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GPR43 – A Prototypic Metabolite Sensor Linking Metabolic and Inflammatory Diseases
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GPR43 – A Prototypic Metabolite Sensor Linking Metabolic and Inflammatory Diseases Craig I. McKenzie,1 Charles R. Mackay,1,2,* and Laurence Macia1,3,4,* Short-chain fatty acids (SCFAs) are released upon fermentation of dietary fiber by gut bacteria. G protein-coupled receptor 43 (GPR43), a key receptor for SCFAs, is expressed on cell types important for immunity and metabolism. GPR43 modulates both inflammatory and metabolic processes, and is crucial for understanding the pathogenesis of ‘Western lifestyle’ diseases. Introduction The increasing incidence of some inflammatory diseases, such as allergies, in the Western world has been attributed to excessive hygiene, a concept known as the hygiene hypothesis. This holds that lack of immune challenge during childhood accounts for inappropriate immune education that then leads to dysregulated immune responses. While this hypothesis is plausible, it alone is unlikely to explain the recent burden of inflammatory diseases [1]. Over the past few decades, Western lifestyle has experienced dramatic changes in the nutritional landscape. Increased consumption of processed food high in fat and sugar has slowly replaced traditional diets that were rich in vegetables, fruits, and grains (and thus high in fiber). Fibers are complex non-digestible polysaccharides found in plants that are fermented by colonic
bacteria into SCFAs. These SCFAs are predominantly acetate, propionate, and butyrate. A major advance in understanding the benefits of dietary fiber has been the discovery of SCFA receptors, with GPR43 being one of the most thoroughly characterized. SCFAs are important for controlling inflammatory responses and metabolic diseases, at least in part through binding to GPR43. This short commentary will highlight recent advances surrounding the role of GPR43 in immunity and metabolism.
inflammasome activation in macrophages, and here GPR43 can play a pathogenic role in a murine model of gout [7]. This demonstrates the importance of cell types and their location when interpreting downstream mechanisms of GPR43 activation because GPR43 appears to play a role in both preventing and promoting inflammation. Such considerations will be particularly relevant for the use of GPR43 agonists or antagonists in the clinic.
Metabolic Role of GPR43 Immune Role of GPR43 GPR43 is expressed on a wide variety of immune cells, including neutrophils, macrophages, dendritic cells, mast cells, lymphocytes, and epithelial cells of colonic tissue [2]. The first definitive assessment of immune responses in Gpr43 / mice revealed that GPR43 is an important regulator of inflammation in models of arthritis and colitis [3]. Following this discovery, GPR43 has been demonstrated to regulate inflammation in a myriad of differing ways. GPR43 signaling reduces the production of inflammatory mediators, and also affects the migration of inflammatory leukocytes [3]. GPR43 on colonic T cells enhances forkhead box P3 (FOXP3) expression via epigenetic modifications that induce T regulatory (Treg) cell differentiation and function [4]. It was recently shown in vivo that GPR43 and fiber can protect against colon cancer, probably through effects on immune and/or epithelial cells [5]. Another study demonstrated enhanced apoptosis in a colon cancer cell line after restoration of otherwise reduced Gpr43 expression [6]. This suggests a dual role for GPR43 in preventing colon cancer by promoting both host immune responses and cancer cell apoptosis. In addition, activation of GPR43 on intestinal colonic epithelial cells maintains epithelial integrity via activation of the NLRP3 (NODlike receptor family, pyrin domain containing 3) inflammasome, and this confers protection in a murine model of colitis [5]. By contrast, GPR43 signaling in peripheral tissues contributes to
