The role of T1R1/T1R3 in satiety

T1R1/T1R3 在饱腹感中的作用

• 批准号: MR/J010944/1
• 负责人: Anjali Amin
• 金额: $ 37.53万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ010944%2F1
• 关键词: role; T1R1; T1R3; satiety

High protein diets inhibit food intake and facilitate weight loss in both animals and humans. Experiments on animals have shown that this effect is not related to reduced palatability. However, these diets are difficult to adhere to and have therefore proved unsuccessful as treatments for obesity. Establishing the biological mechanisms that mediate the beneficial effects of high protein diets may reveal new targets for drugs to treat obesity. Amino acids are the products of protein digestion. Evidence suggests the gut may sense the amino acids generated by protein digestion, and release hormones that signal to the brain to reduce appetite. My project will investigate whether a particular amino acid sensor, called T1R1/T1R3, is involved in the regulation of appetite and whether it is responsible for the beneficial effects of a high protein diet. These experiments will assess the utility of targeting T1R1/T1R3 to treat obesity. The gut responds to products of digestion such as fats and sugars, and similarly may recognise amino acids. There is evidence from both animals and humans that protein affects gut hormones which control appetite. The T1R1/T1R3 sensor was initially discovered in the taste tissue of the tongue but has since been found to be present in the human and rodent gut. It is also found in other regions of the body. However, the role of this sensor in the regulation of hormones controlling appetite has not previously been studied. Certain amino acids, including L-lysine and L-arginine, activate the T1R1/T1R3. My pilot studies in rodents show that L-arginine and L-lysine can stimulate the release of gut hormones that reduce appetite. Work carried out in cells (in test tubes in the laboratory) show that L-lysine and L-arginine stimulate the release of one of the important hormones that regulates appetite, called glucagon-like peptide-1 (GLP-1). Oral administration of L-arginine or L-lysine to rats stimulates the release of the appetite-inhibiting gut hormones GLP-1 and peptide YY (PYY). . In addition, giving L-lysine orally reduces food intake in rodents. These data suggest that targeting T1R1/T1R3 may be a useful approach for anti-obesity agents. Research plan: I will initially determine where in the gut the T1R1/T1R3 sensor is found, and establish whether it is present in the same cells as GLP-1 and PYY. I will then administer amino acids known to activate the T1R1/T1R3 sensor into the regions of the gut which express this sensor in anaesthetised mice, and then measure the release of GLP-1 and PYY. A genetically modified mouse lacking T1R1/T1R3 signalling will be created. I will then administer the same amino acids to these animals and measure the effect on food intake and the hormones that control appetite. These studies will confirm that theT1R1/T1R3 is responsible for the effects of amino acids on appetite and gut hormone release. Following this, a different genetically modified mouse will be created which specifically lacks T1R1/T1R3 signalling in the gut. The effect of amino acids on food intake and gut hormone release will then be determined in these animals. This will establish whether it is specifically the T1R1 sensor in the gut that is necessary for the effects of these amino acids in reducing appetite. The final experiment will study the response of the genetically modified mouse which lacks T1R1/T1R3 signalling in the gut to a high protein diet. I will measure food intake and body weight daily. The animals will be monitored over a 12 week period, after which their levels of body fat and lean tissue will be analysed. These experiments will determine the mechanisms by which the T1R1/T1R3 sensor in the gut regulates food intake and the hormones that control appetite. The results of this experiment may suggest that the T1R1/T1R3 sensor is a promising target for a new drug to tackle obesity.

高蛋白饮食抑制食物摄入，促进动物和人类减肥。动物实验表明，这种影响与降低适口性无关。然而，这些饮食很难坚持，因此被证明是不成功的治疗肥胖。建立高蛋白饮食有益作用的生物学机制可能为肥胖药物的治疗提供新的靶点。氨基酸是蛋白质消化的产物。有证据表明，肠道可以感知蛋白质消化产生的氨基酸，并释放激素，向大脑发出减少食欲的信号。我的项目将调查一种叫做T1R1/T1R3的特殊氨基酸传感器是否参与食欲调节，以及它是否对高蛋白饮食的有益影响负责。这些实验将评估靶向T1R1/T1R3治疗肥胖的效用。肠道对脂肪和糖等消化产物有反应，同样也可以识别氨基酸。动物和人类都有证据表明，蛋白质会影响控制食欲的肠道激素。T1R1/T1R3传感器最初是在舌头的味觉组织中发现的，但后来被发现存在于人类和啮齿动物的肠道中。它也存在于身体的其他部位。然而，这种传感器在调节控制食欲的激素中的作用以前还没有被研究过。某些氨基酸，包括l -赖氨酸和l -精氨酸，激活T1R1/T1R3。我在啮齿类动物身上的初步研究表明，l -精氨酸和l -赖氨酸可以刺激肠道激素的释放，从而降低食欲。在细胞中（在实验室的试管中）进行的研究表明，l -赖氨酸和l -精氨酸刺激了调节食欲的一种重要激素的释放，这种激素被称为胰高血糖素样肽-1 （GLP-1）。大鼠口服l -精氨酸或l -赖氨酸可刺激抑制食欲的肠道激素GLP-1和肽YY （PYY）的释放。此外，口服l -赖氨酸可减少啮齿动物的食物摄入量。这些数据表明，靶向T1R1/T1R3可能是一种有效的抗肥胖药物。研究计划：我将首先确定肠道中T1R1/T1R3传感器的位置，并确定它是否存在于与GLP-1和PYY相同的细胞中。然后，我将把已知的激活T1R1/T1R3传感器的氨基酸注射到麻醉小鼠肠道中表达该传感器的区域，然后测量GLP-1和PYY的释放。将创造出缺乏T1R1/T1R3信号的转基因小鼠。然后，我将给这些动物注射相同的氨基酸，并测量其对食物摄入量和控制食欲的激素的影响。这些研究将证实t1r1 /T1R3负责氨基酸对食欲和肠道激素释放的影响。在此之后，一种不同的转基因小鼠将被创造出来，这种小鼠在肠道中特别缺乏T1R1/T1R3信号。氨基酸对食物摄入和肠道激素释放的影响将在这些动物中被确定。这将确定肠道中的T1R1传感器是否对这些氨基酸减少食欲的作用是必要的。最后的实验将研究肠道中缺乏T1R1/T1R3信号的转基因小鼠对高蛋白饮食的反应。我会每天测量食物摄入量和体重。这些动物将接受为期12周的监测，之后将分析它们的体脂和瘦组织水平。这些实验将确定肠道中T1R1/T1R3传感器调节食物摄入和控制食欲的激素的机制。这项实验的结果可能表明，T1R1/T1R3传感器是一种治疗肥胖的新药的有希望的靶点。

项目成果

L-cysteine suppresses ghrelin and reduces appetite in rodents and humans.

• DOI: 10.1038/ijo.2014.172
• 发表时间: 2015-03
• 期刊: INTERNATIONAL JOURNAL OF OBESITY
• 影响因子: 4.9
• 作者: McGavigan, A. K.;O'Hara, H. C.;Amin, A.;Kinsey-Jones, J.;Spreckley, E.;Alamshah, A.;Agahi, A.;Banks, K.;France, R.;Hyberg, G.;Wong, C.;Bewick, G. A.;Gardiner, J. V.;Lehmann, A.;Martin, N. M.;Ghatei, M. A.;Bloom, S. R.;Murphy, K. G.
• 通讯作者: Murphy, K. G.

Neuromedin B stimulates the hypothalamic-pituitary-gonadal axis in male rats

• DOI: 10.1016/j.regpep.2013.10.002
• 发表时间: 2013-11-10
• 期刊: REGULATORY PEPTIDES
• 作者: Boughton, C. K.;Patel, S. A.;Murphy, K. G.
• 通讯作者: Murphy, K. G.

Hepcidin levels in diabetes mellitus and polycystic ovary syndrome.

• DOI: 10.1111/dme.12262
• 发表时间: 2013-12
• 期刊: Diabetic medicine : a journal of the British Diabetic Association
• 作者: Sam AH;Busbridge M;Amin A;Webber L;White D;Franks S;Martin NM;Sleeth M;Ismail NA;Daud NM;Papamargaritis D;Le Roux CW;Chapman RS;Frost G;Bloom SR;Murphy KG
• 通讯作者: Murphy KG

L-arginine promotes gut hormone release and reduces food intake in rodents.

• DOI: 10.1111/dom.12644
• 发表时间: 2016-05
• 期刊: Diabetes, obesity & metabolism
• 作者: Alamshah A;McGavigan AK;Spreckley E;Kinsey-Jones JS;Amin A;Tough IR;O'Hara HC;Moolla A;Banks K;France R;Hyberg G;Norton M;Cheong W;Lehmann A;Bloom SR;Cox HM;Murphy KG
• 通讯作者: Murphy KG

l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents.

• DOI: 10.1038/ijo.2017.164
• 发表时间: 2017-11
• 期刊: International journal of obesity (2005)
• 作者: Alamshah A;Spreckley E;Norton M;Kinsey-Jones JS;Amin A;Ramgulam A;Cao Y;Johnson R;Saleh K;Akalestou E;Malik Z;Gonzalez-Abuin N;Jomard A;Amarsi R;Moolla A;Sargent PR;Gray GW;Bloom SR;Murphy KG
• 通讯作者: Murphy KG