En el marco del 25 aniversario de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), la directora del Grupo de Interacciones Metabólicas del CNIO, Guadalupe Sabio, conversó sobre su carrera veterinaria e investigadora con la jefa del Departamento de Medicamentos Veterinarios de la AEMPS, Consuelo Rubio.
Author: Sabio lab (Page 8 of 62)
Patricia Rada, Elena Carceller-López, Ana B. Hitos, Beatriz Gómez-Santos, Constanza Fernández-Hernández, Esther Re, Julia Pose-Utrilla, Carmelo García-Monzón, Águeda González-Rodríguez, Guadalupe Sabio, Antonia García, Patricia Aspichueta, Teresa Iglesias & Ángela M. Valverde.
Protein kinase D (PKD) family is emerging as relevant regulator of metabolic homeostasis. However, the precise role of PKD2 in modulating hepatic insulin signaling has not been fully elucidated and it is the aim of this study.
PKD inhibition was analyzed for insulin signaling in mouse and human hepatocytes. PKD2 was overexpressed in Huh7 hepatocytes and mouse liver, and insulin responses were evaluated. Mice with hepatocyte-specific PKD2 depletion (PKD2?Hep) and PKD2fl/fl mice were fed a chow (CHD) or high fat diet (HFD) and glucose homeostasis and lipid metabolism were investigated.
PKD2 silencing enhanced insulin signaling in hepatocytes, an effect also found in primary hepatocytes from PKD2?Hep mice. Conversely, a constitutively active PKD2 mutant reduced insulin-stimulated AKT phosphorylation. A more in-depth analysis revealed reduced IRS1 serine phosphorylation under basal conditions and increased IRS1 tyrosine phosphorylation in PKD2?Hep primary hepatocytes upon insulin stimulation and, importantly PKD co-immunoprecipitates with IRS1. In vivo constitutively active PKD2 overexpression resulted in a moderate impairment of glucose homeostasis and reduced insulin signaling in the liver. On the contrary, HFD-fed PKD2?Hep male mice displayed improved glucose and pyruvate tolerance, as well as higher peripheral insulin tolerance and enhanced hepatic insulin signaling compared to control PKD2fl/fl mice. Despite of a remodeling of hepatic lipid metabolism in HFD-fed PKD2?Hep mice, similar steatosis grade was found in both genotypes.
Results herein have unveiled an unknown role of PKD2 in the control of insulin signaling in the liver at the level of IRS1 and point PKD2 as a therapeutic target for hepatic insulin resistance.
Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A. Dumesic, Sarah E. Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M. Spiegelman, Cintia Folgueira, Alfonso Mora & Guadalupe Sabio.
Aims: skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38? in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.
Methods: we conducted our study using male mice (MCK-cre, p38?MCK-KO and PGC1? MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.
Results: our findings highlight the critical involvement of muscle p38? in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38? triggers changes in mitochondrial dynamics through the activation of PGC1?, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38? kinase, PGC1? activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.
Conclusions: this knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38? and PGC1? pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.
