Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects

Autor: Carolina Temporão, Marta Olivares, Elsa Seixas, Miguel F. Costa, Francisco Corzana, Andreia Barateiro, Nadiya Kubasova, Pedro M. S. D. Cal, Tiago Rodrigues, Sandra H. Vaz, Gonçalo J. L. Bernardes, Yolanda Sanz, Ana Domingos, Eva Rial-Pensado, Carlos Cordeiro, Ana M. Sebastião, Noelia Martínez-Sánchez, Vitka Gres, Benjamin Jenkins, Mafalda M.A. Pereira, Imogen Morris, Raquel Mendes, Albert Koulman, Inês Mahú, Miguel López
Přispěvatelé: Repositório da Universidade de Lisboa, Koulman, Albert [0000-0001-9998-051X], Lopes Bernardes, Goncalo [0000-0001-6594-8917], Apollo - University of Cambridge Repository
Rok vydání: 2020
Předmět:
Zdroj: Cell Metabolism
Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
ISSN: 1550-4131
DOI: 10.1016/j.cmet.2020.04.013
Popis: © 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/).
Anti-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.
This 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).
Databáze: OpenAIRE
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