Free Fatty Acid Receptors (FFARs): Emerging Therapeutic Targets for the Management of Diabetes Mellitus

Abstract

Free fatty acids (FFAs) present in our dietary fats not only act as vital nutrients but also function as signalling molecules and modulate key biological functions through their active involvement in a multitude of energy metabolism pathways. However, it has been reported that excessive intake of dietary fat contributes to the development of different types of Diabetes mellitus. Free fatty acid receptors are the key regulators of the most metabolic disorders. Among them, diabetes mellitus is a severe growing disorder and found in every corner of the world. Various metabolic disorders, particularly for type 2 diabetes mellitus, these different free fatty acid receptors are being explored as drug targets. In the present review, it has been explored various FFAs sensing G-protein coupled receptors (GPR) likes GPR40 (FFAR1), GPR43 (FFAR2), GPR41 (FFAR3), GPR120 (FFAR4), and GPR84 as emerging novel therapeutic targets for antidiabetic drugs. Additionally, this review has covered pre-clinical discovery and development of different selective ligands targeted to these receptors starting from hit identification to lead optimization via chemical modification and the challenges and tactics selected by different medicinal chemists to improve potency, physicochemical properties, safety profiles, and pharmacokinetics of different FFAR agonists for making a potential drug candidate. Several molecules have been withdrawn in the clinical trials without reporting any reasons. We believe that this review will help the researchers to find a new direction in the discovery of new antidiabetic drugs.

Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy

“…Several plasma membrane-associated non-NHR receptors have been examined to explain the rapid non-genomic signaling effects of physiological and synthetic PPAR ligands on MAPKs. Those include GPCRs of the "Free Fatty Acid Receptor" (FFAR) family [119] or the EGFR [120]. In contrast to endocrine NHRs, specific membranal PPAR variants have not been described.…”

“…Free fatty acid receptors (GPR40 (FFAR1), GPR43 (FFAR2), GPR41 (FFAR3), GPR120 (FFAR4), etc.) [119] were originally developed as anti-diabetic targets, albeit with landmark insight into their utility for the treatment of inflammatory diseases. In mice, GPR40 agonist (GW9508) stimulates the function of neutrophils to eliminate infectious pathogens (e.g., Escherichia coli) [143] via increased IL8-guided chemotaxis, phagocytosis and resolvin production.…”

The effect of educational intervention based on social support theory on the perceived stress caused by the covid-19 pandemic in patients with diabetes in hormozgan (2020–2021)

“…Diabetes is a rapidly growing disorder that is prevalent worldwide [ 1 ]. The aging global population and the shift towards sedentary lifestyles have contributed to a rapid increase in the number of diabetes patients [ 2 ].…”

Differential Modulation of Catecholamine and Adipokine Secretion by the Short Chain Fatty Acid Receptor FFAR3 and α2-Adrenergic Receptors in PC12 Cells

“…Short-chain free fatty acids (SCFAs), such as propionate and butyrate, are important metabolites serving as energy sources for the heart and other organs and tissues. At the same time, they function as signaling hormones, stimulating free fatty acid receptors (FFARs), which are also plasma membrane-residing GPCRs [12][13][14]. One of the four mammalian FFARs, FFAR3 (also known as GPR41), regulates cardiovascular function via effects in peripheral sympathetic neurons, wherein it promotes neuronal firing and NE release [15].…”