For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
25
views
42
references
 Top references
cited by
17
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      339
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Small molecule PGC-1α1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration

      research-article
      Author(s): 1 , 5 , 1 , 5 , 1 , 1 , 1 , 1 , 2 , 2 , 2 , 1 , 1 , 3 , 3 , 4 , 4 , 2 , 1 , ∗
      Publication date (Electronic):
      Journal: Molecular Metabolism
      Publisher: Elsevier
      Keywords: Small molecule screening, PGC-1a, PGC-1alpha, PGC-1alpha1, Protein stabilization, UCP1, Mitochondrial respiration, Brown adipose tissue, C/EBP, CCAAT-enhancer-binding proteins, FCCP, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone, HEK, human embryonic kidney, HNF, hepatocyte nuclear factor, HPRT, hypoxanthine-guanine phosphoribosyltransferase, IDP, intrinsically disordered protein, MEF2, myocyte enhancer factor 2, NRF2, nuclear respiratory factors 2, PPAR, peroxisome proliferator-activated receptor, ROS, reactive oxygen species, PGC, peroxisome proliferator-activated receptor-γ coactivator, PTM, post-translational modifications, UCP1, uncoupling protein 1, SREBP1, sterol regulatory element-binding protein 1, XBP1, X-box binding protein 1

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective

          The peroxisome proliferator-activated receptor-γ coactivator-1α1 (PGC-1α1) regulates genes involved in energy metabolism. Increasing adipose tissue energy expenditure through PGC-1α1 activation is potentially beneficial for systemic metabolism. Pharmacological PGC-1α1 activators could be valuable tools in the fight against obesity and metabolic disease. Finding such compounds has been challenging partly because PGC-1α1 is a transcriptional coactivator with no known ligand-binding properties. While, PGC-1α1 activation is regulated by several mechanisms, protein stabilization is a crucial limiting step due to its short half-life under unstimulated conditions.

          Methods

          We designed a cell-based high-throughput screening system to identify PGC-1α1 protein stabilizers. Positive hits were tested for their ability to induce endogenous PGC-1α1 protein accumulation and activate target gene expression in brown adipocytes. Select compounds were analyzed for their effects on global gene expression and cellular respiration in adipocytes.

          Results

          Among 7,040 compounds screened, we highlight four small molecules with high activity as measured by: PGC-1α1 protein accumulation, target gene expression, and uncoupled mitochondrial respiration in brown adipocytes.

          Conclusions

          We identify compounds that induce PGC-1α1 protein accumulation and show that this increases uncoupled respiration in brown adipocytes. This screening platform establishes the foundation for a new class of therapeutics with potential use in obesity and associated disorders.

          Graphical abstract

          Highlights

          • •

            A high-throughput platform to identify PGC-1α1 activators.

          • •

            PGC-1α1 protein stabilizers work as activators in brown adipocytes.

          • •

            Small molecule PGC-1α1 activators induce Ucp1 expression and cellular respiration.

          Related collections

          Most cited references42

          • Record: found
          • Abstract: found
          • Article: not found

          AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

          Sibylle Jager, Christoph Handschin, Julie St-Pierre … (2007)
          Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.
          Article 0 comments Cited 799 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}.

            Shino Nemoto, Maria Fergusson, Toren Finkel (2005)
            In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by approximately 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1alpha. In addition, SIRT1 and PGC-1alpha directly interact and can be co-immunoprecipitated as a molecular complex. A single amino acid mutation in the putative ADP-ribosyltransferase domain of SIRT1 inhibits the interaction of SIRT1 with PGC-1alpha but does not effect the interaction of SIRT1 with either p53 or Foxo3a. We further show that PGC-1alpha is acetylated in vivo. This acetylation is augmented by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. Finally we demonstrate that SIRT1 catalyzes PGC-1alpha deacetylation both in vitro and in vivo. These results provide a direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1alpha, a coactivator that regulates cellular metabolism.
            Article 0 comments Cited 296 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.

              Leandro Z Agudelo, Teresa Femenía, Funda Orhan … (2014)
              Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier. Copyright © 2014 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 278 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                J.L. Ruas
                Journal
                Journal ID (nlm-ta): Mol Metab
                Journal ID (iso-abbrev): Mol Metab
                Title: Molecular Metabolism
                Publisher: Elsevier
                ISSN (Electronic): 2212-8778
                Publication date PMC-release: 03 February 2018
                Publication date Collection: March 2018
                Publication date (Electronic): 03 February 2018
                Volume: 9
                Pages: 28-42
                Affiliations
                [1 ]Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
                [2 ]Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA
                [3 ]Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden
                [4 ]Chemical Biology Consortium Sweden, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
                Author notes
                [∗ ]Corresponding author. Molecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Von Eulers Väg 8, 171 77 Stockholm, Sweden.Molecular and Cellular Exercise PhysiologyDepartment of Physiology and PharmacologyKarolinska InstitutetVon Eulers Väg 8Stockholm171 77Sweden jorge.ruas@ 123456ki.se
                [5]

                These authors contributed equally.

                Article
                Publisher ID: S2212-8778(18)30003-6
                DOI: 10.1016/j.molmet.2018.01.017
                PMC ID: 5870114
                PubMed ID: 29428596
                SO-VID: 41fe6abc-ba7e-4742-a11b-cc4c76084daa
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 2 January 2018
                Date revision received : 12 January 2018
                Date accepted : 19 January 2018
                Categories
                Subject: Original Article

                Keywords: small molecule screening,pgc-1a,pgc-1alpha,pgc-1alpha1,protein stabilization,ucp1,mitochondrial respiration,brown adipose tissue,c/ebp, ccaat-enhancer-binding proteins,fccp, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone,hek, human embryonic kidney,hnf, hepatocyte nuclear factor,hprt, hypoxanthine-guanine phosphoribosyltransferase,idp, intrinsically disordered protein,mef2, myocyte enhancer factor 2,nrf2, nuclear respiratory factors 2,ppar, peroxisome proliferator-activated receptor,ros, reactive oxygen species,pgc, peroxisome proliferator-activated receptor-γ coactivator,ptm, post-translational modifications,ucp1, uncoupling protein 1,srebp1, sterol regulatory element-binding protein 1,xbp1, x-box binding protein 1
                Data availability:
                Keywords: small molecule screening, pgc-1a, pgc-1alpha, pgc-1alpha1, protein stabilization, ucp1, mitochondrial respiration, brown adipose tissue, c/ebp, ccaat-enhancer-binding proteins, fccp, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone, hek, human embryonic kidney, hnf, hepatocyte nuclear factor, hprt, hypoxanthine-guanine phosphoribosyltransferase, idp, intrinsically disordered protein, mef2, myocyte enhancer factor 2, nrf2, nuclear respiratory factors 2, ppar, peroxisome proliferator-activated receptor, ros, reactive oxygen species, pgc, peroxisome proliferator-activated receptor-γ coactivator, ptm, post-translational modifications, ucp1, uncoupling protein 1, srebp1, sterol regulatory element-binding protein 1, xbp1, x-box binding protein 1

                Comments

                Comment on this article

                scite_

                Similar content339

                See all similar

                Cited by17

                See all cited by

                Most referenced authors1,037

                See all reference authors