Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms

Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.

[1]  J. Gordon,et al.  Human nutrition, the gut microbiome and the immune system , 2011, Nature.

[2]  M. Low,et al.  Meal pattern analysis in neural-specific proopiomelanocortin-deficient mice. , 2011, European journal of pharmacology.

[3]  Arthur Kaser,et al.  Gut microbiome, obesity, and metabolic dysfunction. , 2011, The Journal of clinical investigation.

[4]  Wei Sun,et al.  The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. , 2011, Cell metabolism.

[5]  Takafumi Hara,et al.  Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41) , 2011, Proceedings of the National Academy of Sciences.

[6]  G. Frost,et al.  Propionate. Anti-obesity and satiety enhancing factor? , 2011, Appetite.

[7]  M. Cawthorne,et al.  Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids , 2010, FEBS letters.

[8]  H. Parker,et al.  Molecular mechanisms underlying nutrient-stimulated incretin secretion , 2010, Expert Reviews in Molecular Medicine.

[9]  R. Yoshimoto,et al.  Role of MGAT2 and DGAT1 in the release of gut peptides after triglyceride ingestion. , 2009, Biochemical and biophysical research communications.

[10]  A. Peier,et al.  The antiobesity effects of centrally administered neuromedin U and neuromedin S are mediated predominantly by the neuromedin U receptor 2 (NMUR2). , 2009, Endocrinology.

[11]  I. Kato,et al.  Expression of short-chain fatty acid receptor GPR41 in the human colon. , 2009, Biomedical research.

[12]  W. Cefalu,et al.  Butyrate Improves Insulin Sensitivity and Increases Energy Expenditure in Mice , 2009, Diabetes.

[13]  G. Cresci,et al.  GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. , 2009, Cancer research.

[14]  Hitomi Maruta,et al.  Effects of Acetate on Lipid Metabolism in Muscles and Adipose Tissues of Type 2 Diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) Rats , 2009, Bioscience, biotechnology, and biochemistry.

[15]  Masashi Yanagisawa,et al.  Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41 , 2008, Proceedings of the National Academy of Sciences.

[16]  H. Raybould,et al.  CCK1 receptor is essential for normal meal patterning in mice fed high fat diet , 2007, Physiology & Behavior.

[17]  H. Yamashita,et al.  Improvement of Obesity and Glucose Tolerance by Acetate in Type 2 Diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) Rats , 2007, Bioscience, biotechnology, and biochemistry.

[18]  T. Kadowaki,et al.  Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice. , 2006, Biochemical and biophysical research communications.

[19]  T. Iwanaga,et al.  Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine , 2006, Cell and Tissue Research.

[20]  Ki-Choon Choi,et al.  Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. , 2005, Endocrinology.

[21]  S. Mulvihill,et al.  A conscious mouse model of gastric ileus using clinically relevant endpoints , 2005, BMC gastroenterology.

[22]  R. Kedzierski,et al.  Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Parmentier,et al.  Functional Characterization of Human Receptors for Short Chain Fatty Acids and Their Role in Polymorphonuclear Cell Activation* , 2003, Journal of Biological Chemistry.

[24]  S. Dowell,et al.  The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids* , 2003, The Journal of Biological Chemistry.

[25]  C. Malbert,et al.  Ileal short-chain fatty acids inhibit gastric motility by a humoral pathway. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[26]  K. Wada,et al.  Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice. , 2000, American journal of physiology. Endocrinology and metabolism.

[27]  J. Galmiche,et al.  Short-chain fatty acids modify colonic motility through nerves and polypeptide YY release in the rat. , 1998, American journal of physiology. Gastrointestinal and liver physiology.

[28]  E. N. Bergman.  Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. , 1990, Physiological reviews.

[29]  G. Macfarlane,et al.  Short chain fatty acids in human large intestine, portal, hepatic and venous blood. , 1987, Gut.

[30]  R. Reeves,et al.  Sodium butyrate inhibits histone deacetylation in cultured cells , 1978, Cell.

[31]  M. Bohlooly-y,et al.  Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. , 2011, American journal of physiology. Endocrinology and metabolism.

[32]  H. Raybould,et al.  CCK(1) receptor is essential for normal meal patterning in mice fed high fat diet. , 2007, Physiology & behavior.