The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans.

Autor:	Tirosh A; Dalia and David Arabov Endocrinology and Diabetes Research Center, Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel. ghotamis@hsph.harvard.edu amir.tirosh@sheba.health.gov.il.; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Calay ES; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Tuncman G; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Claiborn KC; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Inouye KE; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Eguchi K; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Alcala M; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Rathaus M; Dalia and David Arabov Endocrinology and Diabetes Research Center, Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel., Hollander KS; Dalia and David Arabov Endocrinology and Diabetes Research Center, Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel.; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel., Ron I; Dalia and David Arabov Endocrinology and Diabetes Research Center, Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel., Livne R; Dalia and David Arabov Endocrinology and Diabetes Research Center, Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel., Heianza Y; Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA., Qi L; Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA., Shai I; Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Garg R; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, 5555 Ponce de Leon Boulevard, Coral Gables, FL, USA., Hotamisligil GS; Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA. ghotamis@hsph.harvard.edu amir.tirosh@sheba.health.gov.il.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2019 Apr 24; Vol. 11 (489).
DOI:	10.1126/scitranslmed.aav0120
Abstrakt:	The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid-binding protein 4 (FABP4). Fabp4 -deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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