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Stress kinases in the regulation of inter-organ communication in obesity comorbidities

Author
Herrera Melle, Leticia
Advisor
Sabio Buzo, Guadalupe; Moral Corral, Alfonso
Entity
UAM. Departamento de Bioquímica; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Date
2021-09-17
Subjects
Biología y Biomedicina / Biología; Medicina
URI
http://hdl.handle.net/10486/699824
Note
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 17-09-2021
Esta tesis tiene embargado el acceso al texto completo hasta el 17-03-2023

Licencia de Creative Commons
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.

Abstract

Obesity is characterized by the excessive fat accumulation that develops when energy intake exceeds energy expenditure. Lifestyle changes have increased the prevalence of obesity, which has become a major health problem. In fact, obesity is a well-known risk factor for several chronic diseases, including type 2 diabetes and the most common type of liver cancer, hepatocellular carcinoma (HCC). Therefore, understanding the mechanisms that lead to the development of obesity comorbidities is paramount to decrease their incidence and mortality. One of the signaling pathways that participate in obesity and its adverse consequences is the stress-activated protein kinases (SAPKs) pathway. These proteins include c-Jun NH2-terminal kinases (JNKs) and p38s. While the role of some SAPKs in obesity and its associated pathologies has been studied, the systemic implications of their activation in specific tissues is starting to be addressed. Our main aim in this thesis is to better understand the participation of SAPKs in inter-organ communication in the context of obesity and its associated diseases. Using a conditional mouse model lacking p38α in striated muscle, we observed that muscle p38α deletion protects mice against high-fat diet (HFD)-induced obesity by increasing energy expenditure. This phenotype is accompanied by an increase in mitochondrial oxidative metabolism in skeletal muscle due to the upregulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Importantly, lack of p38α results in the hyperactivation of p38γ, which improves glucose and energy homeostasis through an increase in locomotor activity, a process in which interleukin-15 (IL-15) might be involved. This effect decreases the risk of developing diabetes and liver steatosis, therefore linking local and systemic manifestations of muscle p38α deficiency. Apart from obesity, the incidence of HCC is also higher in men, and both obesity and male sex are characterized by reduced levels of the adipokine adiponectin. We found that the decrease in plasma adiponectin in males is responsible for their increased liver cancer risk. Testosterone activates JNK in white adipocytes, which inhibits adiponectin secretion. Since adiponectin protects against HCC development through the activation of AMP-activated protein kinase (AMPK) and p38α in the liver, JNK-mediated inhibition of adiponectin secretion increases liver cancer cell proliferation. The results from this thesis provide insight into novel roles of stress signaling in skeletal muscle and white adipose tissue, which regulates inter-organ communication in the context of obesity and its comorbidities, opening new research avenues that might be crucial for the prevention and treatment of these diseases
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  • Trabajos de estudiantes (tesis doctorales, TFMs, TFGs, etc.) [19853]

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All the documents from Biblos-e Archivo are protected by copyrights. Some rights reserved.
Universidad Autónoma de Madrid. Biblioteca
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