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

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 ni...

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Main Authors Cal, Karina, Leyva, Alejandro, Rodríguez-Duarte, Jorge, Ruiz, Santiago, Santos, Leonardo, Colella, Lucía, Ingold, Mariana, Vilaseca, Cecilia, Galliussi, German, Ziegler, Lucía, Peclat, Thais R, Bresque, Mariana, Handy, Rachel M, King, Rachel, Dos Reis, Larissa Menezes, Espasandin, Camila, Breining, Peter, Dapueto, Rosina, Lopez, Andrés, Thompson, Katie L, Agorrody, Guillermo, DeVallance, Evan, Meadows, Ethan, Lewis, Sara E, Barbosa, Gabriele Catarine Santana, de Souza, Leonardo Osbourne Lai, Chichierchio, Marina Santos, Valez, Valeria, Aicardo, Adrián, Contreras, Paola, Vendelbo, Mikkel H, Jakobsen, Steen, Kamaid, Andrés, Porcal, Williams, Calliari, Aldo, Verdes, José Manuel, Du, Jianhai, Wang, Yekai, Hollander, John M, White, Thomas A, Radi, Rafael, Moyna, Guillermo, Quijano, Celia, O'Doherty, Robert, Moraes-Vieira, Pedro, Holloway, Graham P, Leonardi, Roberta, Mori, Marcelo A, Camacho-Pereira, Juliana, Kelley, Eric E, Duran, Rosario, Lopez, Gloria V, Batthyány, Carlos, Chini, Eduardo N, Escande, Carlos
Format Journal Article
LanguageEnglish
Published United States 12.07.2023
Subjects
thermogenesis
Adipose tissue
salicylate derivative
creatine
energy expenditure
obesity
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Summary: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 . 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.