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.

安非他明 (AMPH) 类抗肥胖药物作用于大脑，降低食欲并增加运动能力。它们还具有不良心血管作用的特征，尽管没有任何 体内 证据，但其起源归因于心脏中的直接拟交感神经作用。在这里，我们证明 AMPH 的心脏副作用源自大脑，可以通过聚乙二醇化 (PEGyAMPH) 来规避，以排除其中枢作用。PEGyAMPH 不进入大脑，并通过 β ₂ -肾上腺素受体促进 SNS 活动，通过增加脂肪分解和生热作用以及更高的散热性来保护小鼠免受肥胖，这可作为能量汇，在不改变食物摄入或运动活动的情况下增加能量消耗。因此，我们为一类新型的专门外周抗肥胖交感神经促进剂提供了原理验证，该类药物没有任何心血管和大脑相关的副作用。