Obesity and beyond: p38 signaling and organ communication in cardiac and adipose tissue pathophysiology

• Autores: Rafael Romero Becerra
• Directores de la Tesis: Guadalupe Sabio Buzo (dir. tes.), Ivana Nikolić (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2023
• Idioma: inglés
• Número de páginas: 234
• Títulos paralelos:
  • Más allá de la obesidad: señalización de p38 y comunicación entre órganos en la fisiopatología del tejido adiposo y cardiaco
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Obesity and cardiovascular disease (CVD) remain one of the most significant global public health challenges of our time, and their incidence is also expected to grow in the coming decades. CVDs continue to be the leading cause of death globally, regardless of continuous efforts to prevent and curb them. Obesity is the most common metabolic disorder worldwide and its prevalence has reached pandemic proportions. Both diseases are closely related, with obesity contributing directly to the development of CVDs. Adipose tissue dysfunction during obesity directly affects CVD development, including heart failure, in part due to altered secretion of several adipokines and lipidic metabolites that affect cardiac function. Stress-activated p38 kinases have been involved in both, metabolic and cardiac disease, making them a potential target for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by the upstream kinases MKK3 and MKK6. To further elucidate the role of the p38 pathway in cardiac physiology, this work explored the impact of MKK6 deficiency on cardiac hypertrophy and arrhythmia, particularly ventricular fibrillation. The results obtained indicate that MKK6 deficiency induces hyperactivation of the MKK3-p38γ/δ pathway, leading to cardiac hypertrophy through the activation of mTOR. Additionally, p38γ/δ activation promoted susceptibility to stress-induced malignant ventricular arrhythmias by increased phosphorylation of RyR2 and delocalization of the Kv4.3 channel. This was concomitant with sarcoplasmic reticulum Ca2+ leak, action potential duration prolongation, and stress-triggered arrhythmias. The existing evidence regarding the role of the p38 pathway in adipose tissue physiology indicates that this pathway is differently regulated in each adipose tissue depot, with each protein kinase of the pathway having specific functions. Our results show that, upon high-fat diet feeding, global deficiency of MKK6 in adipose tissue promoted increased body weight gain, together with increased food intake and plasma and white adipose tissue levels of agouti-related peptide (AgRP). In contrast, deletion of MKK6 restricted to brown adipocytes led to an opposite phenotype with reduced body weight gain due to increased energy expenditure and brown adipose tissue temperature. Single-nucleus transcriptomic analysis corroborated that MKK6 deletion promoted an increased expression of AgRP in adipocyte progenitor cells within the white adipose tissue, while it caused changes in the populations of brown adipocytes and an upregulation of genes involved in alternative thermogenic mechanisms in brown adipose tissue. Finally, our results show that obesity is associated with a reduced expression of peroxisomeproliferator- activated receptor-γ coactivator-1α (PGC1α) in adipose tissue from mice and humans and that depletion of PGC1α in adipose tissue promotes mitochondrial dysfunction, a hallmark of adipose tissue dysfunction during obesity. Adipose tissue mitochondrial dysfunction due to lack of PGC1α did not lead to obesity or obesity-related comorbidities, but promoted dilated cardiomyopathy, with alteration of several plasma proteins potentially mediating a deleterious adipose tissue–heart communication. The results of this dissertation provide new insights into the role of the poorly investigated p38γ/δ kinases in cardiac pathology and further evince a differential role of the p38 pathway in adipose tissue physiology and obesity susceptibility. Furthermore, they also present a previously unrecognized role of adipose tissue mitochondrial dysfunction in the promotion of obesity-related cardiomyopathy, including the alteration of several obesity-associated plasma proteins and metabolites