PPAR Research最新文献

{"title":"Loss of Hepatocyte-Specific PPAR<i>γ</i> Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet.","authors":"Jose Cordoba-Chacon","doi":"10.1155/2020/9735083","DOIUrl":"https://doi.org/10.1155/2020/9735083","url":null,"abstract":"<p><p>The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPAR<i>γ</i>, <i>Pparg</i>) and the fatty acid translocase (CD36, <i>Cd36</i>) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPAR<i>γ</i> and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPAR<i>γ</i> knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPAR<i>γ</i> and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPAR<i>γ</i> and CD36. The expression of PPAR<i>γ</i> and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"9735083"},"PeriodicalIF":2.9,"publicationDate":"2020-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/9735083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37937500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPAR-Gamma Agonist Pioglitazone Reduced CD68+ but Not CD163+ Macrophage Dermal Infiltration in Obese Psoriatic Patients.","authors":"Ya O Yemchenko, V I Shynkevych, K Ye Ishcheikin, I P Kaidashev","doi":"10.1155/2020/4548012","DOIUrl":"10.1155/2020/4548012","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are of great importance in the development of obesity and psoriasis. Signaling via PPAR-<i>γ</i> in certain macrophage populations is associated with M2-like features and anti-inflammatory profile. In this research, we evaluated the anti-inflammatory action of pioglitazone by the immunohistochemical study of M1 and M2 macrophages in psoriasis-affected skin in obese patients.</p><p><strong>Methods: </strong>We used immunohistochemistry to characterize CD68+ and CD163+ macrophages and pathomorphological description of skin biopsy, obtained from 6 obese psoriatic patients before and after treatment with 15, 30, and 45 mg pioglitazone, once a day during 6 months. Two patients with conventional therapy and without pioglitazone served as control.</p><p><strong>Results: </strong>Generally, CD163+ cell quantities in psoriasis-affected skin significantly dominated over CD68+ before and after all treatment regiments. Among patients who received pioglitazone, some of them clearly responded to treatment from lowest to highest doses by decreasing CD68+ cells. In the group with 30 mg pioglitazone regiment, we detected a significant reduction of CD68+ cells in dermal infiltrates: CI 95% (16-32) before versus CI 95% (2-7) after treatment. Pioglitazone dose escalation led to certain normalization of skin morphology.</p><p><strong>Conclusion: </strong>The immunohistochemical study allows us to show the anti-inflammatory effect of pioglitazone in psoriatic obese patients, which can be mediated by reducing the number of СD68+ macrophages, but not СD163+ macrophages, in the affected dermis.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"4548012"},"PeriodicalIF":3.5,"publicationDate":"2020-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37937499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARG Drives Molecular Networks as an Inhibitor for the Pathologic Development and Progression of Lung Adenocarcinoma.","authors":"Min Zhao,&nbsp;Xiaoyang Li,&nbsp;Yunxiang Zhang,&nbsp;Hongming Zhu,&nbsp;Zhaoqing Han,&nbsp;Yan Kang","doi":"10.1155/2020/6287468","DOIUrl":"https://doi.org/10.1155/2020/6287468","url":null,"abstract":"<p><p>Previous studies showed that low PPARG expression was associated with poor prognosis of lung adenocarcinoma (LA) with limited mechanisms identified. We first conducted a large-scale literature-based data mining to identify potential molecular pathways where PPARG could exert influence on the pathological development of LA. Then a mega-analysis using 13 independent LA expression datasets and a Pathway Enrichment Analysis (PEA) was conducted to study the gene expression levels and the functionalities of PPARG and the PPARG-driven triggers within the molecular pathways. Finally, a protein-protein interaction (PPI) network was established to reveal the functional connection between PPARG and its driven molecules. We identified 25 PPARG-driven molecule triggers forming multiple LA-regulatory pathways. Mega-analysis using 13 LA datasets supported these pathways and confirmed the downregulation of PPARG in the case of LA (<i>p</i> = 1.07<i>e</i> ^-05). Results from the PEA and PPI analysis suggested that PPARG might inhibit the development of LA through the regulation of tumor cell proliferation and transmission-related molecules, including an LA tumor cell suppressor MIR145. Our results suggested that increased expression of PPARG could drive multiple molecular triggers against the pathologic development and prognosis of LA, indicating PPARG as a valuable therapeutic target for LA treatment.