Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression.
Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression.
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DOI：
10.1016/j.molmet.2022.101665
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发表时间：
2023-02
影响因子：
8.1
通讯作者：
Heisler, Lora K.
中科院分区：
文献类型：
--
作者：
Wagner, Stefan;Brierley, Daniel I.;Leeson-Payne, Alasdair;Jiang, Wanqing;Chianese, Raffaella;Lam, Brian Y. H.;Dowsett, Georgina K. C.;Cristiano, Claudia;Lyons, David;Reimann, Frank;Gribble, Fiona M.;de Morentin, Pablo B. Martinez;Yeo, Giles S. H.;Trapp, Stefan;Heisler, Lora K.
超重和肥胖是发达国家的地方病，对人类健康有很大的负面影响。已开发的治疗肥胖症的药物包括G蛋白偶联受体胰高血糖素样肽-1(GLP-1R；例如利拉鲁肽)、5-羟色胺2C(5-HT2CR；例如氯卡瑟林)和黑素皮质素4(MC4R)的激动剂，这些药物主要通过抑制食物摄入来减轻体重。然而，治疗性食物摄取抑制作用的潜在机制仍在定义中，并在这里进行了调查。我们用单核RNA测序(Nuc-Seq)和组织化学方法对孤束核(PPGNTS)中的PPG神经元进行了分析。接下来，我们通过病毒消融PPGNTS神经元，研究了肥胖药物对食物摄入量的影响对PPGNTS神经元的需求。最后，我们评估了利拉鲁肽和氯酪蛋白联合使用对食物摄入量的影响。我们发现5-HT2CRs广泛存在于PPGNTS簇中，而不是GLP-1RS或MC4Rs，并且氯酪蛋白显著激活PPGNTS神经元。因此，消融PPGNTS神经元可以阻止氯酪蛋白减少摄食量，但不能阻止MC4R激动剂黑素-II的减少，这表明了PPGNTS 5-HT2CR表达的功能意义。最后，与单一治疗相比，氯卡瑟林与GLP-1R激动剂利拉鲁肽或exendin-4联合使用产生了更大的食物摄入量减少。这些发现确定了减肥药氯卡色林产生治疗效果的必要机制，即脑干PPGNTS神经元。此外，这些数据揭示了一种策略，通过与5-HT2CR激动剂联合给药，增加目前肥胖一线治疗的GLP-1R激动剂的治疗概况。转录组学显示，大多数PPGNTS神经元表达5-HT2CRs，但不表达MC4Rs。临床前MC4R激动剂不需要PPGNTS神经元减少摄食。减肥药5-HT2CR激动剂氯酪蛋白需要PPGNTS神经元减少食物摄入量。利拉鲁肽和氯酪蛋白联合使用可增强摄食抑制作用。
Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HT2CR; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here. We profiled PPG neurons in the nucleus of the solitary tract (PPGNTS) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGNTS neurons for obesity medication effects on food intake by virally ablating PPGNTS neurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin. We found that 5-HT2CRs, but not GLP-1Rs or MC4Rs, were widespread in PPGNTS clusters and that lorcaserin significantly activated PPGNTS neurons. Accordingly, ablation of PPGNTS neurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPGNTS 5-HT2CR expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy. These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPGNTS neurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HT2CR agonists. Transcriptomics reveals most PPGNTS neurons express 5-HT2CRs, but not MC4Rs. Preclinical MC4R agonist does not require PPGNTS neurons to decrease feeding. Obesity medication 5-HT2CR agonist lorcaserin requires PPGNTS neurons to reduce food intake. Liraglutide and lorcaserin combination produces augmented feeding suppression.
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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：
8.1
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
通讯作者：
Heisler LK
影响因子：
8.1
作者：
Holt MK;Llewellyn-Smith IJ;Reimann F;Gribble FM;Trapp S
通讯作者：
Trapp S
影响因子：
3.3
作者：
Llewellyn-Smith, I. J.;Reimann, F.;Gribble, F. M.;Trapp, S.
通讯作者：
Trapp, S.
影响因子：
64.8
作者：
Ghamari-Langroudi M;Digby GJ;Sebag JA;Millhauser GL;Palomino R;Matthews R;Gillyard T;Panaro BL;Tough IR;Cox HM;Denton JS;Cone RD
通讯作者：
Cone RD