Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like

G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...

that is coded (i.e., its synthesis is directed) by the ''FFAR1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. This gene is located on the short (i.e., "q") arm of

chromosome 19 Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 61.7 million base pairs, the building material of DNA. It is considered the most Gene density, gene-ri ...

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 receptor Free fatty acid receptors (FFARs) are G-protein coupled receptors (GPRs). GPRs (also termed seven-(pass)-transmembrane domain receptors) are a large family of receptors. They reside on their parent cells' surface membranes, bind any one o ...

s (FFARs). This family includes at least three other FFARs ''viz.,''

FFAR2 Free fatty acid receptor 2 (FFAR2), also known as G-protein coupled receptor 43 (GPR43), is a Rhodopsin-like receptor, rhodopsin-like G-protein coupled receptor (GPCR) encoded by the ''FFAR2'' gene. In humans, the ''FFAR2'' gene is located on the ...

(also termed GPR43),

FFAR3 Free fatty acid receptor 3 (FFAR3, also termed GPR41) protein is a G protein coupled receptor (i.e., GPR or GPCR) that in humans is encoded by the ''FFAR3'' gene (i.e., ''GPR41'' gene). GPRs reside on cell surfaces, bind specific signaling molecu ...

(also termed GPR41), and

FFAR4 Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded (i.e., its formation is directed) by the ''FFAR4'' gene. This gene is located on the long (i.e. "q") arm of chromosome ...

(also termed GPR120). FFARs bind and thereby are activated by certain

fatty acids In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

. Studies suggest that FFAR1 may be involved in the development of obesity,

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

, and various emotional, behavioral, learning, and

cognition Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

defects such as

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. 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 Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...

and scarring, and the malignant behavior, i.e., proliferation, invasiveness, and

metastasis Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

, of some types of cancer cells. Various fatty acids, including in particular two

omega-3 fatty acid Omega−3 fatty acids, also called omega−3 oils, ω−3 fatty acids or ''n''−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond three atoms away from the terminal methyl group in their ...

s, docosahexaenoic and

eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic acid) is an omega−3 fatty acid. In physiological literature, it is given the name 20:5(''n''−3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid wi ...

s, have been consumed in

diets The Low Countries comprise the coastal Rhine–Meuse–Scheldt delta region in Western Europe, whose definition usually includes the modern countries of Luxembourg, Belgium, the Netherlands and parts of Northern France. Both Belgium and the ...

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 An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...

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

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. 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 Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

, 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 acid Propionic acid (, from the Greek language, Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula . It is a ...

s. 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 acid Lauric acid, systematically dodecanoic acid, is a saturated fatty acid with a 12-carbon atom chain, thus having many properties of Medium-chain triglyceride, medium-chain fatty acids. It is a bright white, powdery solid with a faint odor of Piment ...

s; 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 acid Docosatetraenoic acid designates any straight chain 22:4 fatty acid. (''See'' Essential fatty acid for nomenclature.) One isomer is of particular interest: * all-''cis''-7,10,13,16-docosatetraenoic acid is an ω-6 fatty acid with the common nam ...

s; 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 An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. 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 The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and therefore may prove useful for inhibiting FFAR1 on cells located in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, i.e. brain and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

. 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 The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

beta cells Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vit ...

which produce and release

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

into the blood; pancreas

alpha cell Alpha cells (α-cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream. Discovery Islets of Langerhans we ...

s which produce and release

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...

, a hormone that increases blood glucose levels; enteroendocrine K, L, and I cells of the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

which respectively produce and release

glucagon-like peptide-1 Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and cer ...

, gastric inhibitory peptide, and

cholecystokinin Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat a ...

which regulate insulin and blood glucose levels;

monocytes Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also i ...

and M2 macrophages which contribute to regulating immune responses such as

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

; bone modeling cells (i.e.

osteoblasts Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts functi ...

and

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated ...

); and taste receptor-bearing cells in the tongue's

taste buds Taste buds are clusters of taste receptor cells, which are also known as gustatory cells. The taste receptors are located around the small structures known as papillae found on the upper surface of the tongue, soft palate, upper esophagus, th ...

. FFAR1 is also expressed in bone marrow-derived macrophages;

neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

in the

, e.g. the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OF ...

