Propionate exerts neuroprotective and neuroregenerative effects in the peripheral nervous system.

In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell's survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. ß-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.

Short-chain fatty acids: possible regulators of insulin secretion.

The benefits of gut microbiota-derived short-chain fatty acids (SCFAs) towards health and metabolism have been emerging since the past decade. Extensive studies have been carried out to understand the mechanisms responsible in initiating the functionalities of these SCFAs towards body tissues, which greatly involves the SCFA-specific receptors free fatty acid receptor 2 (FFAR2) and free fatty acid receptor 3 (FFAR3). This review intends to discuss the potential of SCFAs particularly in regulating insulin secretion in pancreatic ß-cells, by explaining the production of SCFAs in the gut, the fate of each SCFAs after their production, involvement of FFAR2 and FFAR3 signalling mechanisms and their impacts on insulin secretion. Increased secretion of insulin after SCFAs treatments were reported in many studies, but contradicting evidence also exist in several other studies. Hence, no clear consensus was achieved in determining the true potential of SCFA in regulating insulin secretion. In this review, we explore how such differences were possible and hopefully be able to shed some perspectives in understanding SCFAs-signalling behaviour and preferences.

Malic Enzyme 1 (ME1) Promotes Adiposity and Hepatic Steatosis and Induces Circulating Insulin and Leptin in Obese Female Mice.

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 protein) female mice. Adiposity, serum hormone levels, and adipose, mammary gland, liver, and small intestine gene expression patterns were compared between experimental groups after 10 weeks on a diet. Relative to WT female mice, MOD-1 female mice exhibited lower body weights and less adiposity; decreased concentrations of insulin, leptin, and estrogen; higher concentrations of adiponectin and progesterone; smaller-sized mammary gland adipocytes; and reduced hepatosteatosis. MOD-1 mice had diminished expression of Lep gene in abdominal fat; Lep, Pparg, Klf9, and Acaca genes in mammary glands; Pparg and Cdkn1a genes in liver; and Tlr9 and Ffar3 genes in the small intestine. By contrast, liver expression of Cdkn2a and Lepr genes was augmented in MOD-1, relative to WT mice. Results document an integrative role for ME1 in development of female obesity, suggest novel linkages with specific pathways/genes, and further support the therapeutic targeting of ME1 for obesity, diabetes, and fatty liver disease.

The Cognitive Improvement and Alleviation of Brain Hypermetabolism Caused by FFAR3 Ablation in Tg2576 Mice Is Persistent under Diet-Induced Obesity.

Obesity and aging are becoming increasingly prevalent across the globe. It has been established that aging is the major risk factor for Alzheimer's disease (AD), and it is becoming increasingly evident that obesity and the associated insulin resistance are also notably relevant risk factors. The biological plausibility of the link between high adiposity, insulin resistance, and dementia is central for understanding AD etiology, and to form bases for prevention efforts to decrease the disease burden. Several studies have demonstrated a strong association between short chain fatty acid receptor FFAR3 and insulin sensitivity. Interestingly, it has been recently established that FFAR3 mRNA levels are increased in early stages of the AD pathology, indicating that FFAR3 could play a key role in AD onset and progression. Indeed, in the present study we demonstrate that the ablation of the Ffar3 gene in Tg2576 mice prevents the development of cognitive deficiencies in advanced stages of the disease. Notably, this cognitive improvement is also maintained upon a severe metabolic challenge such as the exposure to high-fat diet (HFD) feeding. Moreover, FFAR3 deletion restores the brain hypermetabolism displayed by Tg2576 mice. Collectively, these data postulate FFAR3 as a potential novel target for AD.

Short-Chain Fatty Acid Receptors and Cardiovascular Function.

Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.

Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling.

Propionic acid is a cell nutrient but also a stimulus for cellular signaling. Free fatty acid receptor (FFAR)-3, also known as GPR41, is a Gi/o protein-coupled receptor (GPCR) that mediates some of the propionate's actions in cells, such as inflammation, fibrosis, and increased firing/norepinephrine release from peripheral sympathetic neurons. The regulator of G-protein Signaling (RGS)-4 inactivates (terminates) both Gi/o- and Gq-protein signaling and, in the heart, protects against atrial fibrillation via calcium signaling attenuation. RGS4 activity is stimulated by ß-adrenergic receptors (ARs) via protein kinase A (PKA)-dependent phosphorylation. Herein, we examined whether RGS4 modulates cardiac FFAR3 signaling/function. We report that RGS4 is essential for dampening of FFAR3 signaling in H9c2 cardiomyocytes, since siRNA-mediated RGS4 depletion significantly enhanced propionate-dependent cAMP lowering, Gi/o activation, p38 MAPK activation, pro-inflammatory interleukin (IL)-1ß and IL-6 production, and pro-fibrotic transforming growth factor (TGF)-ß synthesis. Additionally, catecholamine pretreatment blocked propionic acid/FFAR3 signaling via PKA-dependent activation of RGS4 in H9c2 cardiomyocytes. Finally, RGS4 opposes FFAR3-dependent norepinephrine release from sympathetic-like neurons (differentiated Neuro-2a cells) co-cultured with H9c2 cardiomyocytes, thereby preserving the functional ßAR number of the cardiomyocytes. In conclusion, RGS4 appears essential for propionate/FFAR3 signaling attenuation in both cardiomyocytes and sympathetic neurons, leading to cardioprotection against inflammation/adverse remodeling and to sympatholysis, respectively.

Different effects of probiotics and antibiotics on the composition of microbiota, SCFAs concentrations and FFAR2/3 mRNA expression in broiler chickens.

AIMS: The aims of this study were to investigate the effects of probiotics and antibiotics on microbial composition, short chain fatty acids (SCFAs) concentration and free fatty acid receptor 2/3 (FFAR2/3) expression in boiler chickens. METHODS AND RESULTS: A total of 150 1-day-old male broilers were randomly allocated into three groups, control (CON) group, probiotics (PB) group and antibiotics (ATB) group. Results indicated that PB improved the average body weight from 1 to 21 days and feed intake from 21 to 42 days (P < 0·05), while ATB improved the feed efficiency from 1 to 42 days (P < 0·05). Based on 16s rRNA sequencing, PB treatment increased the amount of kingdom bacteria, and the relative abundance of the main bacteria including acetate and butyrate producing bacteria of phylum Firmicutes, family Ruminococcaceae and genus Faecalibacterium. ATB treatment also increased the relative abundance of phylum Firmicutes, family Ruminococcaceae and Lachnospiraceae, however, it introduced some pathogenic bacteria, such as bacteria of family Rikenellaceae and Enterobacteriaceae. Gas chromatography and mass spectrometry (GC-MS) assay revealed that PB increased acetate and butyrate concentrations at both 21 and 42 days, and propionate at 42 days in the colorectum. Moreover qRT-PCR analysis showed PB treatment significantly activated the FFAR2/3 mRNA expressions. On the contrast, ATB treatment lowered the colorectal propionate at 21 days, and decreased acetate, propionate and butyrate concentrations at 42 days, accompanied with decreased FFAR2/3 mRNA expressions. CONCLUSIONS: Compared to the CON birds, an enriched SCFAs producing bacteria with higher SCFAs contents and activated FFAR2/3 expressions are prominent features of PB birds. However, antibiotics treatment plays the reverse effect compared to PB treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: This study brings a significant idea that less SCFAs concentration may be another reason why the antibiotics inhibit the immune system development and immunity of the body.

GPR41 modulates insulin secretion and gene expression in pancreatic ß-cells and modifies metabolic homeostasis in fed and fasting states.

Insulin secretion by pancreatic ß-cells is primarily regulated by glucose; however, hormones and additional nutrients, such as long-chain fatty acids, also play an important role in adjusting insulin output to physiologic needs. To examine the role of short-chain fatty acids (SCFAs) in ß-cell function, we analyzed mouse models of gain and loss of function of GPR41 (FFAR3), a receptor for SCFAs, vs. wild-type control mice. GPR41 gain of function [GPR41-overexpressing transgenic (41 Tg) model] and GPR41 loss of function [GPR41-knockout (KO 41) model] resulted in complementary changes in glucose tolerance, without significant effects on insulin sensitivity. KO 41 mice showed fasting hypoglycemia, which was consistent with increased basal and glucose-induced insulin secretion by islets in vitro Mirroring this, 41 Tg islets showed impaired glucose responsiveness in vitro Microarray analysis of islets from 41 Tg mice indicated significant alterations in gene expression patterns; several of the altered genes were chosen for further analysis and were also observed to change upon incubation of islets and cultured ß-cells with SCFAs in a GPR41-dependent manner. Taken together, our results indicate that GPR41 and its ligands, SCFAs, may play an important role in the fine-tuning of insulin secretion in fed and fasting states.-Veprik, A., Laufer, D., Weiss, S., Rubins, N., Walker, M. D. GPR41 modulates insulin secretion and gene expression in pancreatic ß-cells and modifies metabolic homeostasis in fed and fasting states.

