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
Laboratory of Metabolic Diseases and Aging, Institut Pasteur Montevideo, Uruguay.
Unidad Biofísica, Departamento de Biociencias, Facultad de Veterinaria, Udelar, Uruguay.
Res Sq. 2023 Jul 12:rs.3.rs-3101395. doi: 10.21203/rs.3.rs-3101395/v1.
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.
肥胖相关的II型糖尿病（糖尿病型肥胖症）已大幅增加全球发病率和死亡率。以前，古老药物水杨酸盐显示出治疗II型糖尿病的前景，但因其高剂量需求而无法用于临床。在本研究中，我们展示了一种水杨酸盐的硝基烯烃衍生物，即5-（2-硝基乙烯基）水杨酸（SANA），该分子在饮食诱导的肥胖症（DIO）中具有前所未有的有益作用。SANA降低DIO、肝脏脂肪变性和胰岛素抵抗的剂量比水杨酸盐低40倍。从机制上讲，SANA刺激线粒体呼吸并增加脂肪组织中依赖肌酸的能量消耗。事实上，肌酸的消耗导致SANA作用丧失。此外，我们发现SANA与肌酸激酶CKMT1/2结合，下调CKMT1会干扰SANA的作用。总之，这些数据表明SANA是脂肪组织中依赖肌酸的能量消耗和产热的一流激活剂，并成为治疗糖尿病型肥胖症的候选药物。
