Irisin, a unique non-inflammatory myokine in stimulating skeletal muscle metabolism

Exercise offers several benefits for health, including increased lean body mass and heightened energy expenditure, which may be partially attributable to secretory factors known as myokines. Irisin, a recently identified myokine, was shown to increase metabolic rate and mitochondrial content in both myocytes and adipocytes; however, the mechanism(s) of action still remain largely unexplained. This work investigated if irisin functions by acting as an inflammatory myokine leading to cellular stress and energy expenditure. C2C12 myotubes were treated with various concentrations of irisin, TNFAlpha, or IL6 for various durations. Glycolytic and oxidative metabolism, as well as mitochondrial uncoupling, were quantified by measurement of acidification and oxygen consumption, respectively. Metabolic gene and protein expression were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting, respectively. Mitochondrial content was assessed by fluorescent imaging. NFkappaB activity was assessed using an NFkappaB GFP-linked reporter system. Consistent with previous findings, irisin significantly increased expression of several genes including peroxisome proliferator-activated receptor Alpha coactivator-1Alpha (PGC-1Alpha) leading to increased mitochondrial content and oxygen consumption. Despite some similarities between TNFAlpha and irisin treatment, irisin failed to activate the NFkappaB pathway like TNFAlpha, suggesting that irisin may not act as an inflammatory signal. Irisin has several effects on myotube metabolism which appear to be dependent on substrate availability; however, the precise mechanism(s) by which irisin functions in skeletal muscle remain unclear. Our observations support the hypothesis that irisin does not function through inflammatory NFkappaB activation like other myokines (such as TNFAlpha)

PPARalfa atenúa el estrés del retículo endoplasmático inducido por palmitato en células cardíacas humanas por medio de la inducción de la actividad AMPK / PPARalpha attenuates palmitate-induced endoplasmic reticulum stress in human cardiac cells by enhancing AMPK activity

Introducción El estrés del retículo endoplasmático (RE) se ha relacionado con distintas enfermedades cardiovasculares, como la arteriosclerosis y la hipertrofia e insuficiencia cardíacas. Este estrés del RE altera la señalización de la insulina, contribuyendo al desarrollo de la resistencia a la insulina y la diabetes. Diversos estudios han demostrado que PPARalfa inhibe el estrés del RE, por lo que el objetivo de este trabajo consistió en investigar si la activación de este receptor nuclear era capaz de prevenir el estrés del RE inducido por ácidos grasos saturados en células cardíacas, así como los mecanismos implicados. Métodos: Cardiomiocitos humanos AC16 fueron tratados con palmitato en presencia de diferentes activadores e inhibidores de AMPK y PPARalfa. Para los estudios in vivo, ratones macho fueron alimentados con una dieta rica en grasa (HFD). Posteriormente, se determinó la presencia de distintos marcadores de estrés del RE en células cardíacas por medio del análisis de la expresión génica y la acumulación proteica. Resultados: El palmitato y la dieta HFD indujeron el estrés del RE en células cardíacas, pues incrementaron diversos marcadores de este, como son la expresión génica de ATF3, BiP/GRP78 y CHOP, el splicing de XBP1 y la fosforilación de IRE-1α y eIF2alfa. El tratamiento con Wy-14,643, un agonista de PPARalfa, previno el incremento del estrés del RE inducido por palmitato por medio de la activación de la AMPK. Conclusión: Wy-14,643 podría ser útil para prevenir el estrés del RE y las enfermedades cardiovasculares asociadas en pacientes obesos, e incluso durante la cardiomiopatía diabética, por medio de la activación de AMPK

Introduction Endoplasmic reticulum (ER) stress has been linked to several cardiovascular diseases, such as atherosclerosis, heart failure and cardiac hypertrophy. ER stress impairs insulin signalling, thus contributing to the development of insulin resistance and diabetes. Since several studies have reported that PPARalfa may inhibit ER stress, the main aim of this study consisted in investigating whether activation of this nuclear receptor is able to prevent lipid-induced ER stress in cardiac cells, as well as studying the mechanisms involved. Methods: A cardiomyocyte cell line of human origin, AC16, was treated with palmitate in the presence or absence of several AMPK and PPARα pharmacological agonists and antagonists. For the in vivo studies, wild-type male mice were fed a standard diet, or a high-fat diet (HFD), for two months. At the end of the experiments, several ER stress markers were assessed in cardiac cells or in the mice hearts, using real-time RT-PCR and Western-blot analyses. Results: The results demonstrate that both palmitate and the HFD induced ER stress in cardiac cells, since they upregulated the expression (ATF3, BiP/GRP78 and CHOP), splicing (sXBP1), and phosphorylation (IRE-1α and eIF2α) of several ER stress markers. Interestingly, treatment with the PPARalfa agonist Wy-14,643 prevented an increase in the majority of these ER stress markers in human cardiac cells by means of AMPK activation. Conclusion: These data indicate that PPARα activation by Wy-14,643 might be useful to prevent the harmful effects of ER stress and associated cardiovascular diseases in obese patients, and even during diabetic cardiomyopathy, by enhancing AMPK activity

D) ¿Modula el metabolismo lipídico del miocardio la hipertrofia cardíaca? / No disponible

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Differences in the pharmacokinetics of peroxisome proliferator-activated receptor agonists in genetically obese Zucker and sprague-dawley rats: implications of decreased glucuronidation in obese Zucker rats.

Genetically obese Zucker rats exhibit symptoms similar to those of obese patients with insulin-resistance or Type II diabetes; therefore, they have been used as a genetic model to study obesity, as well as a pharmacological model for the discovery of new drugs for the treatment of Type II diabetes and hyperlipidemia. In the present study, we compared the pharmacokinetics of two novel peroxisome proliferator-activated receptor (PPAR) agonists, MRL-I [(2R)-7-[3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy]-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid] and MRL-II [(2R)-7-[3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy]-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid], in obese Zucker and lean Sprague-Dawley rats following a single intravenous administration. The plasma clearance of both MRL-I and MRL-II was significantly lower in obese Zucker rats (4- and 2-fold, respectively) compared with Sprague-Dawley rats, but without any significant change in the volume of distribution, which resulted in a dramatic increase in the half-life (7- and 3-fold, respectively). The reversible in vitro plasma protein binding of [(14)C]MRL-I and [(14)C]MRL-II was comparable in the two strains, approximately 96% bound. The expression levels of uridine diphosphate-glucuronosyltransferases 1A1, 1A6, 2B1, and CYP2C11 and 3A1 mRNA in liver were lower (30-50%) in Zucker compared with Sprague-Dawley rats, as were the liver glutathione S-transferases (70%), quinone reductase (30%), organic anion-transporting protein 2 (80%), and multidrug resistance-associated protein 2 (Mrp2) (50%) mRNA levels. However, Mrp3 mRNA levels were similar in both strains. Consistent with these observations, the intrinsic clearance (CL(int)), calculated from the V(max)/K(m) of glucuronidation of [(14)C]MRL-I and [(14)C]MRL-II in liver microsomes, was approximately 2-fold lower in obese Zucker rats; the K(m) values were comparable in the two strains for both compounds. In conclusion, differences in the pharmacokinetics of two novel PPAR agonists, both cleared, predominantly, by conjugation, were evident in genetically obese Zucker rats compared with Sprague-Dawley rats. These differences were consistent with changes in the mRNA levels of hepatic drug-metabolizing enzymes and transporters. This information should be considered when comparing pharmacokinetic and efficacious doses in the obese Zucker rats, used as a pharmacological model, with those in Sprague-Dawley rats, which are used widely for drug metabolism and toxicology studies.