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

midbrain The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

caudate nucleus The caudate nucleus is one of the structures that make up the corpus striatum, which is part of the basal ganglia in the human brain. Although the caudate nucleus has long been associated with motor processes because of its relation to Parkinso ...

and spinal cord; various cell types in the

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

; 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 Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and ...

and in generating body heat, i.e.,

thermogenesis Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ('' Sauromatum venosum''), and the giant w ...

, by the brown fat component of fat tissue (see

) 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 Gene knockouts (also known as gene deletion or gene inactivation) are a widely used genetic engineering technique that involves the gene targeting, targeted removal or inactivation of a specific gene within an organism's genome. This can be done t ...

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 SNP genotyping is the measurement of genetic variations of single nucleotide polymorphisms (SNPs) between members of a species. It is a form of genotyping, which is the measurement of more general genetic variation. SNPs are one of the most commo ...

is used to define

single-nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a ...

s in order to detect

germline In biology and genetics, the germline is the population of a multicellular organism's cells that develop into germ cells. In other words, they are the cells that form gametes ( eggs and sperm), which can come together to form a zygote. They dif ...

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 index Body mass index (BMI) is a value derived from the mass (Mass versus weight, weight) and height of a person. The BMI is defined as the human body weight, body mass divided by the square (algebra), square of the human height, body height, and is ...

es, 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 Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

with

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...

at the 180th

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

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 Cervical cancer is a cancer arising from the cervix or in any layer of the wall of the cervix. It is due to the abnormal growth of cells that can invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later sympt ...

cells) made to express Gly180Ser FFAR1 using

transfection Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to des ...

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

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

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by #Nomenclature, several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G ...

, and

ghrelin Ghrelin (; or lenomorelin, INN) is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrel ...

), and

pancreatic islets The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% o ...

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

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 Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...

; 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. A double‐blind (i.e., patients and researchers do not know if the patients are taking a drug or

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

parallel study A parallel study is a type of clinical study where two groups of treatments, A and B, are given so that one group receives only A while another group receives only B. Other names for this type of study include "between patient" and "non-crossover" ...

randomized 63 patients (mean age 55, ranging from 30 to 65 years old) with type 2 diabetes to take the GPR40 agonist MK‐8666 or a placebo for 14 days. MK-8666-treated patients had fasting blood glucose levels that were well below pre-treatment levels by the last treatment day. Placebo-treated patients showed no changes in their blood glucose levels. Among the MK-866-treated patients, 18 instances of mild to moderate drug‐related

adverse event In pharmaceuticals, an adverse event (AE) is any unexpected or harmful medical occurrence that happens to a patient during medical treatment or a clinical trial. Unlike direct side effects, an adverse event does not necessarily mean the medicati ...

s (i.e., pain in the back, neck, extremity, and/or abdomen; headache; constipation; nausea; and diarrhea) occurred. However, one patient developed elevations in the blood levels of three liver enzymes, alanine aminotransferase,

aspartate aminotransferase Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...

and

alkaline phosphatase The enzyme alkaline phosphatase (ALP, alkaline phenyl phosphatase, also abbreviated PhoA) is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryo ...

. Elevations in these enzymes' blood levels suggest the presence of liver damage (see

liver function tests Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial ...

). The patient continued to take MK-8666 for the 14 day treatment period; two weeks thereafter these enzymes returned to normal levels. The study concluded that this case may have reflected mild MK-8666-induced liver damage. The sponsor, Merck & Co., terminated further development of MK-8666 due to it having a possibly unfavorable

risk–benefit ratio A risk–benefit ratio (or benefit-risk ratio) is the ratio of the risk of an action to its potential benefits. Risk–benefit analysis (or benefit-risk analysis) is analysis that seeks to quantify the risk and benefits and hence their ratio. A ...

in type 2 diabetic patients. A study conducted in Japan on 1,222 adults with inadequately controlled (i.e. high blood sugar levels) type 2 diabetes were treated with the highly selective FFAR1 agonist TAK-875 in addition to their in-place treatment regimens for 1 year. Blood sugar levels improved 2 weeks after taking the drug and remained improved throughout the study. However, adverse events that emerged during treatment leading to discontinuance of TAK-875 varied between 2.9% and 9.2% depending on the patients' treatment regimens; the incidence of abnormal liver function tests during the trial varied between 0% and 5.8%, again depending on treatment regimens. Further development of TAK-875 was stopped due to concerns about its possible

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

. A recent review of data from TAK-875 global clinical trials by an independent panel of experts overseeing the clinical development program also had concerns about liver safety. A simulated analysis of these studies suggested that this liver toxicity reflected the inhibition of liver bile acid transporters and

mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

enzymes by TAK-875 and its

glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

metabolite, TAK-875-glucose. The results of these studies have been regarded as proof of the concept that FFAR1 contributes to the regulation of glucose levels in patients with type 2 diabetes and therefore is a potential target for treating these patients with FFAR1 agonists that do not have significant

adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complic ...

such as hepatotoxicity. Recent preclinical studies are examining other FFAR1 agonists for their liver and other toxicities.

Taste

The main detectors and mediators of the five major taste perception elements viz.,

saltiness The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste. Taste is the perception stimulated when a substance in the mouth biochemistry, reacts chemically with taste receptor cells l ...

sourness The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste. Taste is the perception stimulated when a substance in the mouth reacts chemically with taste receptor cells located on t ...

, bitterness,

sweetness Sweetness is a basic taste most commonly perceived when eating foods rich in sugars. Sweet tastes are generally regarded as pleasurable. In addition to sugars like sucrose, many other chemical compounds are sweet, including aldehydes, ketones ...

, and

umami Umami ( from ), or savoriness, is one of the five basic tastes. It is characteristic of broths and cooked meats. People taste umami through taste receptors that typically respond to glutamates and nucleotides, which are widely present in me ...

, are the cell-bound GPRs TAS1R2/TAS1R3, TAS1R1/TAS1R3, and multiple subtypes of TAS2R for sweetness, umami, and bitterness, respectively, and selective cell-bound

ion channels Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...

for saltiness and sourness. However, studies indicate that the taste of substances sometimes involves more than one taste-detecting element. For example, taste of the artificial the sweetener

saccharin Saccharin, also called saccharine, benzosulfimide, or E954, or used in saccharin sodium or saccharin calcium forms, is a non-nutritive artificial sweetener. Saccharin is a sultam that is about 500 times sweeter than sucrose, but has a bitter or ...

appears to be detected by a combination of sweetness and bitterness elements. Cells bearing these taste receptors are on the

tongue The tongue is a Muscle, muscular organ (anatomy), organ in the mouth of a typical tetrapod. It manipulates food for chewing and swallowing as part of the digestive system, digestive process, and is the primary organ of taste. The tongue's upper s ...

's upper surface,

soft palate The soft palate (also known as the velum, palatal velum, or muscular palate) is, in mammals, the soft biological tissue, tissue constituting the back of the roof of the mouth. The soft palate is part of the palate of the mouth; the other part is ...

, upper

esophagus The esophagus (American English), oesophagus (British English), or œsophagus (Œ, archaic spelling) (American and British English spelling differences#ae and oe, see spelling difference) all ; : ((o)e)(œ)sophagi or ((o)e)(œ)sophaguses), c ...

cheek The cheeks () constitute the area of the face below the eyes and between the nose and the left or right ear. ''Buccal'' means relating to the cheek. In humans, the region is innervated by the buccal nerve. The area between the inside of th ...

, and

epiglottis The epiglottis (: epiglottises or epiglottides) is a leaf-shaped flap in the throat that prevents food and water from entering the trachea and the lungs. It stays open during breathing, allowing air into the larynx. During swallowing, it closes ...

(see

Taste buds Taste buds are clusters of taste receptor cells, which are also known as gustatory cells. The taste receptors are located around the small structures known as papillae found on the upper surface of the tongue, soft palate, upper esophagus, th ...

