Regular exercise has both immediate and long-lasting benefits on cardiometabolic health, and has been recommended as a cornerstone of treatment in the management of diabetes and cardiovascular ...conditions. Exerkines, which are defined as humoral factors responsive to acute or chronic exercise, have emerged as important players conferring some of the multiple cardiometabolic benefits of exercise. Over the past decades, hundreds of exerkines released from skeletal muscle, heart, liver, adipose tissue, brain, and gut have been identified, and several exerkines (such as FGF21, IL-6, and adiponectin) have been exploited therapeutically as exercise mimetics for the treatment of various metabolic and cardiovascular diseases. Recent advances in metagenomics have led to the identification of gut microbiota, a so-called “hidden” metabolic organ, as an additional class of exerkines determining the efficacy of exercise in diabetes prevention, cardiac protection, and exercise performance. Furthermore, multiomics-based studies have shown the feasibility of using baseline exerkine signatures to predict individual responses to exercise with respect to metabolic and cardiorespiratory health. This review aims to explore the molecular pathways whereby exerkine networks mediate the cardiometabolic adaptations to exercise by fine-tuning inter-organ crosstalk, and discuss the roadmaps for translating exerkine-based discovery into the therapeutic application and personalized medicine in the management of the cardiometabolic disease.
In this review, A. Xu & colleagues describe the molecular pathways whereby exerkine networks mediate the cardiometabolic adaptations to exercise and discuss the potential translation of exerkine-based discovery into therapeutic application and personalized medicine.
Abstract
Aims
Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis ...in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS. Experiments were designed to determine whether or not A-FABP mediates blood–brain barrier (BBB) disruption, and if so, to explore the molecular mechanisms underlying this deleterious effects.
Methods and results
Circulating A-FABP and its cerebral expression were increased in mice after middle cerebral artery occlusion. Genetic deletion and pharmacological inhibition of A-FABP alleviated cerebral ischaemia injury with reduced infarction volume, cerebral oedema, neurological deficits, and neuronal apoptosis; BBB disruption was attenuated and accompanied by reduced degradation of tight junction proteins and induction of matrix metalloproteinases-9 (MMP-9). In patients with acute IS, elevated circulating A-FABP levels positively correlated with those of MMP-9 and cerebral infarct volume. Mechanistically, ischaemia-induced elevation of A-FABP selectively in peripheral blood monocyte-derived macrophages and cerebral resident microglia promoted MMP-9 transactivation by potentiating JNK/c-Jun signalling, enhancing degradation of tight junction proteins and BBB leakage. The detrimental effects of A-FABP were prevented by pharmacological inhibition of MMP-9.
Conclusion
A-FABP is a key mediator of cerebral ischaemia injury promoting MMP-9-mediated BBB disruption. Inhibition of A-FABP is a potential strategy to improve IS outcome.
Background & Aims Fibroblast growth factor 21 (FGF21), a hormone primarily secreted by the liver in response to peroxisome proliferator-activated receptor-α (PPARα) activation, has recently been ...shown to possess beneficial effects on lipid metabolism and hepatic steatosis in animal models. This study investigated the association of FGF21 with nonalcoholic fatty liver disease (NAFLD) in Chinese patients. Methods Serum FGF21 levels were determined by enzyme-linked immunosorbent assay (ELISA) in 224 NAFLD and 124 control subjects, and their association with parameters of adiposity, glucose, and lipid profiles and levels of liver injury markers was studied. Besides serum concentrations, the mRNA expression of FGF21 in the liver tissue was also quantified by real-time PCR in 17 subjects with different degrees of steatosis, and was correlated with the levels of intrahepatic lipid. The protein levels of FGF21 were determined by quantitative ELISA. Results Serum FGF21 levels in patients with NAFLD (402.38 pg/ml 242.03, 618.25) were significantly higher than those in control subjects (198.62 pg/ml 134.96, 412.62) ( p <0.01). In human liver tissues, FGF21 mRNA expression increased with the degree of steatosis. Both FGF21 mRNA expression and serum FGF21 concentrations were positively correlated with intrahepatic triglyceride (TG) having r = 0.692 and r = 0.662, respectively, at p <0.01. Furthermore, the increased expression of FGF21 was accompanied by elevated protein levels in liver tissues. Conclusions These results support the role of FGF21 as a key regulator of hepatic lipid metabolism in humans, and suggest that serum FGF21 can be potentially used as a biomarker for NAFLD.
