Defining the Role of the Human Lipodystrophy Protein Seipin in Adipose Tissue Development and Metabolic Disease.

定义人类脂肪营养不良蛋白 Seipin 在脂肪组织发育和代谢疾病中的作用。

• 批准号: MR/L002620/1
• 负责人: Justin Rochford
• 金额: $ 43.4万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL002620%2F1
• 关键词: Defining; Role; Human; Lipodystrophy; Protein

Nearly 1 in 4 adults in the UK is obese so obesity represents a major medical and economic challenge of the 21st century. Obesity is a substantial risk factor for the development of a number of serious metabolic diseases, including cardiovascular disease and type 2 diabetes, and also certain cancers. This illustrates the personal and national health implications of the current obesity crisis. Unfortunately, the paucity of effective obesity drug therapies highlights the need for a greater understanding of the biological systems that regulate body weight and how obesity leads to the development of metabolic diseases.The co-incidence of obesity with metabolic diseases might make one think that inhibiting the development of fat (adipose) tissue would be a useful therapy. However, we know from patients unable to make fat tissue (lipodystrophy) that this is not the case. Rather, adipose tissue is a critical safe store for dietary nutrients, especially fat. When this is absent the fat instead accumulates in other tissues causing their dysfunction and resulting in metabolic disease more severe than that seen in obese individuals. We now know that, paradoxically, similar mechanisms may cause metabolic disease in common obesity. Here, whilst fat tissue is abundant, the fat cells within the tissue are dysfunctional and cannot store and release the dietary nutrients as they should. Again this leads to their accumulation in other tissues and so metabolic disease. It is now clear that about 10% of fat cells in humans are renewed each year. If we could make these new cells function better, and/or improve the function of existing fat cells we could significantly reduce metabolic disease in common obesity.This project focuses on a protein called seipin, which when disrupted causes lipodystrophy in humans. Therefore, we know it is essential for human fat tissue development and function. We know very little about what seipin does but if we can work this out we will learn more about the process of fat cell formation and maybe even alter seipin's actions to treat metabolic disease by improving the function of fat cells. We know that losing seipin prevents humans from making fat entirely. However, we don't know if this is because it is needed in the developing early embryo to make the stem cells that will later become fat cells, or if it is instead needed to allow the stem cells to mature into fat cells when the fat tissue appears later in development. In addition we do not know if seipin is needed for the normal renewal of fat cells in adults or to allow the increased fat cell number that happens when adults gain weight in obesity. This project will aim to answer these questions. State of the art methods will also allow us to determine exactly what seipin does inside the developing fat cell and will show us more about why seipin is so important for fat cell formation.Overall we aim to identify the precise functions of seipin, which may allow us to find ways to modify its function. Importantly we will see what the effects of doing this in humans might be and so whether this might provide novel therapies to treat the rising epidemic of obesity associated diseases.

英国近四分之一的成年人肥胖，因此肥胖是21世纪世纪的一个重大医学和经济挑战。肥胖是许多严重代谢疾病（包括心血管疾病和2型糖尿病以及某些癌症）发生的重要风险因素。这说明了当前肥胖危机对个人和国家健康的影响。不幸的是，缺乏有效的肥胖药物治疗突出了需要更好地了解调节体重的生物系统以及肥胖如何导致代谢性疾病的发展。肥胖与代谢性疾病的并发症可能会让人认为抑制脂肪组织的发展将是一种有用的治疗方法。然而，我们从无法制造脂肪组织（脂肪营养不良）的患者那里知道，情况并非如此。相反，脂肪组织是膳食营养素，特别是脂肪的关键安全储存。当缺乏这一点时，脂肪反而积聚在其他组织中，导致它们的功能障碍，并导致比肥胖个体更严重的代谢疾病。我们现在知道，矛盾的是，类似的机制可能会导致普通肥胖症的代谢疾病。在这里，虽然脂肪组织是丰富的，但组织内的脂肪细胞功能失调，不能像它们应该的那样储存和释放膳食营养素。这再次导致它们在其他组织中积累，从而导致代谢疾病。现在很清楚，人类每年约有10%的脂肪细胞更新。如果我们能使这些新细胞更好地发挥作用，和/或改善现有脂肪细胞的功能，我们就能显著减少常见肥胖症的代谢疾病。因此，我们知道它对人体脂肪组织的发育和功能至关重要。我们对seipin的作用知之甚少，但如果我们能解决这个问题，我们将更多地了解脂肪细胞形成的过程，甚至可能通过改善脂肪细胞的功能来改变seipin治疗代谢疾病的作用。我们知道失去seipin会阻止人类完全制造脂肪。然而，我们不知道这是否是因为它在发育中的早期胚胎中需要制造后来成为脂肪细胞的干细胞，或者当脂肪组织在发育后期出现时，它是否需要允许干细胞成熟为脂肪细胞。此外，我们不知道seipin是否需要成年人脂肪细胞的正常更新或允许成年人肥胖时体重增加的脂肪细胞数量增加。本项目旨在回答这些问题。最先进的方法也将使我们能够准确地确定seipin在发育中的脂肪细胞内的作用，并向我们展示为什么seipin对脂肪细胞形成如此重要。总的来说，我们的目标是确定seipin的精确功能，这可能使我们能够找到修改其功能的方法。重要的是，我们将看到在人类身上这样做的效果，以及这是否可能提供新的疗法来治疗日益流行的肥胖相关疾病。

项目成果

Bscl2 Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy.

• DOI: 10.3390/jcm10030441
• 发表时间: 2021-01-23
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Roumane A;Mcilroy GD;Balci A;Han W;Delibegović M;Baldassarre M;Newsholme P;Rochford JJ
• 通讯作者: Rochford JJ

Lorcaserin improves glycemic control via a melanocortin neurocircuit.

• DOI: 10.1016/j.molmet.2017.07.004
• 发表时间: 2017-10
• 期刊: Molecular metabolism
• 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

Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.

• DOI: 10.1016/j.molmet.2018.01.019
• 发表时间: 2018-04
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Mcilroy GD;Suchacki K;Roelofs AJ;Yang W;Fu Y;Bai B;Wallace RJ;De Bari C;Cawthorn WP;Han W;Delibegović M;Rochford JJ
• 通讯作者: Rochford JJ