Citations 2
A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis
Cal, Karina, Leyva, Alejandro , Rodriguez-Duarte, Jorge, Ruiz, Santiago , Santos, Leonardo, Colella, Lucía, Ingold, Mariana , Vilaseca, Cecilia, Galliussi, Germán , Handy, Rachel, Reis, Larissa Menezes dos , Espasandín, Camila , Dapueto, Rosina , Thompson, Katie, Agorrody, Guillermo , DeVallance, Evan , Meadows, Ethan , Barbosa, Gabriele Santana, Souza, Leonardo Osbourne Lai de , Chichierchio, Marina Santos , Valez, Valeria , Aicardo, Adrián , Jakobsen, Steen, Kamaid, Andrés , Porcal, Williams , Calliari, Aldo , Wang, Yekai, Hollander, John M. , White, Thomas A. , Radí, Rafael , O’Doherty, Robert M. , Holloway, Graham P. , Kelley, Eric, Chini, Eduardo N. , Peclat, Thais R , Dos Reis, Larissa Menezes , Thompson, Katie L., Chichierchio, Marina Santos , Aicardo, Adrián , Contreras, Paola , White, Thomas A , Quijano, Celia , Moraes-Vieira, Pedro , Mori, Marcelo A , Lopez, Gloria V , Batthyány, Carlos , Chini, Eduardo Nunes , Escande, Carlos , Rodriguez‐Duarte, Jorge , Ziegler, Lucía , Peclat, Thais , Bresque, Mariana , Handy, Rachel, King, Rachel, Breining, Peter , Lopez, Andres, Lewis, Sara E. , Vendelbo, Mikkel Holm , Verdes, José Manuel , Du, Jianhai , Moyna, Guillermo , Leonardi, Roberta , Camacho-Pereira, Juliana , Durán, Rosario
No container title available | July 12, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
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.
Soluble SorCS1 binds the insulin receptor to enhance insulin sensitivity
Kjølby, Mads , Wellner, Niels, Sørensen, Karen Marie Juul, Gjessing, Anette, Vittrup, Dorthe Maria , Rotman, Maarten , Thotakura, Gangadaar, Hermey, Guido , Madsen, Peder, Prasad, Rashmi B. , Parlevliet, Edwin T., Madsen, Andreas Nygaard , Breining, Peter , Pedersen, Karen, Januliene, Dovile , Manavalan, Arulmani , Vægter, Christian Bjerggaard , Thirup, Søren , Asplund, Olof , Rensen, Patrick C.N. , Holst, Birgitte , Andersen, Olav M. , Moller, Arne, Hansen, Torben , Nykjær, Anders
No container title available | January 28, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Type 2 diabetes has reached endemic proportions and is a substantial burden for the affected patients and the society. Along with lifestyle factors, a number of genetic loci predisposing to type 2 diabetes have been identified, including SORCS1 that encodes the transmembrane receptor SorCS1. The ectodomain of SorCS1 (sol-SorCS1) is shed from plasma membranes but the biological function of this fragment is unknown. Here we show that sol-SorCS1 acts as a high-affinity binding partner for the insulin receptor to stabilize the receptor and increase insulin affinity, protein kinase B activation, and glucose uptake in myocytes. Sol-SorCS1 is liberated from adipocytes, and in diabetic patients the plasma concentration positively correlates with body mass index, but inversely with plasma glucose. In mouse models of insulin resistance, exogenous sol-SorCS1 restored insulin sensitivity. We conclude that sol-SorCS1 increases peripheral insulin sensitivity and propose sol-SorCS1 as a novel insulin sensitizing adipokine and potential antidiabetic agent.