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

肥胖和超重是发达国家的主要问题，这是由于过度消耗卡路里造成的。对于中国和印度等处于经济转型中的国家来说，这正日益成为一个重大问题。在英国等国家，肥胖影响了大约30%的人口，这是一个严重的问题，极大地增加了患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，发育迟缓或发育迟缓是发展中国家较贫穷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，旨在扭转肥胖或发育迟缓的干预措施很困难，尽管可能有很多原因，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，这使得它们无法逆转。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，我们旨在通过研究一种能够可逆和自然地改变其能量平衡和生长轨迹的动物模型来加深我们对长期能量平衡和生长控制机制的理解。对于季节性动物来说，环境光周期的简单变化就会导致摄食量、体重和生长的剧烈而强劲的变化。我们将在这些研究中使用对光周期敏感的F344大鼠。预计所获得的洞察力将有助于提高我们控制能量平衡和人类生长的能力。在我们的工作中，到目前为止，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，它们可能涉及长期的神经内分泌控制能量平衡。信号分子是维甲酸和甲状腺激素，它们控制的两个过程是炎症和新神经元的诞生。它们都表现出对光周期转换的强烈和显著的变化，并且每个都与F344大鼠体重的变化有关。维甲酸是从维生素A中提取的营养成分，与生长发育密切相关。同样，众所周知，甲状腺激素与能量代谢有关。它们各自独立地被认为是能量平衡和生长的神经内分泌调节因子。对这一提议的完全新颖的解释是，维甲酸和甲状腺激素如何控制下丘脑中炎症信号和细胞增殖的平衡，以调节能量平衡和生长。我们推测，这些通路驱动下丘脑的细胞重建过程，进而调节神经内分泌对能量平衡和生长的控制。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，是带来能量平衡和生长长期变化的机制的长期关键--当异常时，正是这些变化导致肥胖或代谢紊乱。我们还将检查所涉及的炎症信号和细胞类型的一些细节。通过这些研究，我们希望为脑内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的证据。预计这将为我们提供新的见解，帮助我们了解炎症--肥胖的病理后果--可能如何扰乱肥胖状态下能量平衡的控制，更重要的是，它可能如何逆转。同样，所获得的见解将帮助我们理解维生素A、甲状腺激素和炎症信号是如何影响生长的，因此也可能有助于我们理解为什么发育迟缓可以抵抗逆转。

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.