). FFAR1 and FFAR4 appear to contribute to some types of taste perception in rodents. 1)

Taste bud Taste buds are clusters of taste receptor cells, which are also known as gustatory cells. The taste receptors are located around the small structures known as papillae found on the upper surface of the tongue, soft palate, upper esophagus, ...

cells in the back of rodents' tongues express FFAR1 while cells in the

epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

of their tongues' circumvallate papillae express FFAR4. 2) ''Ffar1'' and ''Ffar4'' gene knockout mice had diminished taste responses to various fatty acids and a lower preference for consuming these fatty acids. 3) ''Ffar1''

gene knockdown Gene knockdown is an experimental technique by which the expression of one or more of an organism's genes is reduced. The reduction can occur either through genetic modification or by treatment with a reagent such as a short DNA or RNA oligonucleot ...

mice had a reduced intake and preference for sucrose in sucrose preference tests. 4) Human tongue taste bud cells contain FFAR4 but inconclusive studies suggest it may lack FFAR1. And 5) a selective activator of FFAR4, TUG-891, enhanced human's fatty orosensation (i.e., false sensation of taste obtained by tongue stimulation) when added to FFAR4-activating dietary fats but not when added to fat-free mineral oil. This finding suggests that in humans FFAR4 activation enhances but does not directly evoke a sensation of fats. Thus, FFAR1 and FFAR4 appear to mediate fatty acid taste perceptions and FFAR1 appears to mediate sweetness taste perception in rodents; taste bud FFAR4 but not FFAR1 appears to enhance the perception of fatty acids and fatty oils in humans. Further studies are needed to define the presence, locations, and precise roles of FFAR1 and FFAR4 in the various taste perceptions of animals and humans.

Central nervous system

FFAR1 is expressed on the neurons and some other cell types in the olfactory bulb, striatum, hippocampus, midbrain, hypothalamus, cerebellum, cerebral cortex, and caudate nucleus of the brain as well as in the spinal cord. FFAR1-activating fatty acids, particularly docosahexaenoic acid, are thought to play critical roles in neurons by maintaining their surface membrane integrity, survival, synaptic functions (synapses are specialize parts of neurons which communicate with other neurons),

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

functions (e.g. communication between cells), and in suppressing the development of certain central nervous system disorders. However, it is often not clear that docosahexaenoic acid achieves these effects by activating FFAR1. The following studies have implicated FFAR1 in various central nervous system functions and/or disorders. 1) ''Ffar1'' gene knockout mice showed abnormally reduced anxiety-like behavior in anxiety-inducing tasks compared to control mice. 2) ''Ffar1'' gene knockout female mice had abnormally low anxiety responses, abnormally low locomotor activity, and impaired maternal care behavior (i.e., higher rates of offspring neglect and

infanticide Infanticide (or infant homicide) is the intentional killing of infants or offspring. Infanticide was a widespread practice throughout human history that was mainly used to dispose of unwanted children, its main purpose being the prevention of re ...

) compared to control female mice. 3) Obese, diabetic male C57BL6/J mice and db/db obese, diabetic mice (an animal disease model) have fear-associated learning and memory impairments as determined in various behavioral tests; GW5908 and docosahexaenoic acid reduced these impairments and GW1100 blocked docosahexaenoic acid's effects on learning and memory. 4) GW9508 completely restored the learning and memory of mice that had impaired learning and memory due to

scopolamine Scopolamine, also known as hyoscine, or Devil's Breath, is a medication used to treat motion sickness and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva. When used by injection, effects begin a ...

treatment. 5) GW9508 reduced the cognitive deficits in A-beta AD mice (i.e. a mouse model of

); this reduction was blocked by treating the mice with GW1100. 6) GW9508 similarly improved learning and memory in A-beta AD mice evaluated with other cognition tests. And 7) the highly selective FFAR1 agonist TAK-875 reduced the cognitive impairments that occur in APPswe/PS1dE9 mice (another model of Alzheimer disease). These results suggest that FFAR1 may be, and should be evaluated as, a potentile target for the treatment of brain developmental, emotional, and mental impairments such as Alzheimer's disease.

Pain perception

Studies suggest that FFAR1 is involved in

nociception In physiology, nociception , also nocioception; ) is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an organism to receive a pai ...

