title: A Role for Timp3 in Microbiota-Driven Hepatic Steatosis and Metabolic Dysfunction.
abstract: The effect of gut microbiota on obesity and insulin resistance is now recognized, but the underlying host-dependent mechanisms remain poorly undefined. We find that tissue inhibitor of metalloproteinase 3 knockout (Timp3(-/-)) mice fed a high-fat diet exhibit gut microbiota dysbiosis, an increase in branched chain and aromatic (BCAA) metabolites, liver steatosis, and an increase in circulating soluble IL-6 receptors (sIL6Rs). sIL6Rs can then activate inflammatory cells, such as CD11c(+) cells, which drive metabolic inflammation. Depleting the microbiota through antibiotic treatment significantly improves glucose tolerance, hepatic steatosis, and systemic inflammation, and neutralizing sIL6R signaling reduces inflammation, but only mildly impacts glucose tolerance. Collectively, our results suggest that gut microbiota is the primary driver of the observed metabolic dysfunction, which is mediated, in part, through IL-6 signaling. Our findings also identify an important role for Timp3 in mediating the effect of the microbiota in metabolic diseases.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Mavilio
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Marchetti
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Research Unit for Multi-Factorial Diseases, Obesity and Diabetes Scientific Directorate, Bambino Gesù Children Hospital, 00146 Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Fabrizi
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Department of Internal Medicine I, University Hospital Aachen, 52074 Aachen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Stöhr
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Marino
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Casagrande
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Fiorentino
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Cardellini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Department of Internal Medicine I, University Hospital Aachen, 52074 Aachen, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Kappel
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00173 Rome, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.affiliation: INSERM U1048, Université Paul Sabatier, IMC, 31432 Toulouse, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Garret
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00173 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauriello
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Farcomeni
authors.affiliation: Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Remy
authors.initials: R
authors.lastname: Burcelin
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Menghini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. Electronic address: federicm@uniroma2.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D064806:Dysbiosis / Q000378:metabolism / Q000473:pathology; D005234:Fatty Liver / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D000069196:Gastrointestinal Microbiome / Q000502:physiology; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008659:Metabolic Diseases / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000502:physiology*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D019717:Tissue Inhibitor of Metalloproteinase-3; D005947:Glucose