Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty acids ...(SCFAs) produced by gut microbial fermentation of the otherwise indigestible dietary fiber, constitute the major sources of free fatty acids (FFAs) in the metabolic network. Recently, increasing evidence indicates that FFAs serve not only as energy sources but also as natural ligands for a group of orphan G protein-coupled receptors (GPCRs) termed free fatty acid receptors (FFARs), essentially intertwining metabolism and immunity in multiple ways, such as via inflammation regulation and secretion of peptide hormones. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized. In particular, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain saturated and unsaturated fatty acids, while FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs, mainly acetate, butyrate, and propionate. In this review, we discuss the recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses. We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.
Dysbiosis is associated with various diseases. The composition and diversity of gut microbiota affect host physiology through the production of bioactive metabolites. Short-chain fatty acids are the ...main metabolites produced by microbial fermentation of dietary fiber. They play a crucial role in maintaining metabolic, nervous, and immune system. Short-chain fatty acids not only serve as an energy source for the host but also act as for G-protein-coupled receptor signaling molecules and histone deacetylase inhibitors. In particular, the discovery and deorphanization of free fatty acid receptors 2 and 3 (GPR43/41) have shed light on the molecular mechanisms underlying the regulation of physiological processes by short-chain fatty acids. The short-chain fatty acid receptors sense the nutrient status and transduce signals to maintain cellular homeostasis. Dysbiosis affects short-chain fatty acid production and impairs the signaling, leading to cellular dysfunction. We review the current understanding of short-chain fatty acid-mediated regulation of physiological processes and discuss the molecular pharmacology of short-chain fatty acid and the receptor. We also discuss recent advances in the use of prebiotics and probiotics in the treatment of disease.
Accumulating evidence over the past decade has linked the development of metabolic syndrome related to diabetes to variations in gut microbiota, an emerging, critical homeostatic regulator of host ...energy metabolism and immune responses. Mechanistic studies in rodent models have revealed an ever-increasing multitude of molecular mechanisms whereby the gut microbiota interacts with various host sensing and signaling pathways, leading to modulation of endocrine system, immune responses, nervous system activity, and hence, the predisposition to metabolic diseases. Remarkably, the microbiota-driven immune responses in metabolic tissues and the host nutrient-sensing mechanisms of gut microbial metabolites, in particular short-chain fatty acids, have been significantly associated with the proneness to diabetes and related disorders. This review will synthesize the recent efforts on unraveling the mediating role of gut microbiota in the pathogenesis of metabolic diseases, aiming to reveal new therapeutic opportunities.
During feeding, the gut microbiota contributes to the host energy acquisition and metabolic regulation thereby influencing the development of metabolic disorders such as obesity and diabetes. ...Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues. In this review, we summarize the roles of gut microbial SCFAs in the host energy regulation and present an overview of the current understanding of its physiological functions.
Olfactory receptor 78 (Olfr78), which is also known as a receptor for short-chain fatty acids (SCFAs) produced via gut microbial fermentation from indigestible polysaccharides such as dietary fibers, ...is expressed in the enteroendocrine cells of the colon. However, the role of Olfr78 in gut hormone secretion remains unknown. Here, we aimed to investigate the function and mechanism of action of Olfr78 in vivo and in vitro. Toward this, we assessed the expression of Olfr78 in several tissues, affinity of Olfr78 to various monocarboxylates, and the secretion of anorexigenic gut hormone peptide YY (PYY) via Olfr78 using various molecular and biochemical techniques. Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line STC-1 and showed specific affinity to SCFAs such as acetate and propionate, but not butyrate, in a monocarboxylate ligand screening assay using a heterologous expression system. Acetate promoted PYY secretion in STC-1 cells via Olfr78-protein kinase A signaling, whereas the effects were abolished by Olfr78 RNA interference. Colonic SCFAs production via oral administration of fructo-oligosaccharide significantly increased plasma PYY levels, whereas this effect was abolished in Olfr78-deficient and germ-free mice. These results suggested that the SCFA receptor Olfr78 is important for anti-obesity and anorexigenic effects of the gut microbiota and dietary fibers.
•Olfr78 was abundantly expressed in the colon and mouse enteroendocrine cell line.•Olfr78 was activated by SCFAs, acetate and propionate, but not butyrate.•Acetate mediated Olfr78 stimulation promoted PYY secretion in STC-1 cells.•Gut microbial SCFAs increased plasma PYY levels via Olfr78.
