Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model

Riccardo Turchi; Francesca Sciarretta; Veronica Ceci; Marta Tiberi; Matteo Audano; Silvia Pedretti; Concetta Panebianco; Valentina Nesci; Valerio Pazienza; Alberto Ferri; Simone Carotti; Valerio Chiurchiù; Nico Mitro; Daniele Lettieri-Barbato; Katia Aquilano

doi:10.1016/j.isci.2023.107713

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model

iScience. 2023 Aug 28;26(10):107713. doi: 10.1016/j.isci.2023.107713. eCollection 2023 Oct 20.

Authors

Riccardo Turchi¹, Francesca Sciarretta², Veronica Ceci³, Marta Tiberi⁴, Matteo Audano⁵, Silvia Pedretti⁵, Concetta Panebianco⁶, Valentina Nesci^{7

8}, Valerio Pazienza⁶, Alberto Ferri^{8

9}, Simone Carotti^{10

11}, Valerio Chiurchiù^{4

9}, Nico Mitro^{5

12}, Daniele Lettieri-Barbato^{1

2}, Katia Aquilano¹

Affiliations

¹ Department Biology, University of Rome Tor Vergata, Rome, Italy.
² IRCCS Fondazione Santa Lucia, Rome, Italy.
³ PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata, Rome, Italy.
⁴ Laboratory of Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Rome, Italy.
⁵ DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
⁶ Gastroenterology Unit Fondazione IRCSS "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG)-Italy.
⁷ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
⁸ Division of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy.
⁹ Institute of Traslational Pharmacology, IFT-CNR, Rome, Italy.
¹⁰ Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
¹¹ Predictive Molecular Diagnostics, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
¹² Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.

Abstract

Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.

Keywords: Biological sciences; Natural sciences; Neuroscience; Pharmacology.