Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects

Inês Mahú, Andreia Barateiro, Eva Rial-Pensado, Noelia Martinéz-Sánchez, Sandra H Vaz, Pedro M S D Cal, Benjamin Jenkins, Tiago Rodrigues, Carlos Cordeiro, Miguel F Costa, Raquel Mendes, Elsa Seixas, Mafalda M A Pereira, Nadiya Kubasova, Vitka Gres, Imogen Morris, Carolina Temporão, Marta Olivares, Yolanda Sanz, Albert KoulmanFrancisco Corzana, Ana M Sebastião, Miguel López, Gonçalo J L Bernardes, Ana I Domingos

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1120-1135.e7
JournalCell Metabolism
Volume31
Issue number6
DOIs
Publication statusPublished - 2 Jun 2020

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