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"6287468"},"PeriodicalIF":2.9,"publicationDate":"2020-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/6287468","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37923568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Changes in Concentration of Total Antioxidant Status, Acute-Phase Protein, and Prolactin in Patients with Osteoarthritis Subjected to a Complex Spa Treatment with Radon Water: Preliminary Results.","authors":"Jadwiga Kuciel-Lewandowska, Michał Kasperczak, Lilla Pawlik-Sobecka, Małgorzata Paprocka-Borowicz, Jan Gnus","doi":"10.1155/2020/9459418","DOIUrl":"10.1155/2020/9459418","url":null,"abstract":"<p><p>Spa treatment brings many clinical benefits such as improved physical activity, pain relief, and improved quality of life. In the literature, there are only few objective studies evaluating changes in metabolism possibly influencing clinical outcomes. The main purpose of our study was the assessment of the effect of spa treatment on changes in concentration of TAS, CRP, and PRL in patients with osteoarthritis. Patients receiving spa treatment were enrolled. TAS, CRP, and PRL levels were obtained using standard tests before the beginning of treatment as well as on days 5 and 18. The study group consisted of <i>n</i> = 35 patients with peripheral joint and spinal osteoarthritis. The control group consisted of 15 people selected from the resort staff, who also suffered from osteoarthritis and had no contact with radon. An increase in TAS concentration was found in the study group following therapy while the control group was characterized by a significant decrease in TAS. On day 5, an increase in TAS concentration was found in both groups, however, with much worse result in the control group. No changes in CRP concentration were statistically significant. PRL concentration was proven to decrease in a statistically significant way after treatment in the study group. This trial is registered with NCT03274128.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"9459418"},"PeriodicalIF":2.9,"publicationDate":"2020-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37904593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Pparg</i> may Promote Chemosensitivity of Hypopharyngeal Squamous Cell Carcinoma.","authors":"Meng Lian,&nbsp;Jiaming Chen,&nbsp;Xixi Shen,&nbsp;Lizhen Hou,&nbsp;Jugao Fang","doi":"10.1155/2020/6452182","DOIUrl":"https://doi.org/10.1155/2020/6452182","url":null,"abstract":"<p><p>The upregulation of peroxisome proliferator-activated receptor gamma (<i>PPARG</i>) has been shown to increase the chemosensitivity of several human cancers. This study is aimed at studying if <i>PPARG</i> sensitizes hypopharyngeal squamous cell carcinoma (HSCC) in chemotherapeutic treatments and at dissecting possible mechanisms of observed effects. We integrated large-scale literature data and HSCC gene expression data to identify regulatory pathways that link <i>PPARG</i> and chemosensitivity in HSCC. Expression levels of molecules within the <i>PPARG</i> regulatory pathways were compared in 21 patients that underwent chemotherapy for primary HSCC, including 12 chemotherapy-sensitive patients (CSP) and 9 chemotherapy-nonsensitive patients (CNSP). In the CPS group, expression levels of <i>PPARG</i> were higher than that in the CNSP group (log-fold-change = 0.50). Structured text mining identified two chemosensitivity-related regulatory pathways driven by <i>PPARG</i>. In the CSP group, expression levels for 7 chemosensitivity-promoting genes were increased, while for 13 chemosensitivity suppressing the gene expression levels were decreased. Our results support the chemosensitivity-promoting role of <i>PPARG</i> in HSCC tumor cells, most likely by affecting both cell proliferation and cell motility pathways.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"6452182"},"PeriodicalIF":2.9,"publicationDate":"2020-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/6452182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37905255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations.","authors":"Holli-Joi Sullivan,&nbsp;Xiaoyan Wang,&nbsp;Shaina Nogle,&nbsp;Siyan Liao,&nbsp;Chun Wu","doi":"10.1155/2020/5314187","DOIUrl":"https://doi.org/10.1155/2020/5314187","url":null,"abstract":"<p><p>Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPAR<i>γ</i> and a partial activation of PPAR<i>α</i> and PPAR<i>β</i>/<i>δ</i>). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPAR<i>α</i>, PPAR<i>β</i>/<i>δ</i>, and PPAR<i>γ</i>, followed by 3 <i>μ</i>s molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPAR<i>γ</i> (-144.6 kcal/mol), followed by hPPAR<i>α</i> (-138.0 kcal/mol) and hPPAR<i>β</i> (-135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM-GBSA binding energy by residue and the use of two-dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"5314187"},"PeriodicalIF":2.9,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/5314187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37849868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Study of PPAR<i>γ</i> Targets in Human Extravillous and Villous Cytotrophoblasts.","authors":"Fulin Liu,&nbsp;Christine Rouault,&nbsp;Mickael Guesnon,&nbsp;Wencan Zhu,&nbsp;Karine Clément,&nbsp;Séverine A Degrelle,&nbsp;Thierry Fournier","doi":"10.1155/2020/9210748","DOIUrl":"https://doi.org/10.1155/2020/9210748","url":null,"abstract":"<p><p>Trophoblasts, as the cells that make up the main part of the placenta, undergo cell differentiation processes such as invasion, migration, and fusion. Abnormalities in these processes can lead to a series of gestational diseases whose underlying mechanisms are still unclear. One protein that has proven to be essential in placentation is the peroxisome proliferator-activated receptor <i>γ</i> (PPAR<i>γ</i>), which is expressed in the nuclei of extravillous cytotrophoblasts (EVCTs) in the first trimester and villous cytotrophoblasts (VCTs) throughout pregnancy. Here, we aimed to explore the genome-wide effects of PPAR<i>γ</i> on EVCTs and VCTs via treatment with the PPAR<i>γ</i>-agonist rosiglitazone. EVCTs and VCTs were purified from human chorionic villi, cultured <i>in vitro</i>, and treated with rosiglitazone. The transcriptomes of both types of cells were then quantified using microarray profiling. Differentially expressed genes (DEGs) were filtered and submitted for gene ontology (GO) annotation and pathway analysis with ClueGO. The online tool STRING was used to predict PPAR<i>γ</i> and DEG protein interactions, while iRegulon was used to predict the binding sites for PPAR<i>γ</i> and DEG promoters. GO and pathway terms were compared between EVCTs and VCTs with clusterProfiler. Visualizations were prepared in Cytoscape. From our microarray data, 139 DEGs were detected in rosiglitazone-treated EVCTs (RT-EVCTs) and 197 DEGs in rosiglitazone-treated VCTs (RT-VCTs). Downstream annotation analysis revealed the similarities and differences between RT-EVCTs and RT-VCTs with respect to the biological processes, molecular functions, cellular components, and KEGG pathways affected by the treatment, as well as predicted binding sites for both protein-protein interactions and transcription factor-target gene interactions. These results provide a broad perspective of PPAR<i>γ</i>-activated processes in trophoblasts; further analysis of the transcriptomic signatures of RT-EVCTs and RT-VCTs should open new avenues for future research and contribute to the discovery of possible drug-targeted genes or pathways in the human placenta.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"9210748"},"PeriodicalIF":2.9,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/9210748","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37849869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPAR<i>γ</i> Transcription.","authors":"Xianhua Hou,&nbsp;Yuan Li,&nbsp;Yuanyuan Huang,&nbsp;Huan Zhao,&nbsp;Li Gui","doi":"10.1155/2020/2410264","DOIUrl":"https://doi.org/10.1155/2020/2410264","url":null,"abstract":"<p><p>Adenosine receptors A1 (A1AR) and A2a (A2aAR) play an important role in regulating glutamate uptake to avoid glutamate accumulation that causes excitotoxicity in the brain; however, the precise mechanism of the effects of A1AR and A2aAR is unclear. Herein, we report that expression of the A1AR protein in the astrocyte membrane and the level of intracellular glutamate were decreased, while expression of the A2aR protein was elevated in cells exposed to oxygen-glucose deprivation (OGD) conditions. Coimmunoprecipitation (Co-IP) experiments showed that A1AR interacts with A2aAR under OGD conditions. The activation of A1AR and inactivation of A2aAR by 2-chloro-N6-cyclopentyladenosine (CCPA) and SCH58251, respectively, partly reversed OGD-mediated glutamate uptake dysfunction, elevated EAAT2, and PPAR<i>γ</i> protein levels, and suppressed the expression of Ying Yang 1 (YY1). Both the silencing of YY1 and the activation of PPAR<i>γ</i> upregulated EAAT2 expression. Moreover, YY1 silencing elevated the PPAR<i>γ</i> level under both normal and OGD conditions. Histone deacetylase (HDAC)1 was found to interact with YY1, and HDAC1 silencing improved PPAR<i>γ</i> promoter activity. Taken together, our findings suggest that A1AR-A2aAR heteromers regulate EAAT2 expression and glutamate uptake through the YY1-mediated recruitment of HDAC1 to the PPAR<i>γ</i> promoter region.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"2410264"},"PeriodicalIF":2.9,"publicationDate":"2020-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/2410264","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37765427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Peroxisome Proliferator-Activated Receptors (PPARs) with Diabetic Retinopathy in Human and Animal Models: Analysis of the Literature and Genome Browsers.","authors":"Špela Tajnšek,&nbsp;Danijel Petrovič,&nbsp;Mojca Globočnik Petrovič,&nbsp;Tanja Kunej","doi":"10.1155/2020/1783564","DOIUrl":"https://doi.org/10.1155/2020/1783564","url":null,"abstract":"<p><p>Diabetic retinopathy (DR) is a condition that develops after long-lasting and poorly handled diabetes and is presently the main reason for blindness among elderly and youth. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in carbohydrate and fatty-acid metabolism and have also been associated with DR. Three PPAR isoforms are known: <i>PPARG</i>, <i>PPARA</i>, and <i>PPARD</i>. In the present study, we retrieved articles reporting associations between PPARs and DR from PubMed database and compiled the data in two catalogues, for human and animal models. Extracted data was then complemented with additional relevant genomic information. Seven retrieved articles reported testing an association between <i>PPARs</i> with DR in human. Four of them concluded association of <i>PPARG</i> and <i>PPARA</i> with DR in European and Asian populations, having a protective role on DR development. One study reported pathogenic role of <i>PPARG</i>, while two articles reported no association between <i>PPARG</i> and DR among Indian and Chinese populations. Six retrieved articles reported testing of involvement of <i>PPARG</i> and <i>PPARA</i> in DR in animal models, including mouse and rat. The review includes case-control studies, meta-analysis, expression studies, animal models, and cell line studies. Despite a large number of documented sequence variants of the PPAR genes available in genome browsers, researchers usually focus on a small set of previously reported variants. Data extraction from Ensembl genome browser revealed several sequence variants with predicted deleterious effect on protein function which present candidates for further experimental validation. Results of the present analysis will enable more holistic approach for understanding of <i>PPARs</i> in DR development. Additionally, developed catalogues present a baseline for standardized reporting of PPAR-phenotype association in upcoming studies.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"1783564"},"PeriodicalIF":2.9,"publicationDate":"2020-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/1783564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37752484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stimulation of Alpha₁-Adrenergic Receptor Ameliorates Cellular Functions of Multiorgans beyond Vasomotion through PPAR<i>δ</i>.","authors":"Yong-Jik Lee,&nbsp;Hyun Soo Kim,&nbsp;Hong Seog Seo,&nbsp;Jin Oh Na,&nbsp;You-Na Jang,&nbsp;Yoon-Mi Han,&nbsp;Hyun-Min Kim","doi":"10.1155/2020/3785137","DOIUrl":"https://doi.org/10.1155/2020/3785137","url":null,"abstract":"<p><p>Cells can shift their metabolism between glycolysis and oxidative phosphorylation to enact their cell fate program in response to external signals. Widely distributed <i>α</i> ₁-adrenergic receptors (ARs) are physiologically stimulated during exercise, were reported to associate with the activating energetic AMPK pathway, and are expected to have biological effects beyond their hemodynamic effects. To investigate the effects and mechanism of AR stimulation on the physiology of the whole body, various <i>in vitro</i> and <i>in vivo</i> experiments were conducted using the AR agonist midodrine, 2-amino-<i>N</i>-[2-(2,5-dimethoxyphenyl)-2-hydroxy-ethyl]-acetamide. The expression of various biomarkers involved in ATP production was estimated through Western blotting, reverse transcription polymerase chain reaction, oxygen consumption rate, enzyme-linked immunosorbent assay (ELISA), fluorescence staining, and Oil red O staining in several cell lines (skeletal muscle, cardiac muscle, liver, macrophage, vascular endothelial, and adipose cells). In spontaneously hypertensive rats, blood pressure, blood analysis, organ-specific biomarkers, and general biomolecules related to ATP production were measured with Western blot analysis, immunohistochemistry, ELISA, and echocardiography. Pharmacological activation of <i>α</i> ₁-adrenergic receptors in C2C12 skeletal muscle cells promoted mitochondrial oxidative phosphorylation and ATP production by increasing the expression of catabolic molecules, including PPAR<i>δ</i>, AMPK, and PGC-1<i>α</i>, through cytosolic calcium signaling and increased GLUT4 expression, as seen in exercise. It also activated those energetic molecules and mitochondrial oxidative phosphorylation with cardiomyocytes, endothelial cells, adipocytes, macrophages, and hepatic cells and affected their relevant cell-specific biological functions. All of those effects occurred around 3 h (and peaked 6 h) after midodrine treatment. In spontaneously hypertensive rats, <i>α</i> ₁-adrenergic receptor stimulation affected mitochondrial oxidative phosphorylation and ATP production by activating PPAR<i>δ</i>, AMPK, and PGC-1<i>α</i> and the relevant biologic functions of multiple organs, suggesting organ crosstalk. The treatment lowered blood pressure, fat and body weight, cholesterol levels, and inflammatory activity; increased ATP content and insulin sensitivity in skeletal muscles; and increased cardiac contractile function without exercise training. These results suggest that the activation of <i>α</i> ₁-adrenergic receptor stimulates energetic reprogramming via PPAR<i>δ</i> that increases mitochondrial oxidative phosphorylation and has healthy and organ-specific biological effects in multiple organs, including skeletal muscle, beyond its vasomotion effect. In addition, the action mechanism of <i>α</i> ₁-adrenergic receptor may be mainly exerted via PPAR<i>δ</i>.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2020 ","pages":"3785137"},"PeriodicalIF":2.9,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2020/3785137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37677922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}