Among the 22 fibroblast growth factors (FGFs), FGF21 has now emerged as a key metabolic regulator. However, the mechanism whereby FGF21 mediates its metabolic actions per se remains largely unknown. ...Here, we show that FGF21 represses mammalian target of rapamycin complex 1 (mTORC1) and improves insulin sensitivity and glycogen storage in a hepatocyte‐autonomous manner. Administration of FGF21 in mice inhibits mTORC1 in the liver, whereas FGF21‐deficient mice display pronounced insulin‐stimulated mTORC1 activation and exacerbated hepatic insulin resistance (IR). FGF21 inhibits insulin‐ or nutrient‐stimulated activation of mTORC1 to enhance phosphorylation of Akt in HepG2 cells at both normal and IR condition. TSC1 deficiency abrogates FGF21‐mediated inhibition of mTORC1 and augmentation of insulin signaling and glycogen synthesis. Strikingly, hepatic βKlotho knockdown or hepatic hyperactivation of mTORC1/ribosomal protein S6 kinase 1 abrogates hepatic insulin‐sensitizing and glycemic‐control effects of FGF21 in diet‐induced insulin‐resistant mice. Moreover, FGF21 improves methionine‐ and choline‐deficient diet‐induced steatohepatitis. Conclusions: FGF21 acts as an inhibitor of mTORC1 to control hepatic insulin action and maintain glucose homeostasis, and mTORC1 inhibition by FGF21 has the therapeutic potential for treating IR and type 2 diabetes. (Hepatology 2016;64:425‐438)
A large proportion of the postconsumer glass is recycled into the packaging stream again, and some smaller proportions are used for a variety of purposes, including concrete aggregate. However, a ...significant proportion, which does not meet the strict criteria for packaging glass, is sent to landfill, taking the space that could be allocated to more urgent uses. Glass is unstable in the alkaline environment of concrete and could cause deleterious alkali-silica reaction (ASR) problems. This property has been used to advantage by grinding it into a fine glass powder (GLP) for incorporation into concrete as a pozzolanic material. In laboratory experiments, it can suppress the alkali reactivity of coarser glass particles as well as that of natural reactive aggregates. It undergoes beneficial pozzolanic reactions in the concrete and could replace up to 30% of cement in some concrete mixes with satisfactory strength development. The drying shrinkage of the concrete containing GLP was acceptable.
High-strength steel (HSS) members with welded sections exhibit a notably lower residual compressive stress ratio compared with common mild steel (CMS) members. Despite this difference, current codes ...often generalize the findings from CMS members to HSS members, and the previous unified residual stress models are generally conservative. This study focuses on the membrane residual stress distribution in Q690 steel welded box sections. By leveraging experimental results, the influence of section sizes and welding parameters on membrane residual stress was delved into. A larger plate size correlates with a decrease in the residual compressive stress across the section, with a more pronounced reduction observed in adjacent plates. Additionally, augmenting the number of welding passes tends to diminish residual stresses across the section. Results showed that membrane residual stress adhered to the section's self-equilibrium, while the self-equilibrium in the plates was not a uniform pattern. A reliable residual stress simulation method for Q690 steel welded box sections was established using a three-dimensional thermal-elastic-plastic finite element model (3DTEFEM) grounded in experimental data. This method served as the cornerstone for parameter analysis in this study and set the stage for subsequent research. As a result, an accurate unified residual stress model for Q690 steel welded box sections was derived.
Adiponectin is an adipocyte-derived circulating protein with beneficial effects on injured livers. Adiponectin-deficient (adipo(-/-)) mice develop enhanced liver fibrosis, suggesting that adiponectin ...could be a therapeutic target for liver injury. In the present study, we investigated the protective role of ADP355, an adiponectin-based active short peptide, in thioacetamide (TAA)-induced acute injury and chronic liver fibrosis in mice. ADP355 remarkably reduced TAA-induced necroinflammation and liver fibrosis. ADP355 treatment increased liver glycogen, decreased serum alanine transaminase and alkaline phosphatase activity, and promoted body weight gain, hyper-proliferation and hypo-apoptosis. In addition, ADP355 administration suppressed the TAA-induced activation of hepatic stellate cells and macrophages in the liver. These were associated with the inactivation of TGF-β1/SMAD2 signaling and the promotion of AMPK and STAT3 signaling. Sensitivity of adipo(-/-) mice to chronic liver injury was decreased with ADP355. In conclusion, ADP355 could mimic adiponectin's action and may be suitable for the preclinical or clinical therapy of chronic liver injury.
Adiponectin is an insulin-sensitizing adipokine with anti-diabetic, anti-atherogenic, anti-inflammatory and cardioprotective properties. This adipokine is secreted from adipocytes into the ...circulation as three oligomeric isoforms, including trimeric, hexameric and the HMW (high-molecular-mass) oligomeric complex consisting of at least 18 protomers. Each oligomeric isoform of adiponectin exerts distinct biological properties in its various target tissues. The HMW oligomer is the major active form mediating the insulin-sensitizing effects of adiponectin, whereas the central actions of this adipokine are attributed primarily to the hexameric and trimeric oligomers. In patients with Type 2 diabetes and coronary heart disease, circulating levels of HMW adiponectin are selectively decreased due to an impaired secretion of this oligomer from adipocytes. The biosynthesis of the adiponectin oligomers is a complex process involving extensive post-translational modifications. Hydroxylation and glycosylation of several conserved lysine residues in the collagenous domain of adiponectin are necessary for the intracellular assembly and stabilization of its high-order oligomeric structures. Secretion of the adiponectin oligomers is tightly controlled by a pair of molecular chaperones in the ER (endoplasmic reticulum), including ERp44 (ER protein of 44 kDa) and Ero1-Lalpha (ER oxidoreductase 1-Lalpha). ERp44 inhibits the secretion of adiponectin oligomers through a thiol-mediated retention. In contrast, Ero1-Lalpha releases HMW adiponectin trapped by ERp44. The PPARgamma (peroxisome-proliferator-activated receptor gamma) agonists thiazolidinediones selectively enhance the secretion of HMW adiponectin through up-regulation of Ero1-Lalpha. In the present review, we discuss the recent advances in our understanding of the structural and biological properties of the adiponectin oligomeric isoforms and highlight the role of post-translational modifications in regulating the biosynthesis of HMW adiponectin.
