title: Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation.
abstract: Short-chain fatty acids (SCFAs) are the main products of dietary fiber fermentation and are believed to drive the fiber-related prevention of the metabolic syndrome. Here we show that dietary SCFAs induce a peroxisome proliferator-activated receptor-γ (PPARγ)-dependent switch from lipid synthesis to utilization. Dietary SCFA supplementation prevented and reversed high-fat diet-induced metabolic abnormalities in mice by decreasing PPARγ expression and activity. This increased the expression of mitochondrial uncoupling protein 2 and raised the AMP-to-ATP ratio, thereby stimulating oxidative metabolism in liver and adipose tissue via AMPK. The SCFA-induced reduction in body weight and stimulation of insulin sensitivity were absent in mice with adipose-specific disruption of PPARγ. Similarly, SCFA-induced reduction of hepatic steatosis was absent in mice lacking hepatic PPARγ. These results demonstrate that adipose and hepatic PPARγ are critical mediators of the beneficial effects of SCFAs on the metabolic syndrome, with clearly distinct and complementary roles. Our findings indicate that SCFAs may be used therapeutically as cheap and selective PPARγ modulators.
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Netherlands Consortium for Systems Biology, Amsterdam, the Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: den Besten
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Top Institute Food and Nutrition, Wageningen, the Netherlands.
authors.forename: Aycha
authors.initials: A
authors.lastname: Bleeker
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Gerding
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Netherlands Consortium for Systems Biology, Amsterdam, the Netherlands Top Institute Food and Nutrition, Wageningen, the Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: van Eunen
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Netherlands Consortium for Systems Biology, Amsterdam, the Netherlands Top Institute Food and Nutrition, Wageningen, the Netherlands Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Netherlands Consortium for Systems Biology, Amsterdam, the Netherlands Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Reijngoud
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics and Systems Biology, Center for Energy Metabolism and Ageing, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Netherlands Consortium for Systems Biology, Amsterdam, the Netherlands b.m.bakker01@umcg.nl.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bakker
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D005232:Fatty Acids, Volatile / Q000008:administration & dosage* / Q000494:pharmacology; D007333:Insulin Resistance; D007473:Ion Channels / Q000502:physiology; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000502:physiology; D009765:Obesity / Q000517:prevention & control*; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000502:physiology*; D000071246:Uncoupling Protein 2
chemical_list: D005232:Fatty Acids, Volatile; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047495:PPAR gamma; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases