The role of brown fat in Friedreich's Ataxia

Friedreich’s ataxia (FRDA) is a genetic disorder with an incidence of 1:50 000 European people, caused by the decreased in the expression level of the mitochondrial protein frataxin (FXN). FRDA is an autosomal recessive neurodegenerative pathology characterized by systemic clinical picture presenting heart disease and type 2 diabetes mellitus (T2D). We focused on brown adipose tissue (BAT), a mitochondria-rich and anti-diabetic tissue involved in thermoregulation and maintenance of energy balance. We have used a commercially available mouse model of FRDA (FXN knockin/knock-out, KIKO mouse). Firstly, by evaluating important body metabolic parameters, we found that KIKO mice have a significant increase of triglycerides and cholesterol levels, higher level of serum leptin and lower oxygen consumption (VO₂) than WT mice, hinting a diabetic-like profile. In BAT of KIKO mice we found higher dimension of lipid droplets compared to WT, accompanied by a reduction of protein kinase A (PKA) and lipase activity, suggesting an altered lipolysis. Mitochondria isolated from BAT of KIKO mice display a reduced oxygen consumption and transmission electron microscopy analysis highlights altered mitochondrial structure in the number and size of cristae. A blunted overexpression of genes of thermogenic and lipolytic pathways as well as of monocarboxylic acid transport and mitochondria was observed through transcriptomic analysis in BAT of KIKO compared to WT mice upon cold exposure, as also confirmed by qRT-PCR analysis. Then by moving on in vitro system we found that primary adipocytes with FXN deficiency have reduced thermogenesis and lipid catabolism, confirming the results observed in KIKO mice. We have tested if supplementation with butyrate might restore FXN expression and BAT function ultimately halting disease progression. Butyrate is a physiologically produced short chain fatty acid functioning as inhibitor of class I and II histone deacetylases. Butyrate also plays a pivotal role in cell proliferation, differentiation, energy metabolism as well as pathogenesis of T2D, as it enhances lipolysis and thermogenic cascade in adipocytes. We found that the administration of butyrate in the diet restores locomotor activity and reduces the triglyceride and cholesterol levels in KIKO mice. Our data underline BAT dysfunction in FRDA and propose BAT as a good target in order to counteract metabolic complications in FRDA and butyrate as possible treatment for FRDA patients.