Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.
Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.
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DOI：
10.1016/j.cmet.2020.04.013
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发表时间：
2020-06-02
期刊：
影响因子：
29
通讯作者：
Domingos AI
中科院分区：
文献类型：
--
作者：
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
安非他明类的抗肥胖药物（AMPH）在大脑中起作用，以减少食欲和增加运动。它们的特征还在于不良心血管作用，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，我们表明AMPH的心脏副作用来自大脑，可以通过PEG化（PEGyAMPH）来排除其中枢作用。PEGyAMPH不进入大脑，并通过β2-肾上腺素受体促进SNS活动，通过增加脂解和产热作用保护小鼠免受肥胖，同时增加散热，作为能量库增加能量消耗，而不改变食物摄入或运动活动。因此，我们提供了一个新的类别的纯外周抗肥胖交感神经促进剂，没有任何心血管和大脑相关的副作用的原理证明。聚乙二醇化安非他明（PEGyAMPH）不会进入大脑，也没有行为影响PEGyAMPH促进体重减轻，通过耦合产热热散热PEGyAMPH是一种交感神经促进剂，需要β2-肾上腺素受体功能PEGyAMPH是心脏保护，除非直接输送到大脑PEGyAMPH是一种脑保护改性安非他明，是一种心脏中性抗肥胖药物。与安非他明不同，安非他明在大脑中起作用以增加饱腹感和运动，PEGyAMPH将产热与散热结合起来，通过同时促进血管舒张和促进交感神经元的活动来激活全身能量库。
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. 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.
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影响因子：
11.4
作者：
Contreras C;Nogueiras R;Diéguez C;Rahmouni K;López M
通讯作者：
López M
DOI：
10.1046/j.1467-789x.2001.00043.x
发表时间：
2001-11-01
期刊：
Obesity reviews : an official journal of the International Association for the Study of Obesity
影响因子：
--
作者：
Harper, J A;Dickinson, K;Brand, M D
通讯作者：
Brand, M D
影响因子：
3.6
作者：
BORBELY, AA;BAUMANN, IR;WASER, PG
通讯作者：
WASER, PG
白色脂肪组织的神经支配和脂肪分解的控制。
影响因子：
7.4
作者：
Bartness, Timothy J.;Liu, Yang;Shrestha, Yogendra B.;Ryu, Vitaly
通讯作者：
Ryu, Vitaly
DOI：
10.1177/0269881113482532
发表时间：
2013-06
期刊：
Journal of psychopharmacology (Oxford, England)
影响因子：
--
作者：
Heal DJ;Smith SL;Gosden J;Nutt DJ
通讯作者：
Nutt DJ