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 Koulman; Francisco Corzana; Ana M Sebastião; Miguel López; Gonçalo J L Bernardes; Ana I Domingos

doi:10.1016/j.cmet.2020.04.013

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 journal › Article › peer-review

18 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 language	English
Pages (from-to)	1120-1135.e7
Journal	Cell Metabolism
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2020.04.013
Publication status	Published - 2 Jun 2020

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10.1016/j.cmet.2020.04.013

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Mahú, I., Barateiro, A., Rial-Pensado, E., Martinéz-Sánchez, N., Vaz, S. H., Cal, P. M. S. D., Jenkins, B., Rodrigues, T., Cordeiro, C., Costa, M. F., Mendes, R., Seixas, E., Pereira, M. M. A., Kubasova, N., Gres, V., Morris, I., Temporão, C., Olivares, M., Sanz, Y., ... Domingos, A. I. (2020). Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects. Cell Metabolism, 31(6), 1120-1135.e7. https://doi.org/10.1016/j.cmet.2020.04.013

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title = "Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects",

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.",

author = "In{\^e}s Mah{\'u} and Andreia Barateiro and Eva Rial-Pensado and Noelia Martin{\'e}z-S{\'a}nchez and Vaz, {Sandra H} and Cal, {Pedro M S D} and Benjamin Jenkins and Tiago Rodrigues and Carlos Cordeiro and Costa, {Miguel F} and Raquel Mendes and Elsa Seixas and Pereira, {Mafalda M A} and Nadiya Kubasova and Vitka Gres and Imogen Morris and Carolina Tempor{\~a}o and Marta Olivares and Yolanda Sanz and Albert Koulman and Francisco Corzana and Sebasti{\~a}o, {Ana M} and Miguel L{\'o}pez and Bernardes, {Gon{\c c}alo J L} and Domingos, {Ana I}",

year = "2020",

month = jun,

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doi = "10.1016/j.cmet.2020.04.013",

language = "English",

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Mahú, I, Barateiro, A, Rial-Pensado, E, Martinéz-Sánchez, N, Vaz, SH, Cal, PMSD, Jenkins, B, Rodrigues, T, Cordeiro, C, Costa, MF, Mendes, R, Seixas, E, Pereira, MMA, Kubasova, N, Gres, V, Morris, I, Temporão, C, Olivares, M, Sanz, Y, Koulman, A, Corzana, F, Sebastião, AM, López, M, Bernardes, GJL & Domingos, AI 2020, 'Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects', Cell Metabolism, vol. 31, no. 6, pp. 1120-1135.e7. https://doi.org/10.1016/j.cmet.2020.04.013

TY - JOUR

T1 - Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects

AU - Mahú, Inês

AU - Barateiro, Andreia

AU - Rial-Pensado, Eva

AU - Martinéz-Sánchez, Noelia

AU - Vaz, Sandra H

AU - Cal, Pedro M S D

AU - Jenkins, Benjamin

AU - Rodrigues, Tiago

AU - Cordeiro, Carlos

AU - Costa, Miguel F

AU - Mendes, Raquel

AU - Seixas, Elsa

AU - Pereira, Mafalda M A

AU - Kubasova, Nadiya

AU - Gres, Vitka

AU - Morris, Imogen

AU - Temporão, Carolina

AU - Olivares, Marta

AU - Sanz, Yolanda

AU - Koulman, Albert

AU - Corzana, Francisco

AU - Sebastião, Ana M

AU - López, Miguel

AU - Bernardes, Gonçalo J L

AU - Domingos, Ana I

PY - 2020/6/2

Y1 - 2020/6/2

N2 - 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.

AB - 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.

U2 - 10.1016/j.cmet.2020.04.013

DO - 10.1016/j.cmet.2020.04.013

M3 - Article

C2 - 32402266

SN - 1550-4131

VL - 31

SP - 1120-1135.e7

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects

Abstract

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