Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects

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. [Display omitted] •PEGylated amphetamine (PEGyAMPH) does not enter the brain, nor has behavioral effects•PEGyAMPH promotes weight loss, by coupling thermogenesis to heat dissipation•PEGyAMPH is a sympathofacilitator, requiring β2-adrenoceptor function•PEGyAMPH is cardioprotective, unless directly delivered into the brain PEGyAMPH is a brain-sparing modified amphetamine that is a cardioneutral anti-obesity drug. Unlike amphetamines, which act in the brain to increase satiety and locomotion, PEGyAMPH couples thermogenesis to heat dissipation, activating a whole-body energy sink by simultaneously promoting vasodilation and facilitating the activity of sympathetic neurons.