Regulación de la actividad del tejido adiposo por la isoforma de calcineurina A CnAB1

Abstract

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 24-11-2021Esta tesis tiene embargado el acceso al texto completo hasta el 24-05-2023The phosphatase calcineurin (Cn) plays a relevant role in many physiological and pathological processes, including heart diseases. Alternative splicing of CnAβ mRNA produces the CnAβ1 variant, which is evolutionarily conserved in vertebrates. CnAβ1 presents a unique C-terminal domain that is not present in other CnA isoforms and confers this variant singular properties. In contrast to other CnA isoforms, CnAβ1 overexpression improves cardiac function after myocardial infarction in an mTORdependent manner. However, the physiological role of this calcineurin variant in adult mice is virtually unknown. To investigate the role of CnAβ1 in vivo in the context of metabolism we generated a global knockout mouse for this calcineurin variant (CnAβ1Δi12 mice). We found that CnAβ1Δi12 mice fed with a high fat diet (HFD) had reduced body weight compared to wild-type animals. This was accompanied by smaller adipocytes within epidydimal white adipose tissue (eWAT). CnAβ1Δi12 mice showed a consistent metabolic phenotype associated with the decrease of fat mass. CnAβ1Δi12 mice had more body and brown adipose tissue (BAT) temperature due to an increase in nonshivering thermogenesis in BAT. The histological analysis of BAT revealed a reduction in lipid droplets size and RT-qPCR demonstrated high expression of genes related to thermogenesis, lipolysis, fatty acid oxidation and mitochondrial biogenesis. We also observed evident browning of eWAT when mice were fed with HFD. In addition, CnAβ1Δi12 mice showed an increase in adipogenic mRNA markers in brown and white adipocytes. We found an increase in PGC1α protein levels in BAT, the main regulator of mitochondrial biogenesis. Thermoneutral exposure of CnAβ1Δi12 mice largely recovered the phenotype demonstrating that CnAβ1 is necessary for proper temperature regulation. These results suggest that CnAβ1 is a novel regulator of non-shivering thermogenesis and WAT browning and that inhibition of CnAβ1 is a promising strategy to treat obesit