Category: Publications (Page 3 of 19)

The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk

02/12/2024 / Sabio lab

M. Pilar Valdecantos, Laura Ruiz, Cintia Folgueira, Patricia Rada, Beatriz Gomez-Santos, Maite Solas, Ana B. Hitos, Joss Field, Vera Francisco, Carmen Escalona-Garrido, Sebastián Zagmutt, María Calderon-Dominguez, Paula Mera, Irma Garcia-Martinez, Elsa Maymó-Masip, Diana Grajales, Rosa Alen, Alfonso Mora, Neira Sáinz, Irene Vides-Urrestarazu, Nuria Vilarrasa, José M. Arbones-Mainar, Carlos Zaragoza, María J. Moreno-Aliaga, Patricia Aspichueta, Sonia Fernández-Veledo, Joan Vendrell, Dolors Serra, Laura Herrero, Renate Schreiber, Rudolf Zechner, Guadalupe Sabio, David Hornigold, Cristina M. Rondinone, Lutz Jermutus, Joseph Grimsby & Ángela M. Valverde

Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications.

Brown adipose tissue temperature after G49 administration in mice lacking FGF21 (Image: Cintia Folgueira).

Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss. Elevation of OXM, under basal and postprandial conditions, and similar metabolic adaptations after G49 treatment were found in plasma from patients with obesity early after metabolic bariatric surgery.

These results identify G49 as a potential pharmacological alternative sharing with bariatric surgery hormonal and metabolic pathways.

Nat Commun (2024); 15: 10342.

Protein Kinase D2 modulates hepatic insulin sensitivity in male mice

15/10/2024 / Sabio lab

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 (PKD2^ΔHep) and PKD2^fl/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^ΔHep 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^ΔHep 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^ΔHep male mice displayed improved glucose and pyruvate tolerance, as well as higher peripheral insulin tolerance and enhanced hepatic insulin signaling compared to control PKD2^fl/fl mice. Despite of a remodeling of hepatic lipid metabolism in HFD-fed PKD2^ΔHep 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.

Mol Metab. 2024; 102045.

p38α kinase governs muscle strength through PGC1α in mice

07/10/2024 / Sabio lab

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 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, p38α^MCK-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.

Acta Physiol (Oxf) 2024; 3:e14234.