Gut microbiota mediates the effects of diet, thereby modifying host metabolism and the incidence of metabolic disorders. Increased consumption of omega-6 polyunsaturated fatty acid (PUFA) that is ...abundant in Western diet contributes to obesity and related diseases. Although gut-microbiota-related metabolic pathways of dietary PUFAs were recently elucidated, the effects on host physiological function remain unclear. Here, we demonstrate that gut microbiota confers host resistance to high-fat diet (HFD)-induced obesity by modulating dietary PUFAs metabolism. Supplementation of 10-hydroxy-cis-12-octadecenoic acid (HYA), an initial linoleic acid-related gut-microbial metabolite, attenuates HFD-induced obesity in mice without eliciting arachidonic acid-mediated adipose inflammation and by improving metabolic condition via free fatty acid receptors. Moreover, Lactobacillus-colonized mice show similar effects with elevated HYA levels. Our findings illustrate the interplay between gut microbiota and host energy metabolism via the metabolites of dietary omega-6-FAs thereby shedding light on the prevention and treatment of metabolic disorders by targeting gut microbial metabolites.
Nutritional Signaling via Free Fatty Acid Receptors Miyamoto, Junki; Hasegawa, Sae; Kasubuchi, Mayu ...
International Journal of Molecular Sciences,
03/2016, Volume:
17, Issue:
4
Journal Article, Book Review
Peer reviewed
Open access
Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity ...and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs' carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis. In particular, recent studies have shown that the administration of selective agonists of G protein-coupled receptor (GPR) 40 and GPR120 improved glucose metabolism and systemic metabolic disorders. Furthermore, the anti-inflammation and energy metabolism effects of short chain FAs have been linked to the activation of GPR41 and GPR43. In this review, we summarize recent progress in research on FFAs and their physiological roles in the regulation of energy metabolism.
Fermented foods represent a significant portion of human diets with several beneficial effects. Foods produced by bacterial fermentation are enriched in short-chain fatty acids (SCFAs), which are ...functional products of dietary fibers via gut microbial fermentation. In addition to energy sources, SCFAs also act as signaling molecules via G-protein coupled receptors such as FFAR2 and FFAR3. Hence, dietary SCFAs in fermented foods may have a direct influence on metabolic functions. However, the detailed mechanism by dietary SCFAs remains unclear. Here, we show that dietary SCFAs protected against high-fat diet-induced obesity in mice in parallel with increased plasma SCFAs without changing cecal SCFA or gut microbial composition. Dietary SCFAs suppressed hepatic weight and lipid synthesis. These effects were abolished in FFAR3-deficient mice but not FFAR2-deficient. Thus, SCFAs supplementation improved hepatic metabolic functions via FFAR3 without influencing intestinal environment. These findings could help to promote the development of functional foods using SCFAs.
Short-chain fatty acids (SCFAs), which are metabolites derived from the fermentation of dietary fibre by the gut microbiota, are important for host metabolic health. There is interest in probiotics ...for their beneficial effects on metabolic disorders, such as obesity, but the underlying mechanisms remain largely unknown. In this study, we evaluated whether Bifidobacterium animalis subsp. lactis GCL2505 (GCL2505), a probiotic strain capable of proliferating and increasing SCFA levels in the gut, exerts anti-metabolic syndrome effects via the SCFA receptor G protein-coupled receptor 43 (GPR43). A GCL2505 treatment suppressed body fat accumulation, improved glucose tolerance, and enhanced systemic fatty acid oxidation in high-fat diet (HFD)-fed wild type (WT) mice, whereas these effects were not observed in HFD-fed Gpr43 knockout (Gpr43-/-) mice. Caecal and plasma acetate levels were elevated by GCL2505 in WT and Gpr43-/- mice, but the negative correlation between plasma acetate levels and body fat accumulation was observed only in WT mice. We further demonstrated that GCL2505 suppressed insulin signalling in the adipose tissue via GPR43. These results suggested that increases in SCFA levels in response to GCL2505 enhance host energy expenditure, which decreases fat accumulation via activated GPR43.
The balance between bacterial colonization and its containment in the intestine is indispensable for the symbiotic relationship between humans and their bacteria. One component to maintain ...homeostasis at the mucosal surfaces is immunoglobulin A (IgA), the most abundant immunoglobulin in mammals
. Several studies have revealed important characteristics of poly-reactive IgA
, which is produced naturally without commensal bacteria. Considering the dynamic changes within the gut environment, however, it remains uncertain how the commensal-reactive IgA pool is shaped and how such IgA affects the microbial community. Here we show that acetate-one of the major gut microbial metabolites-not only increases the production of IgA in the colon, but also alters the capacity of the IgA pool to bind to specific microorganisms including Enterobacterales. Induction of commensal-reactive IgA and changes in the IgA repertoire by acetate were observed in mice monocolonized with Escherichia coli, which belongs to Enterobacterales, but not with the major commensal Bacteroides thetaiotaomicron, which suggests that acetate directs selective IgA binding to certain microorganisms. Mechanistically, acetate orchestrated the interactions between epithelial and immune cells, induced microbially stimulated CD4 T cells to support T-cell-dependent IgA production and, as a consequence, altered the localization of these bacteria within the colon. Collectively, we identified a role for gut microbial metabolites in the regulation of differential IgA production to maintain mucosal homeostasis.
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