, i.e., the perception of pain. 1) Oral administration of the FFAR1 agonist ZLY50 (which unlike most drugs crosses from the circulation into the central nervous systems' spinal fluid) reduced the pain responses of mice in three pain tests. 2) Injection of the FFAR1 agonist GW9508 into the

spinal canal In human anatomy, the spinal canal, vertebral canal or spinal cavity is an elongated body cavity enclosed within the dorsal bony arches of the vertebral column, which contains the spinal cord, spinal roots and dorsal root ganglia. It is a pro ...

of rats decreased their pain response to spinal nerve ligation and heat; the pain-reducing action of GW9508 on spinal nerve ligation was blocked by the FFAR1 antagonist GW1100 but not the FFAR4 antagonist AH7614. 3) ''Ffar1'' gene knockout mice as well as mice treated with the FFAR1 inhibitor GW1100 had enhanced pain responses in two pain tests. 4) And the intracerebroventricular injection (i.e., injection into a brain ventricle) of docosahexaenoic acid or GW9508 reduced the pain responses of mice to painful pressure on a paw and to radiant heat; their effects were blocked by intracerebroventricular injections of GW1100. These studies suggest that FFAR1 is involved in reducing rodent pain perception and recommend testing for its involvement in the perception of pain in humans.

Cancer

Many studies have suggested that FFAR1 alters the malignant behavior of some types of cultured cancer cells. These malignant behaviors include cultured cancer cell

motility Motility is the ability of an organism to move independently using metabolism, metabolic energy. This biological concept encompasses movement at various levels, from whole organisms to cells and subcellular components. Motility is observed in ...

and proliferation which are regarded as being related to the invasiveness and growth rate, respectively, of cancers in animals and humans. 1) GW9508, which activates FFAR1 but at higher concentrations also activates FFAR4, stimulated the motility of mouse LL/2 and rat RLCNR lung cancer cells; treatment of these cells with GW9508 plus GW1100 reduced these cells motility to levels below GW9508-treated and GW9508-untreated LL/2 and RLCNR cells. (In the presence of GW1100, GW9508 is assumed to act through FFAR4 but not FFAR1.) 2) GW9508 reduced the motility of A549 human lung cancer cells; GW9508 plus GW1100 treatment of these cells further reduced their motility; ''FFAR1'' gene knockdown A549 cells showed less motility than control A549 cells; and GW9508-treated A549 ''FFAR1'' gene knockdown cells had less motility than control or GW9508-treated cells. (GW9508 is assumed to act through FFAR4, not FFAR1, in ''FFAR1'' gene knockdown or GW1100-treated cells.) 3) GW9508 did not alter the proliferation of LL/2, RLCNR, or A549 cells but in combination with GW1100 slightly decreased the proliferation of A549 but not LL/2 or RLCNR cells. These three sets of results suggest that FFAR1 enhances while FFAR4 inhibits the motility of LL/2, RLCNR, and A549 cells and that FFAR4 reduces A549 but not LL/2 or RLCNR cell proliferation. 4) Similar studies using the FFAR4 agonist TUG-891 and eicosapentaenoic acid in control and ''FFAR4'' gene knockdown human DU145 and PC-3 prostate cancer cells suggested that FFA4 promotes these cells motility and proliferation. 5) GW9508 inhibited the motility of hamster pancreas cancer HPD1NR cells (which express FFAR1 but not FFAR4), stimulated the motility of hamster pancreas HPD2NR cancer cells (which express FFAR4 but not FFAR1), and slightly inhibited the motility of human PANC-1 pancreas cancer cells (which express FFAR1 and FFAR4). GW9508 markedly increased the motility of PANC-1 cells when they were also treated with GW1100. These results indicate that FFAR1 inhibits while FFA4 promotes motility in the three types of rodent pancreas cancer cells. And 6) studies in MG-63 human osteosarcoma (i.e. bone cancer) cells and the far more highly mobile MG63-R7 human osteosacromea cells suggest that FFAR1 inhibits and FFAR4 promotes motility. The latter three sets of results indicate that the roles of FFAR1 and FFAR4 in regulating cancer cell motility vary with the types of cancer cells studied.) Finally, studies in patients have shown that FFAR1 is overexpressed in some

insulinoma An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a m ...

s (i.e. cancers derived from pancreas beta cells), in high grade and/or advanced stage ovarian cancers, and in high grade, advanced stage, and/or poor prognosis

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

s. The overexpression of FFAR1 in these cancers suggests that it may play a role in their development and/or progression,

Breast cancer

FFAR1 and FFAR4 are expressed in human

MDA-MB-231 Scientists study the behaviour of isolated cells grown in the laboratory for insights into how cells function in the body in health and disease. Experiments using cell culture are used for developing new diagnostic tests and new treatments for dise ...

