critical signalling molecules due to their role as agonists for different members of the family of free fatty acid receptors (FFARs) [12], [13], [14], [15], [16]. Although widely expressed, their presence on key cell types regulating both metabolic and immune health acts to link the regulation of energy homoeostasis with the control of inflammatory responses [17], [18].
    Overview of the family of free fatty acid receptors
    The role of free fatty acid receptors in metabolism and immune responses
    Conclusions and final remarks
    Conflict of interest
    Acknowledgement These studies were supported in part by the Biotechnology and Biosciences Research Council (grant numbers BB/L027887/1 and BB/K019864/1).
    Free fatty acids (FFAs) are not only essential nutrients but they also contribute to many cellular functions. Nuclear receptors, such as the peroxisome proliferator-activated receptors (PPARs), act as ‘sensors’ of FFAs. They maintain homeostasis under physiological and pathophysiological conditions by coordinating the expression of proteins that are involved in the uptake, synthesis, transport, storage, degradation and elimination of lipids . However, it appears that some of the biological effects of FFAs may be mediated by alternative mechanisms. Some effects appear to occur independently of PPARs and rather to involve cell surface receptors , . Recently, a strategy to deorphanize G-protein-coupled receptors (GPCRs) successfully identified multiple receptors for FFAs that function on the cell surface and play significant roles in nutritional regulation (). FFAR2 and FFAR3 are activated by short-chain FFAs, whereas FFAR1 and GPR120 are activated by medium- and long-chain FFAs. This review is an attempt to summarize the recent advances in our understanding of free fatty acid receptors (FFARs) and their physiological functions. FFAR1 (GPR40)
    Conclusion Recently, multiple GPCRs that are activated by several classes of FFA have been identified. They function on the cell surface and play significant roles in nutritional regulation (Fig. 3). They act independently of PPARs, which are transcription factors whose ligands include FFAs and which mediate a range of important metabolic functions [57]. FFARs belong to the nutrient-sensing GPCRs [58], which directly monitor the level of nutrients in the extracellular environment and mediate the secretion or production of peptide hormones. The ligands for some nutrient-sensing GPCRs bind with lower affinity (in the micromolar or millimolar range) than that of the classical high affinity ligands, such as hormones or growth factors, for their receptors [59]. Due to the low binding affinity of FFAs (in the micromolar range) and nonspecific binding to other fatty acid-binding proteins, it is difficult to show the direct binding of FFAs to FFARs. However, as mentioned above, we have successfully developed a flow cytometry-based assay that can be used to detect the direct binding of FFAs to FFARs (Fig. 1) [24]. Our approach should be useful for the study of other GPCRs that have a low affinity for their ligands. To elucidate the physiological functions of these nutrient-sensing receptors, it is necessary to detect and analyze not only the mRNA for the receptors but also the protein product. Utilizing specific antibodies and knockout mice, we identified novel tissue distributions of the FFAR1 and GPR120 proteins. In addition, we and other groups discovered selective ligands for these FFARs. Further studies using the flow-cytometry assay, specific antibodies, and selective agonists might reveal novel physiological roles of these FFARs in energy homeostasis. The functional analysis of these FFARs should be valuable for understanding nutrient metabolism and might lead to the discovery of novel therapies and drugs for metabolic diseases.