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      Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults

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          Abstract

          Objective

          The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.

          Design

          To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.

          Results

          Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.

          Conclusions

          These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.

          Trial registration number

          NCT00750438.

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          Most cited references34

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          Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation.

          Short chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are produced at high concentration by bacteria in the gut and subsequently released in the bloodstream. Basal acetate concentrations in the blood (about 100 microm) can further increase to millimolar concentrations following alcohol intake. It was known previously that SCFAs can activate leukocytes, particularly neutrophils. In the present work, we have identified two previously orphan G protein-coupled receptors, GPR41 and GPR43, as receptors for SCFAs. Propionate was the most potent agonist for both GPR41 and GPR43. Acetate was more selective for GPR43, whereas butyrate and isobutyrate were more active on GPR41. The two receptors were coupled to inositol 1,4,5-trisphosphate formation, intracellular Ca2+ release, ERK1/2 activation, and inhibition of cAMP accumulation. They exhibited, however, a differential coupling to G proteins; GPR41 coupled exclusively though the Pertussis toxin-sensitive Gi/o family, whereas GPR43 displayed a dual coupling through Gi/o and Pertussis toxin-insensitive Gq protein families. The broad expression profile of GPR41 in a number of tissues does not allow us to infer clear hypotheses regarding its biological functions. In contrast, the highly selective expression of GPR43 in leukocytes, particularly polymorphonuclear cells, suggests a role in the recruitment of these cell populations toward sites of bacterial infection. The pharmacology of GPR43 matches indeed the effects of SCFAs on neutrophils, in terms of intracellular Ca2+ release and chemotaxis. Such a neutrophil-specific SCFA receptor is potentially involved in the development of a variety of diseases characterized by either excessive or inefficient neutrophil recruitment and activation, such as inflammatory bowel diseases or alcoholism-associated immune depression. GPR43 might therefore constitute a target allowing us to modulate immune responses in these pathological situations.
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            Econometric methods for fractional response variables with an application to 401(k) plan participation rates

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              Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

              The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
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                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                November 2015
                10 December 2014
                : 64
                : 11
                : 1744-1754
                Affiliations
                [1 ]Nutrition and Dietetic Research Group, Section of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital , London, UK
                [2 ]Stable Isotope Biochemistry Laboratory, Scottish Universities Environmental Research Centre, University of Glasgow , Glasgow, UK
                [3 ]Section of Investigative Medicine, Imperial College London, Hammersmith Hospital , London, UK
                [4 ]School of Science, University of the West of Scotland , Hamilton, UK
                [5 ]Institute of Psychological Sciences, University of Leeds , Leeds, UK
                [6 ]Metabolic and Molecular Imaging Research Group, MRC Clinical Science Centre, Imperial College London, Hammersmith Hospital , London, UK
                [7 ]Imperial Clinical Trials Unit, School of Public Health, Imperial College London , London, UK
                [8 ]Department of Food and Nutritional Sciences, University of Reading , Reading, UK
                [9 ]Leatherhead Food Research, Randall's Road Leatherhead , Surrey, UK
                [10 ]Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
                Author notes
                [Correspondence to ] Professor Gary Frost, Nutrition and Dietetic Research Group, Section of Investigative Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, London W12 0NN, UK; g.frost@ 123456imperial.ac.uk

                ESC, AV, AP and DJM contributed equally.

                Article
                gutjnl-2014-307913
                10.1136/gutjnl-2014-307913
                4680171
                25500202
                0170001c-e43b-466f-b6d3-c94978524ec1
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

                History
                : 24 June 2014
                : 5 September 2014
                : 23 September 2014
                Categories
                1506
                1612
                Gut Microbiota
                Original article
                Custom metadata
                unlocked
                press-release

                Gastroenterology & Hepatology
                nutritional supplementation,obesity,gut hormones,appetite,colonic fermentation

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