Background & Aims Fibroblast growth factor 21 (FGF21), a hormone predominantly secreted by the liver, has been shown to be positively associated with the severity of non-alcoholic fatty liver disease ...(NAFLD) in cross-sectional studies. We investigated the prospective association of FGF21 with NAFLD development in a 3-year prospective study involving a population-based cohort comprising 808 Chinese subjects. Methods Serum FGF21 levels at baseline and follow-up were measured using an enzyme-linked immunosorbent assay. Independent predictors of NAFLD development were identified using multiple logistic regressions. The predicting accuracy of the models was evaluated using area under the receiver-operating characteristic (ROC) curves (AUCs). Results In subjects who had progressed to NAFLD, the baseline FGF21 concentration (319.12 pg/ml 172.65, 518.78) was significantly higher than that in subjects who did not develop NAFLD (199.10 pg/ml 123.56, 322.80) ( p <0.001). At follow-up, significant increase of FGF21 level was observed in those subjects who developed NAFLD ( p < 0.05). Baseline FGF21 was an independent predictor of NAFLD (OR: 7.102 95% CI 2.488–20.270; p < 0.001), together with body mass index (BMI) (OR: 1.489 95% CI 1.310–1.691; p < 0.001). The ROC-AUC was 0.816 (95% CI 0.766–0.867) for the FGF21 Model, which was calculated with FGF21 and BMI. FGF21 Model <0.13 can be used to rule out (sensitivity = 85.71%, negative likelihood ratio = 0.23) and ⩾0.30 can be rule in (specificity = 86.34%, positive likelihood ratio = 3.66) ultrasonography-diagnosed NAFLD after 3 years. Conclusions High serum FGF21 concentration was an independent predictor of NAFLD in humans. The FGF21 Model and its cut-offs may be useful for early diagnosis and intervention of NAFLD.
Fibroblast growth factor 21 (FGF21) is a liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders. It enhances glucose uptake by inducing the expression of ...glucose transporter-1 (GLUT1) in adipocytes. Here we investigated the signaling pathways that mediate FGF21-induced GLUT1 expression and glucose uptake in vitro and in animals. Quantitative real-time PCR and a luciferase reporter assay showed that FGF21 induced GLUT1 expression through transcriptional activation. The truncation of the GLUT1 promoter from −3145 to −3105 bp, which contains two highly conserved serum response element (SRE) and E-Twenty Six (ETS) binding motif, dramatically decreased FGF21-induced promoter activity of the GLUT1 gene. A chromatin immunoprecipitation assay demonstrated that the transcription factors serum response factor (SRF) and Ets-like protein-1 (Elk-1) were recruited to the GLUT1 promoter upon FGF21 stimulation. The siRNA-mediated knockdown of either SRF or Elk-1 resulted in a marked attenuation in FGF21-induced GLUT1 expression and glucose uptake in adipocytes. In C57 lean mice, a single intravenous injection of FGF21 induced phosphorylation of Elk-1 at Ser383 and SRF at Ser103 and also led to the recruitment of Elk-1 and SRF to the GLUT1 promoter in epididymal fats. By contrast, such effects of in vivo FGF21 administration were blunted in high fat diet-induced obese mice. In conclusion, FGF21 induces GLUT1 expression and glucose uptake through sequential activation of ERK1/2 and SRF/Elk-1, which in turn triggers the transcriptional activation of GLUT1 in adipocytes. The impairment in this signaling pathway may contribute to FGF21 resistance in obese mice.
Background: FGF21 increases glucose uptake in adipocytes by enhancing the expression of glucose transporter-1 (GLUT1).
Results: FGF21 induces the phosphorylation of the transcription factors serum response factor (SRF) and Ets-like protein-1 (Elk-1), which in turn bind to a highly conserved cis-element within the GLUT1 gene promoter for transcriptional activation. Such a stimulatory effect of FGF21 is impaired in adipose tissue of diet-induced obese mice.
Conclusion: SRF and Elk-1 act synergistically to mediate FGF21-induced GLUT1 gene expression in adipocytes.
Significance: The findings provide new molecular insights into the metabolic actions of FGF21 in its major target tissue.
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