Role of the SCT-activated gut-brown fat-brain axis in the control of food intake

SCT激活的肠-棕色脂肪-脑轴在控制食物摄入中的作用

• 批准号: 532683878
• 负责人: Privatdozent Dr. Uwe Firzlaff
• 金额: --
• 依托单位: Lehrstuhl für Zoologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/532683878?language=en
• 关键词: Role; SCT; activated; gut; brown

The endocrine action of the gut hormone secretin, discovered 120 years ago, was initially thought to be restricted to the enteric system. Meanwhile, various effects of secretin in other organs have been reported. We identified the gut hormone as physiological mediator of meal-associated thermogenesis in brown adipose tissue (BAT). Prandial release of secretin stimulates BAT thermogenesis, which induces meal termination and thereby plays a role in the regulation of hunger and satiation demonstrating a regulatory function of BAT beyond its role as a mere catabolic heater organ. Secretin’s effect on food intake is dependent on functional BAT, namely UCP1. Vice versa, antibody-based neutralization of endogenous secretin results in an attenuated meal-induced rise of BAT temperature as well as increased food intake leading to the establishment of a gut-BAT-brain axis. This is contradictory to a previous study proposing that the anorexigenic action of secretin is mediated by central action of secretin in the brain via the secretin receptor on hypothalamic proopiomelanocortinergic neurons. We therefore aim to determine the relative contribution of central as well as direct effects of secretin in meal-associated BAT-thermogenesis and subsequent satiation by conditional knockout of the secretin receptor. This approach will enable us to compare the impact of cell-specific secretin receptor ablation either in BAT or in hypothalamic POMCergic neurons on parameters of feeding behaviour, energy balance, and obesity. Pertaining to the secretin-mediated BAT activation another essential piece of the picture related to the mechanism of communication from BAT to brain is missing. Revealing the afferent pathway of BAT-brain communication will complement the understanding of the gut-BAT-brain axis. In principle, the signalling can operate through three different mechanisms: Convective heat transfer from BAT to brain by blood circulation, neuronal transmission from BAT to brain and endocrine batokine signalling. Even though our data suggest heat transfer as a signal, complementary and redundant pathways often control physiological processes. In addition to heat transfer, several lines of evidence also point at the involvement of afferent sensory nerves and batokines. We here aim to decipher the involvement of these pathways. A role of secretin in BAT activation and in the control of food intake is also evident in humans. Secretin-mediated BAT activation is associated with increased satiation, delayed motivation to resume eating, and reduced central responses to appetizing food items. Thus, secretin affects the homeostatic and the hedonic regulation of food intake. While the homeostatic system responds to the depletion of energy stores, the hedonic system is driven by rewarding value of highly palatable foods. Therefore, we aim to deepen our understanding of the role of secretin in homeostatic- and hedonic-driven food intake.

120年前发现的肠激素分泌素的内分泌作用最初被认为仅限于肠道系统。同时，已经报道了促胰液素在其他器官中的各种作用。我们确定了在棕色脂肪组织（BAT）的膳食相关的产热的生理介质的肠道激素。胰泌素的餐时释放刺激BAT产热，其诱导进餐终止，从而在饥饿和饱足的调节中起作用，证明BAT的调节功能超出其仅仅作为分解代谢加热器器官的作用。促分泌素对食物摄入的影响取决于功能性BAT，即UCP 1。反之亦然，内源性促胰液素的基于抗体的中和导致减弱的进餐诱导的BAT温度升高以及增加的食物摄入，导致肠-BAT-脑轴的建立。这与先前的一项研究相矛盾，该研究提出，促胰液素的促肾上腺皮质激素作用是由促胰液素在脑中的中枢作用通过下丘脑前阿黑皮素能神经元上的促胰液素受体介导的。因此，我们的目标是确定中央的相对贡献，以及在膳食相关的BAT产热和随后的饱食的分泌素受体的条件性敲除的分泌素的直接影响。这种方法将使我们能够比较BAT或下丘脑POMCergic神经元中细胞特异性分泌素受体消融对摄食行为，能量平衡和肥胖参数的影响。关于促分泌素介导的BAT激活，另一个与BAT与大脑沟通机制相关的重要部分缺失了。揭示BAT-大脑通信的传入通路将补充对肠道-BAT-大脑轴的理解。原则上，信号传导可以通过三种不同的机制进行：通过血液循环从BAT到大脑的对流热传递，从BAT到大脑的神经元传递和内分泌细胞因子信号传导。尽管我们的数据表明热传递是一种信号，但互补和冗余的通路通常控制着生理过程。除了热传递，一些证据也指出传入感觉神经和batokines的参与。我们在这里的目的是破译这些途径的参与。促胰液素在BAT激活和控制食物摄入中的作用在人类中也是明显的。促分泌素介导的BAT激活与增加的饱足感、延迟的恢复进食的动机和减少的对开胃食物的中枢反应相关。因此，促胰液素影响食物摄取的稳态和享乐调节。当体内平衡系统对能量储存的消耗做出反应时，享乐系统由高度可口的食物的奖励价值驱动。因此，我们的目标是加深我们的理解，分泌素的作用，在稳态和享乐驱动的食物摄入。