GPR43 exerts more than purely immune functions because it is expressed by adipocytes and pancreatic islets [8] as well as by enteroendocrine cells in the gut. These cells play an important role in metabolism by controlling energy use, storage, and feeding behavior. Indeed, GPR43 represents one of the most intriguing links between metabolism and inflammation. Recent work in rodents shows that GPR43 plays a complex role in metabolism. Propionate in the colon activates GPR43 on enteroendocrine cells and induces peptide YY and glucagon-like peptide-1 release, hormones that suppress appetite [9]. However, two studies using Gpr43 / mice fed high-fat diets reported conflicting results. One study demonstrated that Gpr43 / mice were leaner than wild-type controls, which correlated with higher rates of energy expenditure and lower macrophage content in white adipose tissue [10]. This was in contrast to another study that found essentially the opposite results, with GPR43 impairing insulin signaling and thus fat storage in adipocytes [11]. It is conceivable that the gut microbiota may influence these outcomes. In the study of Kimura et al. [11] it was shown that Gpr43 / mice develop spontaneous obesity, while under germ-free conditions they remain lean. Therefore, microbial production of SCFAs appears to play a role in both appetite and obesity by acting via GPR43. However, the underlying mechanisms for prevention or promotion of obesity remain poorly understood. Another
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
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recent study demonstrated that GPR43 signaling in murine pancreatic islets can enhance insulin secretion and protect against the development of insulin resistance under obesogenic conditions [8]. Given that insulin resistance is both a hallmark of chronic obesity and a major contributor to diabetes, GPR43 agonists may be promising targets for drug development for metabolic disorders. However, the exact mechanisms behind the metabolic functions of GPR43 need to be unraveled. GPR43 couples to either the pertussis toxin-sensitive Gi/o or -insensitive Gq subunits. Indeed, a recent study investigating glucose-stimulated insulin secretion (GSIS) in murine islets revealed that different GPR43 agonists could either increase or inhibit GSIS [12], with Gq/11 increasing GSIS whereas Gi/o decreased GSIS. This dichotomy exists in mice, but whether it holds for human GPR43 is unclear. Both G protein subunits are simultaneously activated by human GPR43 signaling [2], suggesting potential regulation of insulin release by SCFAs both in rodents and in humans. GPR43 signaling is likely to be even more complex because this receptor (in common with most metabolitesensing GPCRs) also signals through barrestin. It is also possible that GPR43 signaling in islets or adipose tissue leads to inflammasome activation, as is the case in gut epithelium and macrophages.
explain the link between metabolism and inflammation? GPR43 may enhance FOXP3 expression and function in Tregs, which may alter macrophage infiltration in white adipose tissue and associated inflammatory responses in obesity. Furthermore, Tregs have been shown to reduce insulin resistance. Maintenance of epithelial integrity by GPR43 may also prevent insulin resistance through reduced translocation of bacterial lipopolysaccharide that would otherwise induce inflammation in adipose tissue. An interesting consideration is – why has the metabolite sensor GPR43 evolved to function in both the metabolic and immune systems? Dietary fiber is a typical foodstuff, and GPR43 may therefore simply be a sensor for nutrition in general. The presence or absence of adequate nutrition may feed back to metabolic processes as well as immune responses. Another possibility is that GPR43 has simply been ‘adopted’ by the immune system to regulate proper immune responses in the gut (where SCFA concentrations are high). Interestingly, the gut microbiome may play its part through its ability (or not) to produce the relevant metabolites. Regardless, GPR43 and related metabolite sensors such as GPR41 and GPR109A offer an exciting new opportunity to understand and treat metabolic diseases and inflammation. 1
Concluding Remarks GPR43 plays an important role in inflammation and metabolism. The practical benefits of dietary fiber and SCFAs have been appreciated for decades, and it is now clear that at least part of this benefit is mediated by GPR43. Indeed, GPR43 small-molecule agonists may find utility in human metabolic syndrome or inflammatory diseases. Given the possibility of variable signaling to different GPR43 agonists, care may be required to bias signaling of G protein subunits for desired effects on human metabolism or inflammation. However, many questions remain. Will the mouse studies translate to humans? How might GPR43 biology
512
Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road,
