Lorcaserin improves glycemic control via a melanocortin neurocircuit.
Lorcaserin improves glycemic control via a melanocortin neurocircuit.
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DOI：
10.1016/j.molmet.2017.07.004
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发表时间：
2017-10
影响因子：
8.1
通讯作者：
Heisler LK
中科院分区：
文献类型：
--
作者：
Burke LK;Ogunnowo-Bada E;Georgescu T;Cristiano C;de Morentin PBM;Valencia Torres L;D'Agostino G;Riches C;Heeley N;Ruan Y;Rubinstein M;Low MJ;Myers MG;Rochford JJ;Evans ML;Heisler LK
2型糖尿病（T2 D）的发病率和死亡率不断增加，强调需要更全面地了解调节葡萄糖稳态的机制，以加快新药的鉴定。最近的报告表明，肥胖药物氯卡色林，一种5-羟色胺（5-HT，血清素）2C受体（5-HT 2CR）激动剂，改善了与肥胖T2 D患者体重减轻相关的血糖控制。在这里，我们评估氯卡色林是否对肥胖有影响而不减轻体重，以及如何实现这种效果。利用常见和遗传性T2 D的小鼠模型来探索氯卡色林对血糖控制的直接作用。在摄食量或体重不减少的情况下，氯卡色林剂量依赖性地改善T2 D小鼠模型的血糖控制。研究这种作用的机制，我们揭示了一个必要的和足够的神经化学介质氯卡色林的葡萄糖调节作用，脑前阿黑皮素（POMC）肽。为了进一步阐明氯卡色林的治疗脑回路，我们检查了POMC肽的受体靶点。我们证明，氯卡色林需要功能性黑皮质素4受体胆碱能节前神经元（MC 4 RChAT）发挥其对葡萄糖稳态的影响。相比之下，MC 4 RChAT信号传导不影响氯卡色林对进食的影响，表明支持氯卡色林治疗血糖和厌食作用的神经回路存在分歧。高胰岛素-正葡萄糖钳夹研究表明，氯卡色林可减少肝脏葡萄糖生成，增加葡萄糖处置，并改善胰岛素敏感性。这些数据表明，氯卡色林在大脑中的作用代表了T2 D的一种机制上的新型治疗：对一种流行的全球疾病具有重要意义的发现。肥胖药物氯卡色林直接改善血糖控制，而不改变能量平衡或体重。与目前的一线2型糖尿病药物不同，氯卡色林在大脑中起作用，以改善血糖控制。脑阿黑皮素原（POMC）肽是氯卡色林葡萄糖调节作用的神经化学介质。氯卡色林增加胰岛素敏感性，减少肝脏葡萄糖生成并增加葡萄糖处置。
The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT2CR) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved. Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control. Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4RChAT) to exert its effects on glucose homeostasis. In contrast, MC4RChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity. These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease. Obesity medication lorcaserin directly improves glycemic control without altering energy balance or body weight. Unlike current frontline type 2 diabetes medications, lorcaserin acts within the brain to improve glycemic control. Brain Pro-opiomelanocortin (POMC) peptides are a neurochemical mediator of lorcaserin's glucoregulatory effects. Lorcaserin increases insulin sensitivity, reduces hepatic glucose production and increases glucose disposal.
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影响因子：
3.5
作者：
Anderson EJ;Çakir I;Carrington SJ;Cone RD;Ghamari-Langroudi M;Gillyard T;Gimenez LE;Litt MJ
通讯作者：
Litt MJ
影响因子：
8.1
作者：
Burke LK;Doslikova B;D'Agostino G;Greenwald-Yarnell M;Georgescu T;Chianese R;Martinez de Morentin PB;Ogunnowo-Bada E;Cansell C;Valencia-Torres L;Garfield AS;Apergis-Schoute J;Lam DD;Speakman JR;Rubinstein M;Low MJ;Rochford JJ;Myers MG;Evans ML;Heisler LK
通讯作者：
Heisler LK
影响因子：
15.9
作者：
Berglund, Eric D.;Vianna, Claudia R.;Elmquist, Joel K.
通讯作者：
Elmquist, Joel K.
影响因子：
15.9
作者：
Berglund, Eric D.;Liu, Chen;Elmquist, Joel K.
通讯作者：
Elmquist, Joel K.
影响因子：
3.2
作者：
Burke, L. K.;Heisler, L. K.
通讯作者：
Heisler, L. K.