MCF-7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers ...

, and SK-BR-3 breast cancer cells and appear to regulate some of their and other types of breast cancer cells' malignant behaviors. 1) MDA-MB-231 cells that did not express ''FFAR1'' (due to ''FFAR1'' gene knockdown) or overexpressed FFRA1 (due to

with a FFAR1-producing

plasmid A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria and ...

) had lower and higher proliferation responses, respectively, to the FFAR1/FFAR4 activator, oleic acid, compared to control MDA-MB-231 cells. 2) T-47D human breast cancer cells (which express very low levels of FFAR4) and MCF-7 cells transfected with the FFAR-1-producing plasmid had increased proliferative responses to oleic acid compared to control cells. 3) The highly selective FFAR4 agonist TUG-891 reduced the proliferation of MCF-7 and MDA-MB-231 cells. 4) GW9508 increased the motility of FFAR4 knockdown MCF-7 and SK-BR-3 breast cancer cells compared to their respective control (i.e., FFAR4-expressing) MCF7 and SK-BR-3 cells. 5) GW9508 increased the development of lung tumors in nude mice injected with control MDA-MB-231 cells but did not do so in nude mice injected with FFAR4 knockdown MDA-MB-231 cells. These studies suggest that FFAR1 promotes the proliferation but inhibits the motility and FFAR4 promotes the motility and lung metastasis of human breast cancer cells. And 6)

Clinical studies Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

have reported that FFAR4 levels are higher in certain types of more aggressive human breast cancers and therefore may be a marker of disease severity and a target for treating these cancers (see FFAR4 in breast cancer). Similar studies on FFAR1 in human breast cancer are needed to determine its medical relevancy.

Tissue fibrosis

Recent studies suggest that FFAR1 is involved in pathological tissue

, i.e., the healing of tissue injury in which

connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...

replaces normal tissue leading to tissue remodeling, the formation of permanent scar tissue, and damaged organs. 1) ''Ffar1'' gene knockout mice were protected from developing fibrotic kidneys in three models of this disease (unilateral obstruction of a single kidney's

ureter The ureters are tubes composed of smooth muscle that transport urine from the kidneys to the urinary bladder. In an adult human, the ureters typically measure 20 to 30 centimeters in length and about 3 to 4 millimeters in diameter. They are lin ...

, long-term kidney

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...

due to reducing blood flow to a single kidney, and adenine diet-induced chronic fibrotic kidney disease). 2) PBI-4050 (i.e., 3-pentylbenzeneacetic acid sodium salt), a FFAR1 agonist, blocked the development of fibrosis in rodent kidney, liver, heart, lung, pancreas, and skin models of pathological fibrosis. 3) In a model of

non-alcoholic fatty liver disease An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...

. ''Ffar1'' gene knockout mice developed less liver inflammation and fibrosis than control mice. And 4)

topical application A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

of GW5908 to small

skin biopsy Skin biopsy is a biopsy technique in which a skin lesion is removed to be sent to a pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 day ...

-like wounds (also termed punch wounds) in the skin of male mice increased the levels of

type I collagen Type I collagen is the most abundant collagen of the human body, consisting of around 90% of the body's total collagen in vertebrates. Due to this, it is also the most abundant protein type found in all vertebrates. Type I forms large, eosinop ...

in the wound tissues; however it also decreased the size of these wounds and increased the speed with which the wounds healed. This last observation suggests that GW5908 can have positive as well as negative effects on the resolution of tissue injury. Note, however, that the role(s) of FFAR1 ''versus'' FFAR4 in the actions of GW9808 in this study was not defined. Overall, these studies suggest that FFAR1 may be a target for suppressing the development and/or progression of pathological tissue fibrosis.

References

{{G protein-coupled receptors G protein-coupled receptors

Activators and inhibitors of the free fatty acid receptors

Cells and tissues expressing FFAR1

FFAR1 functions and activities

Fat tissue development and thermogenesis

Obesity

Type 2 diabetes

Taste

Central nervous system

Pain perception

Cancer

Breast cancer

Tissue fibrosis

See also

References