Clayton, Victoria 3800, Australia 2 Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA 3 Charles Perkins Centre, The University of Sydney, NSW 2006, Australia 4 School of Medical Sciences, The University of Sydney, NSW 2006, Australia *Correspondence: charles.mackay@pfizer.com (C.R. Mackay), [email protected] (L. Macia) http://dx.doi.org/10.1016/j.tem.2015.07.009 References 1. Macia, L. et al. (2012) Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 245, 164–176 2. Brown, A.J. et al. (2003) The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 3. Maslowski, K.M. et al. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
4. Smith, P.M. et al. (2013) The microbial metabolites, shortchain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 5. Macia, L. et al. (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 6. Tang, Y. et al. (2011) G-protein-coupled receptor for shortchain fatty acids suppresses colon cancer. Int. J. Cancer 128, 847–856 7. Vieira, A.T. et al. (2015) A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol. 67, 1646–1656 8. McNelis, J.C. et al. (2015) GPR43 potentiates beta cell function in obesity. Diabetes 64, 3203–3217 9. Psichas, A. et al. (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424–429 10. Bjursell, M. et al. (2011) Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 300, E211–E220 11. Kimura, I. et al. (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4, 1829 12. Priyadarshini, M. et al. (2015) An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol. Endocrinol. 29, 1055–1066
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Insulin-Mediated Diseases: Adrenal Mass and Polycystic Ovary Syndrome Giovanna Muscogiuri,1,* Annamaria Colao,1 and Francesco Orio2,3 Adrenal incidentalomas (AIs) and polycystic ovary syndrome (PCOS) have often been associated with compensatory hyperinsulinemia and insulin resistance (IR). The link between these diseases and IR may be changes in hormone secretions that provoke IR and in turn promote the growth of adrenal gland masses and/or ovarian cysts through compensatory hyperinsulinemia. AI Incidentaloma Management Adrenal masses occasionally detected during radiological examinations, the
GPR43 – A Prototypic Metabolite Sensor Linking Metabolic and Inflammatory Diseases Craig I. McKenzie,1 Charles R. Mackay,1,2,* and Laurence Macia1,3,4,* Short-chain fatty acids (SCFAs) are released upon fermentation of dietary fiber by gut bacteria. G protein-coupled receptor 43 (GPR43), a key receptor for SCFAs, is expressed on cell types important for immunity and metabolism. GPR43 modulates both inflammatory and metabolic processes, and is crucial for understanding the pathogenesis of ‘Western lifestyle’ diseases. Introduction The increasing incidence of some inflammatory diseases, such as allergies, in the Western world has been attributed to excessive hygiene, a concept known as the hygiene hypothesis. This holds that lack of immune challenge during childhood accounts for inappropriate immune education that then leads to dysregulated immune responses. While this hypothesis is plausible, it alone is unlikely to explain the recent burden of inflammatory diseases [1]. Over the past few decades, Western lifestyle has experienced dramatic changes in the nutritional landscape. Increased consumption of processed food high in fat and sugar has slowly replaced traditional diets that were rich in vegetables, fruits, and grains (and thus high in fiber). Fibers are complex non-digestible polysaccharides found in plants that are fermented by colonic
bacteria into SCFAs. These SCFAs are predominantly acetate, propionate, and butyrate. A major advance in understanding the benefits of dietary fiber has been the discovery of SCFA receptors, with GPR43 being one of the most thoroughly characterized. SCFAs are important for controlling inflammatory responses and metabolic diseases, at least in part through binding to GPR43. This short commentary will highlight recent advances surrounding the role of GPR43 in immunity and metabolism.
inflammasome activation in macrophages, and here GPR43 can play a pathogenic role in a murine model of gout [7]. This demonstrates the importance of cell types and their location when interpreting downstream mechanisms of GPR43 activation because GPR43 appears to play a role in both preventing and promoting inflammation. Such considerations will be particularly relevant for the use of GPR43 agonists or antagonists in the clinic.
Metabolic Role of GPR43 Immune Role of GPR43 GPR43 is expressed on a wide variety of immune cells, including neutrophils, macrophages, dendritic cells, mast cells, lymphocytes, and epithelial cells of colonic tissue [2]. The first definitive assessment of immune responses in Gpr43 / mice revealed that GPR43 is an important regulator of inflammation in models of arthritis and colitis [3]. Following this discovery, GPR43 has been demonstrated to regulate inflammation in a myriad of differing ways. GPR43 signaling reduces the production of inflammatory mediators, and also affects the migration of inflammatory leukocytes [3]. GPR43 on colonic T cells enhances forkhead box P3 (FOXP3) expression via epigenetic modifications that induce T regulatory (Treg) cell differentiation and function [4]. It was recently shown in vivo that GPR43 and fiber can protect against colon cancer, probably through effects on immune and/or epithelial cells [5]. Another study demonstrated enhanced apoptosis in a colon cancer cell line after restoration of otherwise reduced Gpr43 expression [6]. This suggests a dual role for GPR43 in preventing colon cancer by promoting both host immune responses and cancer cell apoptosis. In addition, activation of GPR43 on intestinal colonic epithelial cells maintains epithelial integrity via activation of the NLRP3 (NODlike receptor family, pyrin domain containing 3) inflammasome, and this confers protection in a murine model of colitis [5]. By contrast, GPR43 signaling in peripheral tissues contributes to
GPR43 exerts more than purely immune functions because it is expressed by adipocytes and pancreatic islets [8] as well as by enteroendocrine cells in the gut. These cells play an important role in metabolism by controlling energy use, storage, and feeding behavior. Indeed, GPR43 represents one of the most intriguing links between metabolism and inflammation. Recent work in rodents shows that GPR43 plays a complex role in metabolism. Propionate in the colon activates GPR43 on enteroendocrine cells and induces peptide YY and glucagon-like peptide-1 release, hormones that suppress appetite [9]. However, two studies using Gpr43 / mice fed high-fat diets reported conflicting results. One study demonstrated that Gpr43 / mice were leaner than wild-type controls, which correlated with higher rates of energy expenditure and lower macrophage content in white adipose tissue [10]. This was in contrast to another study that found essentially the opposite results, with GPR43 impairing insulin signaling and thus fat storage in adipocytes [11]. It is conceivable that the gut microbiota may influence these outcomes. In the study of Kimura et al. [11] it was shown that Gpr43 / mice develop spontaneous obesity, while under germ-free conditions they remain lean. Therefore, microbial production of SCFAs appears to play a role in both appetite and obesity by acting via GPR43. However, the underlying mechanisms for prevention or promotion of obesity remain poorly understood. Another
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
511
recent study demonstrated that GPR43 signaling in murine pancreatic islets can enhance insulin secretion and protect against the development of insulin resistance under obesogenic conditions [8]. Given that insulin resistance is both a hallmark of chronic obesity and a major contributor to diabetes, GPR43 agonists may be promising targets for drug development for metabolic disorders. However, the exact mechanisms behind the metabolic functions of GPR43 need to be unraveled. GPR43 couples to either the pertussis toxin-sensitive Gi/o or -insensitive Gq subunits. Indeed, a recent study investigating glucose-stimulated insulin secretion (GSIS) in murine islets revealed that different GPR43 agonists could either increase or inhibit GSIS [12], with Gq/11 increasing GSIS whereas Gi/o decreased GSIS. This dichotomy exists in mice, but whether it holds for human GPR43 is unclear. Both G protein subunits are simultaneously activated by human GPR43 signaling [2], suggesting potential regulation of insulin release by SCFAs both in rodents and in humans. GPR43 signaling is likely to be even more complex because this receptor (in common with most metabolitesensing GPCRs) also signals through barrestin. It is also possible that GPR43 signaling in islets or adipose tissue leads to inflammasome activation, as is the case in gut epithelium and macrophages.
explain the link between metabolism and inflammation? GPR43 may enhance FOXP3 expression and function in Tregs, which may alter macrophage infiltration in white adipose tissue and associated inflammatory responses in obesity. Furthermore, Tregs have been shown to reduce insulin resistance. Maintenance of epithelial integrity by GPR43 may also prevent insulin resistance through reduced translocation of bacterial lipopolysaccharide that would otherwise induce inflammation in adipose tissue. An interesting consideration is – why has the metabolite sensor GPR43 evolved to function in both the metabolic and immune systems? Dietary fiber is a typical foodstuff, and GPR43 may therefore simply be a sensor for nutrition in general. The presence or absence of adequate nutrition may feed back to metabolic processes as well as immune responses. Another possibility is that GPR43 has simply been ‘adopted’ by the immune system to regulate proper immune responses in the gut (where SCFA concentrations are high). Interestingly, the gut microbiome may play its part through its ability (or not) to produce the relevant metabolites. Regardless, GPR43 and related metabolite sensors such as GPR41 and GPR109A offer an exciting new opportunity to understand and treat metabolic diseases and inflammation. 1
Concluding Remarks GPR43 plays an important role in inflammation and metabolism. The practical benefits of dietary fiber and SCFAs have been appreciated for decades, and it is now clear that at least part of this benefit is mediated by GPR43. Indeed, GPR43 small-molecule agonists may find utility in human metabolic syndrome or inflammatory diseases. Given the possibility of variable signaling to different GPR43 agonists, care may be required to bias signaling of G protein subunits for desired effects on human metabolism or inflammation. However, many questions remain. Will the mouse studies translate to humans? How might GPR43 biology
512
Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road,
Clayton, Victoria 3800, Australia 2 Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA 3 Charles Perkins Centre, The University of Sydney, NSW 2006, Australia 4 School of Medical Sciences, The University of Sydney, NSW 2006, Australia *Correspondence: charles.mackay@pfizer.com (C.R. Mackay), [email protected] (L. Macia) http://dx.doi.org/10.1016/j.tem.2015.07.009 References 1. Macia, L. et al. (2012) Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 245, 164–176 2. Brown, A.J. et al. (2003) The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312–11319 3. Maslowski, K.M. et al. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286
Trends in Endocrinology & Metabolism, October 2015, Vol. 26, No. 10
4. Smith, P.M. et al. (2013) The microbial metabolites, shortchain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 5. Macia, L. et al. (2015) Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6, 6734 6. Tang, Y. et al. (2011) G-protein-coupled receptor for shortchain fatty acids suppresses colon cancer. Int. J. Cancer 128, 847–856 7. Vieira, A.T. et al. (2015) A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol. 67, 1646–1656 8. McNelis, J.C. et al. (2015) GPR43 potentiates beta cell function in obesity. Diabetes 64, 3203–3217 9. Psichas, A. et al. (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int. J. Obes. 39, 424–429 10. Bjursell, M. et al. (2011) Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 300, E211–E220 11. Kimura, I. et al. (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4, 1829 12. Priyadarshini, M. et al. (2015) An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol. Endocrinol. 29, 1055–1066
Forum
Insulin-Mediated Diseases: Adrenal Mass and Polycystic Ovary Syndrome Giovanna Muscogiuri,1,* Annamaria Colao,1 and Francesco Orio2,3 Adrenal incidentalomas (AIs) and polycystic ovary syndrome (PCOS) have often been associated with compensatory hyperinsulinemia and insulin resistance (IR). The link between these diseases and IR may be changes in hormone secretions that provoke IR and in turn promote the growth of adrenal gland masses and/or ovarian cysts through compensatory hyperinsulinemia. AI Incidentaloma Management Adrenal masses occasionally detected during radiological examinations, the