1. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue
- Author
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Massimo Federici, Roberta Bernardini, Federico Iacovelli, Stefano Rufini, Riccardo Turchi, Maria Zingariello, Raffaella Faraonio, Mattia Falconi, Lorenzo De Angelis, Katia Aquilano, Fiorella Piemonte, Giulio Guidobaldi, Piergiorgio La Rosa, Daniele Lettieri-Barbato, Simone Carotti, Maria Francesconi, Maurizio Mattei, Sergio Morini, Flavia Tortolici, Viviana Casagrande, Turchi, R, Tortolici, F, Guidobaldi, G, Iacovelli, F, Falconi, M, Rufini, S, Faraonio, R, Casagrande, V, Federici, M, De Angelis, L, Carotti, S, Francesconi, M, Zingariello, M, Morini, S, Bernardini, R, Mattei, M, La Rosa, P, Piemonte, F, Lettieri-Barbato, D, and Aquilano, K.
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,diabetes mellitus, type 2 ,Friedreich ataxia ,insulin resistance ,Immunology ,Adipose tissue ,GPX4 ,Biochemistry ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Adipocyte ,Brown adipose tissue ,medicine ,lcsh:QH573-671 ,Settore BIO/10 ,biology ,lcsh:Cytology ,Lipid metabolism ,Cell Biology ,Biological sciences ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,type 2 ,Adipogenesis ,diabetes mellitus ,Frataxin ,biology.protein ,Thermogenesis ,030217 neurology & neurosurgery - Abstract
Decreased expression of mitochondrial frataxin (FXN) causes Friedreich’s ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
- Published
- 2020