Gut Microbiota-Induced Modulation of the Central Nervous System Function in Parkinson's Disease Through the Gut-Brain Axis and Short-Chain Fatty Acids.

Recent insights into Parkinson's disease (PD), a progressive neurodegenerative disorder, suggest a significant influence of the gut microbiome on its pathogenesis and progression through the gut-brain axis. This study integrates 16S rRNA sequencing, high-throughput transcriptomic sequencing, and animal model experiments to explore the molecular mechanisms underpinning the role of gut-brain axis in PD, with a focus on short-chain fatty acids (SCFAs) mediated by the SCFA receptors FFAR2 and FFAR3. Our findings highlighted prominent differences in the gut microbiota composition between PD patients and healthy individuals, particularly in taxa such as Escherichia_Shigella and Bacteroidetes, which potentially impact SCFA levels through secondary metabolite biosynthesis. Notably, fecal microbiota transplantation (FMT) from healthy to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models significantly improved motor function, enhanced dopamine and serotonin levels in the striatum, and increased the number of dopaminergic neurons in the substantia nigra while reducing glial cell activation. This therapeutic effect was associated with increased levels of SCFAs such as acetate, propionate, and butyrate in the gut of MPTP-lesioned mice. Moreover, transcriptomic analyses revealed upregulated expression of FFAR2 and FFAR3 in MPTP-lesioned mice, indicating their crucial role in mediating the benefits of FMT on the central nervous system. These results provide compelling evidence that gut microbiota and SCFAs play a critical role in modulating the gut-brain axis, offering new insights into PD's etiology and potential targets for therapeutic intervention.

GPCR-mediated effects of fatty acids and bile acids on glucose homeostasis.

Fatty acids and glucose are key biomolecules that share several commonalities including serving as energy substrates and as signaling molecules. Fatty acids can be synthesized endogenously from intermediates of glucose catabolism via de-novo lipogenesis. Bile acids are synthesized endogenously in the liver from the biologically important lipid molecule, cholesterol. Evidence abounds that fatty acids and bile acids play direct and indirect roles in systemic glucose homeostasis. The tight control of plasma glucose levels during postprandial and fasted states is principally mediated by two pancreatic hormones, insulin and glucagon. Here, we summarize experimental studies on the endocrine effects of fatty acids and bile acids, with emphasis on their ability to regulate the release of key hormones that regulate glucose metabolism. We categorize the heterogenous family of fatty acids into short chain fatty acids (SCFAs), unsaturated, and saturated fatty acids, and highlight that along with bile acids, these biomolecules regulate glucose homeostasis by serving as endogenous ligands for specific G-protein coupled receptors (GPCRs). Activation of these GPCRs affects the release of incretin hormones by enteroendocrine cells and/or the secretion of insulin, glucagon, and somatostatin by pancreatic islets, all of which regulate systemic glucose homeostasis. We deduce that signaling induced by fatty acids and bile acids is necessary to maintain euglycemia to prevent metabolic diseases such as type-2 diabetes and related metabolic disorders.

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

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 most metabolic disorders. Among them, diabetes mellitus is a severe growing disorder and found in every corner of the world. For various metabolic disorders, particularly type 2 diabetes mellitus, these different free fatty acid receptors are being explored as drug targets. In the present review, various FFAs sensing G-protein coupled receptors (GPR) like GPR40 (FFAR1), GPR43 (FFAR2), GPR41 (FFAR3), GPR120 (FFAR4), and GPR84 are being explored 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.

Conservation of members of the free fatty acid receptor gene family in common carp.

Accumulating evidence supports the crucial role intestinal microbiota and their metabolites play in the homeostasis of organisms. An important class of metabolites that have been shown to affect the immune system are short chain fatty acids (SCFAs). These SCFAs can affect the host cells via passive diffusion or via ligation to receptors, among others G-protein coupled receptor (GPR) 41 and 43. GPR41 and GPR43 are both part of a family of GPR40-related receptors. Mammalian studies have shown an important role for GPR41 and GPR43 in the modulation of immune responses by SCFAs. However, up till date, no validated coding sequences for orthologues of these SCFA receptors have been published for teleost fish. We used genomic resources and cDNA cloning, to identify and validate ten coding sequences for gpr40L genes in common carp. Phylogenetic analysis showed a division into three subclasses, putatively named class a, b and c, and showed the common carp genes had a closer phylogenetic relationship to mammalian GPR43 than to mammalian GPR41. Synteny analysis revealed a clear conservation of syntenic relationships between gpr40L in the genomes of spotted gar and common carp with the relevant region in the human genome. This conservation of synteny validates the genes identified, as gpr40L. Finally, presence of gpr40L genes was investigated in silico for genomes of 25 different, mostly teleost, fish species largely confirming the observations for gpr40L of common carp with regards to both, subdivision in three subclasses a-c and conservation of synteny. Our data provide an important first step towards an understanding of the role and function of receptors for SCFAs and immunomodulation in fish.

Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer.

Short-chain fatty acids (SCFAs) are the main metabolites produced by the bacterial fermentation of dietary fiber, and they play a critical role in the maintenance of intestinal health. SCFAs are also essential for modulating different processes, and they have anti-inflammatory properties and immunomodulatory effects. As the inflammatory process predisposes the development of cancer and promotes all stages of tumorigenesis, an antitumor effect has also been associated with SCFAs. This is strongly supported by epidemiological studies showing that a diet rich in fiber is linked to a reduced risk of colon cancer and has significant clinical benefits in patients with inflammatory bowel disease (IBD). SCFAs may signal through the metabolite-sensing G protein-coupled receptors free fatty acid receptor 3 [FFAR3 or G protein-coupled receptor 41 (GPR41)], FFAR2 (GPR43), and GPR109A (also known as hydroxycarboxylic acid receptor 2 or HCAR2) expressed in the gut epithelium and immune cells. This review summarizes the existing knowledge regarding the SCFA-mediated suppression of inflammation and carcinogenesis in IBD and colon cancer.

Molecular characterization of free fatty acid receptors FFAR2 and FFAR3 in the domestic cat.

G protein-coupled receptors 41 and 43 were identified and characterized as free fatty acid receptors (FFAR) 3 and 2, respectively. FFAR2 and FFAR3 mediate short-chain fatty acids (SCFAs) as signalling molecules. The present study aimed to give molecular characterization of FFAR2 and FFAR3 in the domestic cat. High homology with that in other mammals was revealed by cDNA cloning of cat FFAR2 FFAR3. We analyzed the tissue distribution of cat FFAR2 and FFAR3 mRNA using quantitative polymerase chain reaction. The inhibition of intracellular cAMP concentrations was observed in cells transfected with cat FFAR2 or FFAR3 and treated with SCFAs. The activation of nuclear factor of activated T cells-luciferase reporter was only observed in cat FFAR2 transfected cells but not in FFAR3. Split luciferase assay (NanoLuc Binary Technology; NanoBiT) for FFAR2 or FFAR3 and Arrestin-3/ß-arrestin-2 revealed acetate-/propionate-induced recruitment to cat FFAR2 or FFAR3 in CHO-K1 cells. Our results indicate that FFAR2 and FFAR3 are functional receptor proteins that are expressed in cat tissues and show differential distribution patterns.

Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View.

The role of the gut microbiome in human health is becoming apparent. The major functional impact of the gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or are absorbed into circulation to impact distant cells/organs. Short-chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through the fermentation of non-digestible fibers. SCFAs are known to function through various mechanisms, however, their signaling through free fatty acid receptors 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is a new therapeutic approach. FFAR2/3 are widely expressed in diverse cell types in human and mice, and function as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulate neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response, and hormone synthesis. FFAR2/3 function through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discuss the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as a drug target to prevent human diseases.

Short-chain fatty acids and regulation of pancreatic endocrine secretion in mice.

The intestinal microbiota has been demonstrated to influence host metabolism, and has been proposed to affect the development of obesity and type 2 diabetes (T2D), possibly through short-chain fatty acids (SCFAs) produced by fermentation of dietary fiber. There are some indications that SCFAs inhibit glucose-stimulated insulin secretion (GSIS) in rodents, but research on this subject is sparse. However, it has been reported that receptors for SCFAs, free fatty acid receptor 2 (FFAR2) and FFAR3 are expressed not only on gut endocrine cells secreting GLP-1 and PYY, but also on pancreatic islet cells. We hypothesized that SCFAs might influence the endocrine secretion from pancreatic islets similar to their effects on the enteroendocrine cells. We studied this using isolated perfused mouse pancreas which responded adequately to changes in glucose and to infusions of arginine. None of the SCFAs, acetate, propionate and butyrate, influenced glucagon secretion, whereas they had weak inhibitory effects on somatostatin and insulin secretion. Infusions of two specific agonists of FFAR2 and FFAR3, CFMB and Compound 4, respectively, did not influence the pancreatic secretion of insulin and glucagon, whereas both induced strong increases in the secretion of somatostatin. In conclusion, the small effects of acetate, propionate and butyrate we observed here may not be physiologically relevant, but the effects of CFMB and Compound 4 on somatostatin secretion suggest that it may be possible to manipulate pancreatic secretion pharmacologically with agonists of the FFAR2 and 3 receptors, a finding which deserves further investigation.

Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway.

Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.

FFAR3 modulates insulin secretion and global gene expression in mouse islets.

The short chain fatty acid (SCFA) receptor (free fatty acid receptor-3; FFAR3) is expressed in pancreatic ß cells; however, its role in insulin secretion is not clearly defined. Here, we examined the role of FFAR3 in insulin secretion. Using islets from global knockout FFAR3 (Ffar3(-/-)) mice, we explored the role of FFAR3 and ligand-induced FFAR3 signaling on glucose stimulated insulin secretion. RNA sequencing was also performed to gain greater insight into the impact of FFAR3 deletion on the islet transcriptome. First exploring insulin secretion, it was determined that Ffar3(-/-) islets secrete more insulin in a glucose-dependent manner as compared to wildtype (WT) islets. Next, exploring its primary endogenous ligand, propionate, and a specific agonist for FFAR3, signaling by FFAR3 inhibited glucose-dependent insulin secretion, which occurred through a Gαi/o pathway. To help understand these results, transcriptome analyses by RNA-sequencing of Ffar3(-/-) and WT islets observed multiple genes with well-known roles in islet biology to be altered by genetic knockout of FFAR3. Our data shows that FFAR3 signaling mediates glucose stimulated insulin secretion through Gαi/o sensitive pathway. Future studies are needed to more rigorously define the role of FFAR3 by in vivo approaches.

Free fatty acid receptors as therapeutic targets for the treatment of diabetes.

Nutrition regulates energy balance; however, dysfunction of energy balance can cause metabolic disorders, such as obesity and diabetes. Fatty acids are an essential energy source and signaling molecules that regulate various cellular processes and physiological functions. Recently, several orphan G protein-coupled receptors were identified as free fatty acid receptors (FFARs). GPR40/FFAR1 and GPR120/FFAR4 are activated by medium- and/or long-chain fatty acids, whereas GPR41/FFAR3 and GPR43/FFAR2 are activated by short-chain fatty acids. FFARs are regarded as targets for novel drugs to treat metabolic disorders, such as obesity and type 2 diabetes, because recent studies have showed that these receptors are involved in the energy metabolism in various tissues, including adipose, intestinal, and immune tissue. In this review, we summarize physiological roles of the FFARs, provide a comprehensive overview of energy regulation by FFARs, and discuss new prospects for treatment of metabolic disorders.

Regulation of Energy Homeostasis by GPR41.

Imbalances in energy regulation lead to metabolic disorders such as obesity and diabetes. Diet plays an essential role in the maintenance of body energy homeostasis by acting not only as energy source but also as a signaling modality. Excess energy increases energy expenditure, leading to a consumption of it. In addition to glucose, mammals utilize short-chain fatty acids (SCFAs), which are produced by colonic bacterial fermentation of dietary fiber, as a metabolic fuel. The roles of SCFAs in energy regulation have remained unclear, although the roles of glucose are well-studied. Recently, a G-protein-coupled receptor deorphanizing strategy successfully identified GPR41 (also called free fatty acid receptor 3 or FFAR3) as a receptor for SCFAs. GPR41 is expressed in adipose tissue, gut, and the peripheral nervous system, and it is involved in SCFA-dependent energy regulation. In this mini-review, we focus on the role of GPR41 in host energy regulation.