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Brain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effects

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dc.contributor.authorMahú, Inês
dc.contributor.authorBarateiro, Andreia
dc.contributor.authorRial-Pensado, Eva
dc.contributor.authorMartinéz-Sánchez, Noelia
dc.contributor.authorVaz, Sandra H.
dc.contributor.authorCal, Pedro M.S.D.
dc.contributor.authorJenkins, Benjamin
dc.contributor.authorRodrigues, Tiago M.
dc.contributor.authorCordeiro, Carlos
dc.contributor.authorCosta, Miguel F.
dc.contributor.authorMendes, Raquel
dc.contributor.authorSeixas, Elsa
dc.contributor.authorPereira, Mafalda M.A.
dc.contributor.authorKubasova, Nadiya
dc.contributor.authorGres, Vitka
dc.contributor.authorMorris, Imogen
dc.contributor.authorTemporão, Carolina
dc.contributor.authorOlivares, Marta
dc.contributor.authorSanz, Yolanda
dc.contributor.authorKoulman, Albert
dc.contributor.authorCorzana, Francisco
dc.contributor.authorSebastião, Ana M
dc.contributor.authorLópez, Miguel
dc.contributor.authorBernardes, Gonçalo J. L.
dc.contributor.authorDomingos, Ana I.
dc.date.accessioned2021-07-28T13:57:37Z
dc.date.available2021-07-28T13:57:37Z
dc.date.issued2020
dc.description© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).pt_PT
dc.description.abstractAnti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.pt_PT
dc.description.sponsorshipThis work was supported by the Fundação Para a Ciência e Tecnologia (FCT - PTDC-BIM-MET-3750-2014 and LISBOA-01-0145-FEDER-030892), the European Molecular Biology Organization (EMBO - Installation Grant 3037), the Human Frontier Science Program (HFSP - RGY0070/2016), Maratona da Saúde (Diabetes - 2016), the European Research Council (ERC-2017-COG-771431), and the Howard Hughes Medical Institute/Wellcome International research scholar award (HHMI - 208576/Z/17/Z). G.J.L.B. is a Royal Society university Research Fellow (URF\R\180019) and FCT Investigator (IF/00624/2015). B.J. and A.K. were supported by the BBSRC (BB/M027252/1/bbsrc). We also acknowledge the Portuguese Mass Spectrometry Network (LISBOA-01-0145-FEDER-022125), the Project EU_FT-ICR_MS, funded by the European Union Horizon 2020 research and innovation program under grant agreement no. 731077. The contribution of Y.S., M.O., and F.C. was supported by Ministerio de Ciencia, Innovación y Universidades (grants AGL2017-88801-P and RTI2018-099592-B-C21). The contribution of M.L. was supported by the Xunta de Galicia (2015-CP079 and 2016-PG068), the Ministerio de Economía y Competitividad (MINECO) co-funded by the FEDER Program of EU (RTI2018-101840-B-I00 and BFU2015-70454-REDT/Adipoplast), the Atresmedia Corporación and the “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/HR19/52160022. I.M. (PD/BD/52437/2013), A.B. (SFRH/BPD/96794/2013), P.M.S.D.C. (SFRH/BPD/103172/2014) and S.H.V. (SFRH/BPD/81627/2011) were supported by FCT; N.M.S. (ED481B 2016/168-0) was supported by Xunta de Galicia; and E.R.P. (BES-2015-072743) was supported by Ministerio de Economía y Competitividad (MINECO).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCell Metab. 2020 Jun 2;31(6):1120-1135.e7.pt_PT
dc.identifier.doi10.1016/j.cmet.2020.04.013pt_PT
dc.identifier.eissn1932-7420
dc.identifier.issn1550-4131
dc.identifier.urihttp://hdl.handle.net/10451/49187
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationPTDC-BIM-MET-3750-2014pt_PT
dc.relationLISBOA-01-0145-FEDER-030892pt_PT
dc.relationModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
dc.relationEuropean Network of Fourier-Transform Ion-Cyclotron-Resonance Mass Spectrometry Centers
dc.relationTE ROLE OF S100B IN MULTIPLE SCLEROSIS: FROM A BIOMARKER TO A THERAPEUTIC TARGET
dc.relationA “Click and CO Release” approach for the targeted delivery of therapeutic CO in vivo
dc.relationMODULATION OF THE BIDIRECTIONAL COMMUNICATION BETWEEN NEURONS AND ASTROCYTES AT THE SYNAPSE: INFLUENCE OF BDNF AND P2 RECEPTORS
dc.relationPROGRAMA DOUTORAL EM BIOLOGIA INTEGRATIVA E BIOMEDICINA IBB 2014
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/cell-metabolismpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAmphetaminept_PT
dc.subjectHeat dissipationpt_PT
dc.subjectLipolysispt_PT
dc.subjectObesitypt_PT
dc.subjectSympathetic-nervous-systempt_PT
dc.subjectSympathofacilitatorspt_PT
dc.subjectSympathomimeticspt_PT
dc.subjectTachycardiapt_PT
dc.subjectThermogenesispt_PT
dc.subjectThermoregulationpt_PT
dc.titleBrain-sparing sympathofacilitators mitigate obesity without adverse cardiovascular effectspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberIF/00624/2015/CP1287/CT0002
oaire.awardNumber731077
oaire.awardNumberSFRH/BPD/96794/2013
oaire.awardNumberSFRH/BPD/103172/2014
oaire.awardNumberSFRH/BPD/81627/2011
oaire.awardNumberPD/BD/52437/2013
oaire.awardTitleModulation and targeting of calcium channels with ligand-drug conjugates for cancer therapy
oaire.awardTitleEuropean Network of Fourier-Transform Ion-Cyclotron-Resonance Mass Spectrometry Centers
oaire.awardTitleTE ROLE OF S100B IN MULTIPLE SCLEROSIS: FROM A BIOMARKER TO A THERAPEUTIC TARGET
oaire.awardTitleA “Click and CO Release” approach for the targeted delivery of therapeutic CO in vivo
oaire.awardTitleMODULATION OF THE BIDIRECTIONAL COMMUNICATION BETWEEN NEURONS AND ASTROCYTES AT THE SYNAPSE: INFLUENCE OF BDNF AND P2 RECEPTORS
oaire.awardTitlePROGRAMA DOUTORAL EM BIOLOGIA INTEGRATIVA E BIOMEDICINA IBB 2014
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F00624%2F2015%2FCP1287%2FCT0002/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/731077/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F96794%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F103172%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F81627%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F52437%2F2013/PT
oaire.citation.endPage1135pt_PT
oaire.citation.issue6pt_PT
oaire.citation.startPage1120pt_PT
oaire.citation.titleCell Metabolismpt_PT
oaire.citation.volume31pt_PT
oaire.fundingStreamInvestigador FCT
oaire.fundingStreamH2020
oaire.fundingStreamOE
person.familyNamePereira Barateiro Macedo
person.familyNameHenriques Vaz
person.familyNameCal
person.familyNameRodrigues
person.familyNameSebastião
person.familyNameBernardes
person.givenNameAndreia
person.givenNameSandra Cristina
person.givenNamePedro
person.givenNameTiago M.
person.givenNameAna M
person.givenNameGonçalo
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project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
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