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.

Mavilio, M., Marchetti, V., Fabrizi, M., Stöhr, R., Marino, A., Casagrande, V., et al. (2016). A Role for Timp3 in Microbiota-Driven Hepatic Steatosis and Metabolic Dysfunction. CELL REPORTS [10.1016/j.celrep.2016.06.027].

A Role for Timp3 in Microbiota-Driven Hepatic Steatosis and Metabolic Dysfunction

MARCHETTI, VALENTINA;FABRIZI, MARTA;MARINO, ARIANNA;FIORENTINO, LOREDANA;CARDELLINI, MARINA;MONTELEONE, IVAN;MAURIELLO, ALESSANDRO;MONTELEONE, GIOVANNI;Farcomeni, A;MENGHINI, ROSSELLA;FEDERICI, MASSIMO
Conceptualization
2016-06-29

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.
29-giu-2016
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/09 - MEDICINA INTERNA
Settore MED/08 - ANATOMIA PATOLOGICA
English
FP7-FLORINASH grant agreement HEALTH-F2-2009-241913
Mavilio, M., Marchetti, V., Fabrizi, M., Stöhr, R., Marino, A., Casagrande, V., et al. (2016). A Role for Timp3 in Microbiota-Driven Hepatic Steatosis and Metabolic Dysfunction. CELL REPORTS [10.1016/j.celrep.2016.06.027].
Mavilio, M; Marchetti, V; Fabrizi, M; Stöhr, R; Marino, A; Casagrande, V; Fiorentino, L; Cardellini, M; Kappel, B; Monteleone, I; Garret, C; Mauriello, A; Monteleone, G; Farcomeni, A; Burcelin, R; Menghini, R; Federici, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/159207
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