Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded (i.e., its synthesis is directed) by the FFAR1 gene. This gene is located on the short (i.e., "q") arm of chromosome 19 at position 13.12 (location notated as 19q13.12). G protein-coupled receptors (also termed GPRs or GPCRs) reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2 (also termed GPR43), FFAR3 (also termed GPR41), and FFAR4 (also termed GPR120). FFARs bind and thereby are activated by certain fatty acids.
Studies suggest that FFAR1 may be involved in the development of obesity, type 2 diabetes, and various emotional, behavioral, learning, and cognition defects such as Alzheimer's disease. FFAR1 may also be involved in the perception of pain, the tastes of and preferences for eating fatty and sweet foods, the pathological replacement of injured tissue with fibrosis and scarring, and the malignant behavior, i.e., proliferation, invasiveness, and metastasis, of some types of cancer cells.
Various fatty acids, including in particular two omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids, have been consumed in diets and supplements for the purposes of preventing or treating the disorders that recent studies suggest are associated with abnormalities in FFAR1's functions. It is now known that these fatty acids activate (i.e. are agonists of) FFAR1 as well as FFAR4. While dietary and supplemental omega-3 fatty acids have had no or only marginally significant therapeutic effects on these disorders (see health effects of omega-3 fatty acid supplementation), drugs have been developed that are more potent and selective in activating FFAR1 than the omega-3 fatty acids. Furthermore, drugs have been developed that potently inhibit (i.e. are antagonists of) FFAR1. This raised the possibility that the drugs may be more effective than the omega-3 fatty acids in treating these diseases and prompted studies testing their effectiveness to do so. These studies, which are preclinical studies on cultured cells and animal models of disease plus some clinical studies, are detailed here.
Activators and inhibitors of the free fatty acid receptors
FFARs are activated by specific types of fatty acids. FFAR2 and FFAR3 are activated by short-chain fatty acids (i.e., fatty acid chains consisting of 2 to 5 carbon atoms) such as acetic, butyric, and propionic acids. FFAR1 and FFAR4 are activated by 1) medium-chain fatty acids (i.e., fatty acids consisting of 6-12 carbon atoms) such as capric and lauric acids; 2) long-chain and very long-chain fatty acids (i.e. fatty acids consisting respectively of 13 to 21 or more than 21 carbon atoms) unsaturated fatty acids such as myristic and steric acids; 3) long chain monounsaturated fatty acidss such as oleic and palmitoleic acids; 4) long and very long chain polyunsaturated fatty acids such as the omega-3 fatty acids alpha-linolenic, eicosatrienoic, eicosapentaenoic, and docosahexaenoic acids and omega-6 fatty acids such as linoleic, gamma-linolenic, dihomo-gamma-linolenic, arachidonic, and docosatetraenoic acids; and 5) the omega hydroxy fatty acid, 20-hydroxyeicosatetraenoic acid. Among the fatty acids that activate FFAR1 (and FFAR4), docosahexaenoic and eicosapentaenoic acids are commonly regarded as the main dietary fatty acids that do so and may be useful therapeutic agents.
The drugs that are full agonists (i.e., can fully activate) FFAR1 include GW5809 (about 60-fold more potent in activating FFAR1 than FFAR4) and five drugs, AM 1638, AP8, compound 1 SCO-267, and T-3601386 which have no reports clearly defining their ability to activate FFAR4. The drugs that are partial agonists (i.e., activate but cannot fully activate) FFAR1 include TAK-875, also termed fasiglifam, which is >1,000 more potent in activating FFAR1 than FFAR4, MK‐8666, which activates FFAR1 and said to be less effective in activating FFAR4, and two drugs, AMG 837T and LY3104607 which have no reports clearly defining their ability to activate FFAR4. GW1100 and ANT203 are antagonist, i.e., inhibit the activation, of FFAR1 but do not inhibit FFAR4 and DC260126 which inhibits FFAR1 but its effect on FFAR4 has not been clearly reported. ZLY50 is a newly described selective FFAR1 agonist (>400 more potent in activating FFAR1 than FFAR4) that crosses the blood–brain barrier and therefore may prove useful for inhibiting FFAR1 on cells located in the central nervous system, i.e. brain and spinal cord.
Cells commonly express both FFAR1 and FFAR4. The fatty acids which activate these two FFARs, including docosahexaenoic and eicosapentaenoic acids, are about equally potent in activating FFAR1 and FFAR4; they also have diverse FFAR1-independent as well as FFAR4-independent means of altering cell functions. Furthermore, most of the studies on FFAR1 agonist drugs have used GW9508, a drug that activates FFAR1 but at higher concentrations also activates FFAR4. Finally, many of the FFAR1 agonists and antagonists have not been defined for their impact on FFAR4 and none of them have been fully evaluated for possible FFAR-independent means of altering cell functions. Accordingly, many FFAR1 studies have not clearly determined if the action(s) of a given fatty acid or drug involves FFAR1, FFAR4, both FFARs, FFAR-independent pathways, or combinations of these function-altering avenues. The studies reported here address these issues by focusing on those that included examinations of the effects of FFAR1 and FFAR4 inhibitors by themselves or as blockers of the actions of FFAR1 and FFAR4 and/or included experiments using cells or animals that lacked, under-expressed, or overexpressed FFAR1 or FFAR4.
Cells and tissues expressing FFAR1 FFAR1 is highly expressed in pancreas beta cells which produce and release insulin into the blood; pancreas alpha cells which produce and release glucagon, a hormone that increases blood glucose levels; enteroendocrine K, L, and I cells of the gastrointestinal tract which respectively produce and release glucagon-like peptide-1, gastric inhibitory peptide, and cholecystokinin which regulate insulin and blood glucose levels; monocytes and M2 macrophages which contribute to regulating immune responses such as inflammation; bone modeling cells (i.e. osteoblasts and osteoclasts); and taste receptor-bearing cells in the tongue's taste buds. FFAR1 is also expressed in bone marrow-derived macrophages; neurons in the central nervous system, e.g. the olfactory bulb, striatum, hippocampus, midbrain, hypothalamus, cerebellum, cerebral cortex, caudate nucleus and spinal cord; various cell types in the spleen; and various types of cancer cells.
FFAR1 functions and activities Fat tissue development and thermogenesis Studies to date have implicated FFAR4 but not FFAR1 in the development and remodeling of fat tissue and in generating body heat, i.e., thermogenesis, by the brown fat component of fat tissue (see FFAR4) in rodents. Indeed, FRAR1 has not yet been reported to be expressed in the fat tissue of mice or humans.
Obesity The following studies have suggested that FFAR1 contributes to the regulation of obesity. 1) Ffar1 gene knockout mice (i.e., mice made to lack Ffar1 genes) became obese when fed a low-fat diet whereas control mice became obese only when fed a high-fat diet. 2) The FFAR1 agonist SCO-267 reduced the food intake and body weights in diet-induced obese rats, in rats made diabetic by neonatal treatment with streptozotocin, and in obese mice but not in Ffar1 knockout obese mice. 3) Another FFAR1 agonist, T-3601386, likewise reduced the food intake and body weight in obese mice but not in Ffar1 gene knockout mice. 4) SNP genotyping is used to define single-nucleotide polymorphisms in order to detect germline substitutions of a single nucleotide at specific positions in all the genetic material of an organism. SNP genotyping found three variant FFAR1 gene SNPs in individuals with higher body weights, body mass indexes, and fatty tissue masses than individuals not carrying one of these SNP genes. The SNP gene carriers did not evidence abnormal insulin or pancreatic beta cell functions. This study suggested but did not show that the cited SNP FFAR1 protein variants were dysfunctional. And 5) a similar study found another SNP in the FFAR1 gene. This SNP replaced serine with glycine at the 180th amino acid of FFAR1. It and the more common FFAR1 protein it replaces are termed Gly180Ser and Gly180Gly, respectively. Gly180Ser FFAR1 was present in 0.42, 1.8, and 2.60% of non-obese, moderately obese, and severely obese individuals, respectively, and its carriers showed reduced plasma insulin responses to an oral lipid challenge. Studies on HeLa cells (i.e., cells derived from human cervical cancer cells) made to express Gly180Ser FFAR1 using transfection methods had significantly lower calcium mobilization responses to oleic acid than Hela cells transfected with Gly180Gly FFAR1. This suggests that Gly180Ser FFAR1 is dysfunctional. Modulation of the nutrient taste-sensing pathways (see below section on Taste) using foods, dietary supplements, or drugs that target FFAR1 (and FFAR4, see FFAR4-dependent taste perception) may prove useful for treating obesity and obesity-related disorders.
Type 2 diabetes Studies have suggested that FFAR1 acts to suppress the development and/or pathological effects (e.g. inadequate insulin secretion) of type 2 diabetes. 1) Fatty acid activators of FFAR1/FFAR4 enhanced the glucose-stimulated secretion of insulin from cultured mouse pancreas beta-cells, INS-1 rat beta cells, mouse MIN6 beta cells (these cells like other beta cells make and release insulin but are genetically altered to also make and release glucagon, somatostatin, and ghrelin), and pancreatic islets isolated from humans. These fatty acid activators did not have this action in the absence of concurrent glucose stimulation. 2) The FFAR1 agonist TAK-875 increased the amount of insulin released by glucose-stimulated cultured INS-1 cells and isolated rat pancreatic islets. TAK-875 did not have this action in the absence of concurrent glucose stimulation. 3) The FFAR1 agonist AMG 837 stimulated mouse MIN6 cells to secrete insulin; it also reduce the rises in plasma glucose occurring in glucose tolerance tests in control but not Ffar1 gene knockout mice. 4) Other FFAR1 agonist drugs including TUG-424, AM-1638, AM-5262, LY2881835, MK-2305, and ZLY50 increased insulin secretion and improved glucose tolerance in mice, enhanced glucose-stimulated insulin secretion in mouse and human cultured pancreatic islet cells, and/or improved glucose levels in diabetic mice. 5) Ffar1 gene knockout mice had impaired secretion of glucagon-like peptide-1 and gastric inhibitory polypeptide into the circulation. These two hormones are secreted from intestinal L-cells and intestinal K-cells, respectively, when stimulated by dietary glucose or fatty acids and act to promote insulin secretion. And 6) Ffar1 gene knockout mice fed a high-fat diet for 11 weeks developed obesity, high fasting blood glucose levels, glucose intolerance, and insulin resistance; control mice feed the high fat diet did not develop these diabetic-like abnormalities. Thus, FFAR1 appears to regulate insulin secretion and blood glucose levels thereby suppressing the development and/or pathological consequences of type 2 diabetes in rodents.