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

Author:

Turchi Riccardo,Sciarretta Francesca,Tiberi Marta,Audano Matteo,Pedretti Silvia,Panebianco Concetta,Nesci Valentina,Pazienza Valerio,Ferri Alberto,Carotti Simone,Chiurchiù Valerio,Mitro Nico,Lettieri-Barbato DanieleORCID,Aquilano KatiaORCID

Abstract

ABSTRACTFriedreich’s ataxia (FA) is a genetic neurodegenerative disease caused by mutation inFXNgene encoding for the mitochondrial protein frataxin (FXN). Patients with FA display an increased risk of developing diabetes that may aggravate disease prognosis. Recent studies have indicated that in addition to increased visceral adiposity, FA patients undergo a low-grade inflammatory state. The expansion of white adipose tissue (WAT) plays a fundamental role in the development of type 2 diabetes as it becomes insulin-resistant and a source of inflammatory molecules (adipokines). In this work, we have characterized visceral WAT (vWAT) at metabolic and immunological level in a murine FA model (KIKO) to test whether dysfunction of vWAT could be involved in FA metabolic complications. Through RNAseq analyses we found an alteration of inflammatory, angiogenesis and fibrosis genes in vWAT of KIKO mice. We also found other diabetes-related hallmarks such as increased lipid droplet size, immune cell infiltration and increased expression of pro-inflammatory cytokines. In addition, by targeted metabolomics we disclosed a raise in lactate production, an event usually associated with obesity and diabetes and that triggers activation of vWAT resident macrophages. To reproduce anin vitromodel of FA, we downregulated FXN protein in cultured white adipocytes and recapitulated the diabetes-like features observed in vWAT. Real time monitoring of adipocyte metabolism evidenced metabolic rewiring towards glycolysis according to increased lactate production. Analysis of fecal samples revealed a reduction of some butyrate-producing bacteria in KIKO mice. As this microbiota derived short-chain fatty was demonstrated to exert anti-diabetic function, we fed KIKO mice with a butyrate-enriched diet for 16 weeks. This dietary approach limited vWAT alterations and mitigated other diabetes-like signatures both inin vitroandin vivomodels.In conclusion, this study identified vWAT as an important player in the onset of metabolic complications typical of FA and suggests butyrate as safe and promising adjuvant tool to treat metabolic complications in FA.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3