Inflammatory signals regulate neuroendocrine control of growth and energy balance through re-modelling of mammalian hypothalamus

炎症信号通过重塑哺乳动物下丘脑来调节神经内分泌对生长和能量平衡的控制

• 批准号: BB/K001043/1
• 负责人: Peter Morgan
• 金额: $ 80.97万
• 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: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK001043%2F1
• 关键词: Inflammatory; signals; regulate; neuroendocrine; control

Obesity and overweight are major problems in the developed world, which are due to the overconsumption of calories. Increasingly it is becoming a significant problem for countries in economic transition, such as China and India. In countries such as the UK obesity affects about 30% of the population and it is a serious problem that dramatically increases the risk of clinical disease such as type-2 diabetes, cardiovascular disease and cancer. At the other end of the spectrum, growth retardation or stunting is a major problem for the poorer parts of the developing world as this reduces healthy life expectancy. Interventions designed to reverse either obesity or stunting have proved difficult and while there may be many reasons for this, one possibility is that both obesity and stunting involve long-term changes in the mechanisms controlling energy balance and growth, which make them recalcitrant to reversal. Both these physiological axes are controlled through the neuroendocrine system. In this study we aim to further our understanding of the mechanisms controlling long-term energy balance and growth by studying an animal model which is able to reversibly and naturally vary its energy balance and growth trajectory. For seasonal animals a simple change in environmental photoperiod induces dramatic and robust changes in food intake, body weight and growth. We will use the photoperiodically sensitive F344 rat in these studies. It is anticipated that the insights gained will contribute to improvements in our ability to control energy balance and growth in humans.In our work to date we have identified two types of signalling molecules and two types of cellular changes that are potentially involved in the long-term neuroendocrine control of energy balance. The signalling molecules are retinoic acid and thyroid hormone, and the two processes they control are inflammation and the birth of new neurons. All show robust and marked changes in response to switch in photoperiod and are each associated with change in body weight in the F344 rat. Retinoic acid, which is nutritionally derived from Vitamin A, has been strongly associated with growth and development. Similarly thyroid hormone has a well-known association with energy metabolism. Independently, each has recently been proposed as a neuroendocrine regulator of energy balance and growth. Completely novel to this proposal is the explanation of how retinoic acid and thyroid hormone control the balance of inflammatory signaling and cell proliferation in the hypothalamus to regulate energy balance and growth. We postulate that these pathways drive a process of cellular re-modelling of the hypothalamus, which in turn modulates neuroendocrine control of energy balance and growth. In this project we will test these ideas by blocking inflammatory signalling or cell proliferation to determine whether they are, as we predict, the long-sought for key to the mechanism that brings about long-term change in energy balance and growth - the very changes that, when abnormal, lead to obesity or metabolic disorders. We will also examine some of the details of the inflammatory signals and cell types involved. From these studies we hope to provide direct evidence for the role of inflammation and cell proliferation in the brain in the physiological control of energy balance. It is anticipated that this will provide new insights to help us understand how inflammation, which is a pathological consequence of obesity, may disrupt the control of energy balance in the obese state and more importantly how it may be reversed. Similarly the insights gained will help us understand how Vitamin A, thyroid hormone and inflammatory signalling influence growth and thus may also help us understanding why stunting can be resistant to reversal.

肥胖和超重是发达国家的主要问题，这是由于卡路里的过度消耗造成的。对于中国和印度等经济转型国家来说，它日益成为一个重大问题。在英国等国家，肥胖影响着约 30% 的人口，这是一个严重的问题，会显着增加 2 型糖尿病、心血管疾病和癌症等临床疾病的风险。另一方面，生长迟缓或发育迟缓是发展中国家较贫困地区的一个主要问题，因为这会降低健康预期寿命。事实证明，旨在逆转肥胖或发育迟缓的干预措施很困难，虽然造成这种情况的原因可能有很多，但一种可能性是，肥胖和发育迟缓都涉及控制能量平衡和生长的机制的长期变化，这使得它们难以逆转。这两个生理轴都是通过神经内分泌系统控制的。在这项研究中，我们旨在通过研究能够可逆地自然改变其能量平衡和生长轨迹的动物模型，进一步了解控制长期能量平衡和生长的机制。对于季节性动物来说，环境光周期的简单变化就会引起食物摄入、体重和生长的巨大而剧烈的变化。我们将在这些研究中使用光周期敏感的 F344 大鼠。预计所获得的见解将有助于提高我们控制人类能量平衡和生长的能力。在迄今为止的工作中，我们已经确定了两种类型的信号分子和两种类型的细胞变化，它们可能参与能量平衡的长期神经内分泌控制。信号分子是视黄酸和甲状腺激素，它们控制的两个过程是炎症和新神经元的诞生。所有这些都显示出响应光周期切换的强烈而显着的变化，并且每种变化都与 F344 大鼠的体重变化相关。视黄酸的营养成分来自维生素 A，与生长和发育密切相关。同样，甲状腺激素与能量代谢也有众所周知的关联。最近，每一种都被独立地提出作为能量平衡和生长的神经内分泌调节剂。该提案的全新之处在于解释了视黄酸和甲状腺激素如何控制下丘脑炎症信号和细胞增殖的平衡，从而调节能量平衡和生长。我们假设这些途径驱动下丘脑的细胞重塑过程，进而调节能量平衡和生长的神经内分泌控制。在这个项目中，我们将通过阻断炎症信号或细胞增殖来测试这些想法，以确定它们是否如我们预测的那样，是长期寻找的导致能量平衡和生长长期变化的机制的关键——这种变化在异常时会导致肥胖或代谢紊乱。我们还将检查相关炎症信号和细胞类型的一些细节。通过这些研究，我们希望为大脑炎症和细胞增殖在能量平衡的生理控制中的作用提供直接证据。预计这将提供新的见解，帮助我们了解炎症（肥胖的病理后果）如何破坏肥胖状态下能量平衡的控制，更重要的是如何逆转它。同样，获得的见解将帮助我们了解维生素 A、甲状腺激素和炎症信号如何影响生长，从而也可能帮助我们了解为什么发育迟缓难以逆转。

项目成果

Preclinical models for obesity research.

• DOI: 10.1242/dmm.026443
• 发表时间: 2016-11-01
• 期刊: Disease models & mechanisms
• 影响因子: 4.3
• 作者: Barrett P;Mercer JG;Morgan PJ
• 通讯作者: Morgan PJ

Fenretinide treatment prevents diet-induced obesity in association with major alterations in retinoid homeostatic gene expression in adipose, liver, and hypothalamus.

• DOI: 10.2337/db12-0458
• 发表时间: 2013-03
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Mcilroy GD;Delibegovic M;Owen C;Stoney PN;Shearer KD;McCaffery PJ;Mody N
• 通讯作者: Mody N

A neuroendocrine role for chemerin in hypothalamic remodelling and photoperiodic control of energy balance.

• DOI: 10.1038/srep26830
• 发表时间: 2016-05-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Helfer G;Ross AW;Thomson LM;Mayer CD;Stoney PN;McCaffery PJ;Morgan PJ
• 通讯作者: Morgan PJ