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Category: Publications (Page 2 of 18)

Protein Kinase D2 modulates hepatic insulin sensitivity in male mice

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.

PKD2 controls insulin signaling in the liver at the level of IRS1.

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 (PKD2ΔHep) 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 PKD2ΔHep 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 PKD2ΔHep 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 PKD2ΔHep 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 PKD2ΔHep 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.

p38α kinase governs muscle strength through PGC1α in mice

Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A. Dumesic, Sarah E. Wilensky, Elena RodríguezLuis Leiva-VegaAinoa CaballeroMarta 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 p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.

Higher muscle strength in p38αMCK-KO mice (Image: Alfonso Mora).

Methods: we conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α 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 p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α 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 p38α and PGC1α 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.

Remodeling p38 signaling in muscle controls locomotor activity via IL-15

Cintia Folgueira, Leticia Herrera-Melle, Juan Antonio López, Victor Galvan-Alvarez, Marcos Martin-Rincon, María Isabel Cuartero, Alicia García-Culebras, Phillip A. Dumesic, Elena Rodríguez, Luis Leiva-Vega, Marta León, Begoña Porteiro, Cristina Iglesias, Jorge L. Torres, Lourdes Hernández-Cosido, Clara Bonacasa, Miguel Marcos, María Ángeles Moro, Jesús Vázquez, Jose A. L. Calbet, Bruce M. Spiegelman, Alfonso Mora & Guadalupe Sabio.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health.

Active p38γ increases locomotor activity (Image: Cintia Folgueira).

Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases.

These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

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