Loza-Valdes Angel, El-Merahbi Rabih, Kassouf Toufic, Demczuk Agnieszka, Reuter Saskia, Viera Jonathan Trujillo, Karwen Till, Noh Minhe, Löffler Mona C, Romero-Becerra Rafael, Torres Jorge L, Marcos Miguel, Sabio Guadalupe, Wojda Urszula, Sumara Grzegorz
Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warszawa, Poland.
Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080, Würzburg, Germany.
Biochem Biophys Res Commun. 2022 Jul 5;612:119-125. doi: 10.1016/j.bbrc.2022.04.070. Epub 2022 Apr 27.
Kinases represent one of the largest druggable families of proteins. Importantly, many kinases are aberrantly activated/de-activated in multiple organs during obesity, which contributes to the development of diabetes and associated diseases. Previous results indicate that the complex between Extracellular-regulated kinase 3 (ERK3) and Mitogen-Activated Protein Kinase (MAPK)-activated protein kinase 5 (MK5) suppresses energy dissipation and promotes fatty acids (FAs) output in adipose tissue and, therefore promotes obesity and diabetes. However, the therapeutic potential of targeting this complex at the systemic level has not been fully explored. Here we applied a translational approach to target the ERK3/MK5 complex in mice. Importantly, deletion of ERK3 in the whole body or administration of MK5-specific inhibitor protects against obesity and promotes insulin sensitivity. Finally, we show that the expression of ERK3 and MK5 correlates with the degree of obesity and that ERK3/MK5 complex regulates energy dissipation in human adipocytes. Altogether, we demonstrate that ERK3/MK5 complex can be targeted in vivo to preserve metabolic health and combat obesity and diabetes.
激酶是最大的可成药蛋白家族之一。重要的是，在肥胖过程中，许多激酶在多个器官中被异常激活/失活，这促进了糖尿病及相关疾病的发展。先前的研究结果表明，细胞外调节激酶3（ERK3）与丝裂原活化蛋白激酶（MAPK）激活的蛋白激酶5（MK5）之间的复合物会抑制脂肪组织中的能量消耗，并促进脂肪酸（FAs）输出，因此会促进肥胖和糖尿病。然而，在全身水平上靶向该复合物的治疗潜力尚未得到充分探索。在此，我们采用转化医学方法在小鼠中靶向ERK3/MK5复合物。重要的是，全身敲除ERK3或给予MK5特异性抑制剂可预防肥胖并提高胰岛素敏感性。最后，我们发现ERK3和MK5的表达与肥胖程度相关，并且ERK3/MK5复合物调节人脂肪细胞中的能量消耗。总之，我们证明了ERK3/MK5复合物在体内可作为靶点，以维持代谢健康并对抗肥胖和糖尿病。
