title: Butyrate Regulates Liver Mitochondrial Function, Efficiency, and Dynamics in Insulin-Resistant Obese Mice.
abstract: Fatty liver, oxidative stress, and mitochondrial dysfunction are key pathophysiological features of insulin resistance and obesity. Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been demonstrated to be protective against insulin resistance and fatty liver. Here, hepatic mitochondria were identified as the main target of the beneficial effect of both butyrate-based compounds in reverting insulin resistance and fat accumulation in diet-induced obese mice. In particular, butyrate and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK-acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Both treatments consistently increased utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of the mitochondrial dynamic toward fusion by butyrate and FBA resulted in the improvement not only of mitochondrial cell energy metabolism but also of glucose homeostasis. In conclusion, butyrate and its more palatable synthetic derivative, FBA, modulating mitochondrial function, efficiency, and dynamics, can be considered a new therapeutic strategy to counteract obesity and insulin resistance.
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Maria Pina
authors.initials: MP
authors.lastname: Mollica
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Mattace Raso
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Gina
authors.initials: G
authors.lastname: Cavaliere
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Trinchese
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Filippo
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Aceto
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Prisco
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pirozzi
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Guida
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Lama
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Crispino
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Tronino
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Vaio
authors.affiliation: Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.|European Laboratory for Investigation of Food Induced Diseases, University of Naples Federico II, Naples, Italy.|CEINGE Advanced Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Berni Canani
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Calignano
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy meli@unina.it.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001823:Body Composition / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002087:Butyrates; D005227:Fatty Acids; C000621902:N-(1-carbamoyl-2-phenyl-ethyl)butyramide; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose