Enterocyte superoxide dismutase 2 deletion drives obesity

Oihane Garcia-Irigoyen; Fabiola Bovenga; Marilidia Piglionica; Elena Piccinin; Marica Cariello; Maria Arconzo; Claudia Peres; Paola Antonia Corsetto; Angela Maria Rizzo; Marta Ballanti; Rossella Menghini; Geltrude Mingrone; Philippe Lefebvre; Bart Staels; Takuji Shirasawa; Carlo Sabbà; Gaetano Villani; Massimo Federici; Antonio Moschetta

doi:10.1016/j.isci.2021.103707

Enterocyte superoxide dismutase 2 deletion drives obesity

iScience. 2021 Dec 27;25(1):103707. doi: 10.1016/j.isci.2021.103707. eCollection 2022 Jan 21.

Authors

Oihane Garcia-Irigoyen¹, Fabiola Bovenga¹, Marilidia Piglionica¹, Elena Piccinin^{1

2}, Marica Cariello¹, Maria Arconzo¹, Claudia Peres¹, Paola Antonia Corsetto³, Angela Maria Rizzo³, Marta Ballanti⁴, Rossella Menghini⁵, Geltrude Mingrone^{6

7

8}, Philippe Lefebvre⁹, Bart Staels⁹, Takuji Shirasawa¹⁰, Carlo Sabbà¹, Gaetano Villani², Massimo Federici^{4

5}, Antonio Moschetta^{1

11}

Affiliations

¹ Clinica Medica "Cesare Frugoni", Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124 Bari, Italy.
² Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124 Bari, Italy.
³ Department of Pharmacological and Biomolecular Sciences, University of Milan, Via D. Trentacoste 2, 20133 Milan, Italy.
⁴ Center for Atherosclerosis, Policlinico Tor Vergata, 00133 Rome, Italy.
⁵ Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
⁶ Department of Internal Medicine, Catholic University, Rome, Italy.
⁷ Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
⁸ Diabetes and Nutritional Sciences, Hodgkin Building, Guy's Campus, King's College London, London, UK.
⁹ Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
¹⁰ Department of Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
¹¹ IRCCS Istituto Tumori "Giovanni Paolo II", Viale O. Flacco 65, 70124 Bari, Italy.

Abstract

Compelling evidence support an involvement of oxidative stress and intestinal inflammation as early events in the predisposition and development of obesity and its related comorbidities. Here, we show that deficiency of the major mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) in the gastrointestinal tract drives spontaneous obesity. Intestinal epithelium-specific Sod2 ablation in mice induced adiposity and inflammation via phospholipase A2 (PLA2) activation and increased release of omega-6 polyunsaturated fatty acid arachidonic acid. Remarkably, this obese phenotype was rescued when fed an essential fatty acid-deficient diet, which abrogates de novo biosynthesis of arachidonic acid. Data from clinical samples revealed that the negative correlation between intestinal Sod2 mRNA levels and obesity features appears to be conserved between mice and humans. Collectively, our findings suggest a role of intestinal Sod2 levels, PLA2 activity, and arachidonic acid in obesity presenting new potential targets of therapeutic interest in the context of this metabolic disorder.

Keywords: Lipid; Molecular physiology; Obesity medicine.