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A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis

C. Escande,K. Cal,A. Leyva,Jorge Rodríguez-Duarte,Santiago Ruiz,Leonardo Santos,Lucía Colella,M. Ingold,Cecilia Vilaseca,Germán Galliussi,Lucía Ziegler,Thais R. Peclat,Mariana Bresque,Rachel M Handy,R. King,L. M. Dos Reis,Camila Espasandín,P. Breining,R. Dapueto,Andrés López,Katie L. Thompson,Guillermo Agorrody,E. DeVallance,Ethan M Meadows,Sara E. Lewis,G. Barbosa,Leonardo Osbourne Lai de Souza,Marina Santos Chichierchio,Valeria Valez,Adrián Aicardo,Paola Contreras,M. Vendelbo,S. Jakobsen,A. Kamaid,W. Porcal,A. Calliari,J. Verdes,Jianhai Du,Yekai Wang,J. Hollander,T. White,R. Radi,G. Moyna,C. Quijano,R. O’Doherty,P. Moraes-Vieira,G. Holloway,Roberta Leonardi,M. Mori,Juliana Camacho-Pereira,E. Kelley,R. Durán,G. López,C. Batthyány,E. Chini

Published 2023 in Research Square

ABSTRACT

Abstract Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

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