A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.
Carlos EscandeKarina CalAlejandro LeyvaJorge Rodriguez-DuarteSantiago RuizLeonardo SantosLucía ColellaMariana IngoldCecilia VilasecaGerman GalliussiLucía ZieglerEduardo Nunes ChiniMariana BresqueRachel HandyRachel KingLarissa Menezes Dos ReisCamila EspasandinPeter BreiningRosina DapuetoAndres LopezKatie ThompsonGuillermo AgorrodyEvan DeVallanceEthan MeadowsSara LewisGabriele Santana BarbosaLeonardo Osbourne Lai de SouzaMarina Santos ChichierchioValeria ValezAdrian AicardoPaola ContrerasMikkel VendelboSteen JakobsenAndres KamaidWilliams PorcalAldo CalliariJose VerdesJianhai DuYekai WangJohn HollanderThomas A WhiteRafael RadiGuillermo MoynaCelia QuijanoRobert O'DohertyPedro Manoel Mendes de Moraes-VieiraGraham HollowayRoberta LeonardiMarcelo Alves da Silva MoriJuliana Camacho-PereiraEric KelleyRosario DuranGloria V LópezCarlos BatthyanyEduardo Nunes ChiniPublished in: Research square (2023)
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.
Keyphrases
- insulin resistance
- adipose tissue
- high fat diet
- high fat diet induced
- type diabetes
- metabolic syndrome
- glycemic control
- polycystic ovary syndrome
- high dose
- skeletal muscle
- cardiovascular disease
- weight loss
- signaling pathway
- low dose
- weight gain
- big data
- cell proliferation
- body mass index
- machine learning
- emergency department
- electronic health record
- mouse model
- deep learning
- artificial intelligence
- physical activity