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  • In summary the SAR of a series


    In summary, the SAR of a series of phenylpropanoic acid-free fatty Brefeldin A receptor agonists is described which resulted in the identification of potent FFA4 agonists. The superior pharmacokinetic properties of compound led to its selection as an in vivo tool compound which afforded robust efficacy in two rodent models of type 2 diabetes. In vivo results with compound detail the potential for FFA4 agonists as treatments for type 2 diabetes and additional factors associated with metabolic syndrome.
    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 acid (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).
    Introduction The incidence of type 2 diabetes mellitus (T2DM) has been on the increase, making it a serious health care problem. It was estimated that about 415 million adults were living with diabetes globally in 2015 [1]. Although several synthetic drugs such as sulfonylureas, biguanides, alpha-glucosidase inhibitors and others are currently being used for the treatment/management of T2DM, some of them have been associated with adverse effects such as hypoglycemia, liver damage, gastrointestinal symptoms, and weight gain. This therefore underscores the need for new and safer treatment options for T2DM. Free fatty acids (FFAs), which are obtained from dietary fat or endogenous synthesis, function as nutrients and signaling molecules. Studies have shown that free fatty acid receptors 1–4 which are G-protein coupled receptors, bind free fatty acids and serve as receptors for these FFAs. Short chain FFAs (SCFAs) activate FFA receptors 2 and 3 (FFAR2 and FFAR3) while medium-chain and long-chain FFAs (MCFAs/LCFAs) activate FFA receptors 1 and 4 (FFAR1 and FFAR4) respectively [2,3].