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Attilio Pingitore, Edward S Chambers, Thomas Hill, Inmaculada Ruz Maldonado, Bo Liu, Gavin Bewick, Douglas J Morrison, Tom Preston, Gareth A Wallis, Catriona Tedford, Ramón Castañera González, Guo Cai Huang, Pratik Choudhary, Gary Frost, Shanta J Persaud
AIMS: Diet-derived short chain fatty acids (SCFAs) improve glucose homeostasis in vivo, but the role of individual SCFAs and their mechanisms of action have not been defined. This study evaluated the effects of increasing colonic delivery of the SCFA propionate on β-cell function in humans and the direct effects of propionate on isolated human islets in vitro. MATERIALS AND METHODS: For 24 weeks human subjects ingested an inulin-propionate ester that delivers propionate to the colon...
October 20, 2016: Diabetes, Obesity & Metabolism
Zhiwei Ang, Jun Zhi Er, Nguan Soon Tan, Jinhua Lu, Yih-Cherng Liou, Johannes Grosse, Jeak Ling Ding
Knockout mice studies implicate the mammalian short-chain fatty acid (SCFA) receptors, FFAR2 and FFAR3- in colitis, arthritis and asthma. However, the correlation with human biology is uncertain. Here, we detected FFAR2 and FFAR3 expression in human monocytes via immunohistochemistry. Upon treatment with acetate SCFA or FFAR2- and FFAR3-specific synthetic agonists, human monocytes displayed elevated p38 phosphorylation and attenuated C5, CCL1, CCL2, GM-CSF, IL-1α, IL-1β and ICAM-1 inflammatory cytokine expression...
September 26, 2016: Scientific Reports
S Sivaprakasam, A Gurav, A V Paschall, G L Coe, K Chaudhary, Y Cai, R Kolhe, P Martin, D Browning, L Huang, H Shi, H Sifuentes, M Vijay-Kumar, S A Thompson, D H Munn, A Mellor, T L McGaha, P Shiao, C W Cutler, K Liu, V Ganapathy, H Li, N Singh
Composition of the gut microbiota has profound effects on intestinal carcinogenesis. Diet and host genetics play critical roles in shaping the composition of gut microbiota. Whether diet and host genes interact with each other to bring specific changes in gut microbiota that affect intestinal carcinogenesis is unknown. Ability of dietary fibre to specifically increase beneficial gut microbiota at the expense of pathogenic bacteria in vivo via unknown mechanism is an important process that suppresses intestinal inflammation and carcinogenesis...
2016: Oncogenesis
Roman M Stilling, Marcel van de Wouw, Gerard Clarke, Catherine Stanton, Timothy G Dinan, John F Cryan
Several lines of evidence suggest that brain function and behaviour are influenced by microbial metabolites. Key products of the microbiota are short-chain fatty acids (SCFAs), including butyric acid. Butyrate is a functionally versatile molecule that is produced in the mammalian gut by fermentation of dietary fibre and is enriched in butter and other dairy products. Butyrate along with other fermentation-derived SCFAs (e.g. acetate, propionate) and the structurally related ketone bodies (e.g. acetoacetate and d-β-hydroxybutyrate) show promising effects in various diseases including obesity, diabetes, inflammatory (bowel) diseases, and colorectal cancer as well as neurological disorders...
October 2016: Neurochemistry International
Stephanie R Villa, Medha Priyadarshini, Miles H Fuller, Tanya Bhardwaj, Michael R Brodsky, Anthony R Angueira, Rockann E Mosser, Bethany A Carboneau, Sarah A Tersey, Helena Mancebo, Annette Gilchrist, Raghavendra G Mirmira, Maureen Gannon, Brian T Layden
The regulation of pancreatic β cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of β cell function, including regulation of β cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of β cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote β cell expansion by direct and indirect mechanisms. Free Fatty Acid Receptor 2 (FFA2) is a β cell-expressed GPCR that is activated by short chain fatty acids, particularly acetate...
2016: Scientific Reports
Joseph Lim, Christiani Jeyakumar Henry, Sumanto Haldar
Type 2 diabetes prevalence worldwide is increasing and the burden is particularly high in Asian countries. Identification of functional food ingredients to curb the rise of diabetes among various Asian population groups is warranted. Vinegar is widely consumed throughout Asia, where the principle bioactive component is acetic acid. This review has collated data from human intervention trials to show that vinegar consumption seems more effective in modulating glycemic control in normal glucose-tolerant individuals than in either type 2 diabetics or in those with impaired glucose tolerance...
August 2016: Molecular Nutrition & Food Research
Renan Corrêa-Oliveira, José Luís Fachi, Aline Vieira, Fabio Takeo Sato, Marco Aurélio R Vinolo
Short-chain fatty acids (SCFAs) are bacterial fermentation products, which are chemically composed by a carboxylic acid moiety and a small hydrocarbon chain. Among them, acetic, propionic and butyric acids are the most studied, presenting, respectively, two, three and four carbons in their chemical structure. These metabolites are found in high concentrations in the intestinal tract, from where they are uptaken by intestinal epithelial cells (IECs). The SCFAs are partially used as a source of ATP by these cells...
April 2016: Clinical & Translational Immunology
Frank Reimann, Fiona M Gribble
The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1, are secreted from intestinal K- and L cells, respectively, with the former being most abundant in the proximal small intestine, whereas the latter increase in number towards the distal gut. Although an overlap between K- and L cells can be observed immunohistochemically or in murine models expressing fluorescent markers under the control of the two hormone promoters, the majority (>80%) of labeled cells seems to produce only one of these hormones...
April 2016: Journal of Diabetes Investigation
Adnan Munkarah, Ismail Mert, Jasdeep Chhina, Suhail Hamid, Laila Poisson, Sharon Hensley-Alford, Shailendra Giri, Ramandeep Rattan
OBJECTIVES: Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets. METHODS: The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas...
April 2016: Gynecologic Oncology
Bi-Oh Park, Seong Heon Kim, Gye Yeong Kong, Da Hui Kim, Mi So Kwon, Su Ui Lee, Mun-Ock Kim, Sungchan Cho, Sangku Lee, Hyun-Jun Lee, Sang-Bae Han, Young Shin Kwak, Sung Bae Lee, Sunhong Kim
GPR43/Free Fatty Acid Receptor 2 (FFAR2) is known to be activated by short-chain fatty acids and be coupled to Gi and Gq family of heterotrimeric G proteins. GPR43 is mainly expressed in neutrophils, adipocytes and enteroendocrine cells, implicated to be involved in inflammation, obesity and type 2 diabetes. However, several groups have reported the contradictory data about the physiological functions of GPR43, so that its roles in vivo remain unclear. Here, we demonstrate that a novel compound of pyrimidinecarboxamide class named as BTI-A-404 is a selective and potent competitive inverse agonist of human GPR43, but not the murine ortholog...
January 15, 2016: European Journal of Pharmacology
Henry J Pownall, Antonio M Gotto
Although high-density lipoprotein-cholesterol (HDL-C) concentration is a negative risk factor for atherosclerotic cardiovascular disease (CVD), efforts to reduce CVD risk by raising HDL-C have not been uniformly successful. Many studies have shown that alcohol consumption, that increases plasma HDL-C concentration, reduces CVD incidence. However, recent genetic studies in large populations have not only removed HDL-C from the causal link between plasma HDL-C concentration and reduced CVD risk, but also suggest that the association is weak...
January 2016: Trends in Endocrinology and Metabolism: TEM
P Friedrichs, H Sauerwein, K Huber, L F Locher, J Rehage, U Meyer, S Dänicke, B Kuhla, M Mielenz
We recently showed that the mRNA expression of genes encoding for specific nutrient sensing receptors, namely the free fatty acid receptors (FFAR) 1, 2, 3, and the hydroxycarboxylic acid receptor (HCAR) 2, undergo characteristic changes during the transition from late pregnancy to lactation in certain adipose tissues (AT) of dairy cows. We hypothesised that divergent energy intake achieved by feeding diets with either high or low portions of concentrate (60% v. 30% concentrate on a dry matter basis) will alter the mRNA expression of FFAR 1, 2, 3, as well as HCAR2 in subcutaneous (SCAT) and retroperitoneal AT (RPAT) of dairy cows in the first 3 weeks postpartum (p...
April 2016: Animal: An International Journal of Animal Bioscience
Miles Fuller, Medha Priyadarshini, Sean M Gibbons, Anthony R Angueira, Michael Brodsky, M Geoffrey Hayes, Petia Kovatcheva-Datchary, Fredrik Bäckhed, Jack A Gilbert, William L Lowe, Brian T Layden
The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice...
November 15, 2015: American Journal of Physiology. Endocrinology and Metabolism
Mingli Zhao, Weiming Zhu, Jianfeng Gong, Lugen Zuo, Jie Zhao, Jing Sun, Ning Li, Jieshou Li
G protein-coupled receptor 43/free fatty acid receptor 2 (GPR43/FFAR2) is essential for polymorphonuclear (PMN) recruitment. We investigated the expression of GPR43/FFAR2 in the colon from Crohn's disease patients and whether dietary fiber in enteral nutrition increases GPR43+ polymorphonuclear infiltration in mucosa. Segments of ascending colon and white blood cells from peripheral blood were obtained from 46 Crohn's disease patients and 10 colon cancer patients. The Crohn's disease patients were grouped by the activity of disease (active or remission) and enteral nutrition with or without dietary fiber...
July 2015: Nutrients
Medha Priyadarshini, Stephanie R Villa, Miles Fuller, Barton Wicksteed, Charles R Mackay, Thierry Alquier, Vincent Poitout, Helena Mancebo, Raghavendra G Mirmira, Annette Gilchrist, Brian T Layden
G protein-coupled receptors have been well described to contribute to the regulation of glucose-stimulated insulin secretion (GSIS). The short-chain fatty acid-sensing G protein-coupled receptor, free fatty acid receptor 2 (FFAR2), is expressed in pancreatic β-cells, and in rodents, its expression is altered during insulin resistance. Thus, we explored the role of FFAR2 in regulating GSIS. First, assessing the phenotype of wild-type and Ffar2(-/-) mice in vivo, we observed no differences with regard to glucose homeostasis on normal or high-fat diet, with a marginally significant defect in insulin secretion in Ffar2(-/-) mice during hyperglycemic clamps...
July 2015: Molecular Endocrinology
Daniel Erny, Anna Lena Hrabě de Angelis, Diego Jaitin, Peter Wieghofer, Ori Staszewski, Eyal David, Hadas Keren-Shaul, Tanel Mahlakoiv, Kristin Jakobshagen, Thorsten Buch, Vera Schwierzeck, Olaf Utermöhlen, Eunyoung Chun, Wendy S Garrett, Kathy D McCoy, Andreas Diefenbach, Peter Staeheli, Bärbel Stecher, Ido Amit, Marco Prinz
As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties...
July 2015: Nature Neuroscience
Camille Meslin, Colette Desert, Isabelle Callebaut, Anis Djari, Christophe Klopp, Frédérique Pitel, Sophie Leroux, Pascal Martin, Pascal Froment, Edith Guilbert, Florence Gondret, Sandrine Lagarrigue, Philippe Monget
Free fatty acid receptors (FFAR) belong to a family of five G-protein coupled receptors that are involved in the regulation of lipid metabolism, so that their loss of function increases the risk of obesity. The aim of this study was to determine the expansion of genes encoding paralogs of FFAR2 in the chicken, considered as a model organism for developmental biology and biomedical research. By estimating the gene copy number using quantitative polymerase chain reaction, genomic DNA resequencing, and RNA sequencing data, we showed the existence of 23 ± 1...
May 2015: Genome Biology and Evolution
Mayu Kasubuchi, Sae Hasegawa, Takero Hiramatsu, Atsuhiko Ichimura, Ikuo Kimura
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)...
April 2015: Nutrients
Sameer Mohammad
Besides being an important source of fuel and structural components of biological membranes, free fatty acids (FFAs) are known to display a wide variety of roles that include modulation of receptor signaling and regulation of gene expression among many. FFAs play a significant role in maintaining metabolic homeostasis by activating specific G-Protein Coupled Receptors (GPCRs) in pancreatic β cells, immune cells, white adipose tissue, intestine and several other tissues. Free Fatty acid receptor 2 (FFAR2) also known as GPR43 belongs to this group of GPCRs and has been shown to participate in a number of important biological activities...
2015: Current Drug Targets
Hiroki Sekiguchi, Mayu Kasubuchi, Sae Hasegawa, Nicolas Pelisch, Ikuo Kimura, Atsuhiko Ichimura
Excessive dietary intake of fat is strongly involved in the development of type 2 diabetes (T2D). Free fatty acids (FFAs), which are provided from dietary fat, are not only important nutrients, but also act as signaling molecules and stimulate key biological functions. Recent physiological and pharmacological studies have shown that several G-protein coupled receptors, such as FFAR1-4, are receptors for FFAs. FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids, whereas FFAR2 and FFAR3 are activated by short-chain fatty acids (SCFAs)...
2015: Current Diabetes Reviews
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