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

Abstract

Friedreichs ataxia (FA) is a genetic neurodegenerative disease caused by mutation in FXN gene 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 an in vitro model 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 in in vitro and in vivo models. 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.