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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 publication

DOI

10.1016/j.cmet.2020.04.013

Type

Journal article

Journal

Cell Metab

Publication Date

02/06/2020

Volume

31

Pages

1120 - 1135.e7

Keywords

amphetamine, heat dissipation, lipolysis, obesity, sympathetic-nervous-system, sympathofacilitators, sympathomimetics, tachycardia, thermogenesis, thermoregulation