Targeting ERK3/MK5 complex for treatment of obesity and diabetes.

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 Extrace...

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Authors: 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
Format: article
Publication Date:2022
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/15738
Online Access:http://hdl.handle.net/20.500.12105/15738
Access Level:Open access
Keyword:Diabetes Mellitus
Protein Serine-Threonine Kinases
Animals
Description
Summary: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.

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