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

120年前发现的胃肠激素促胰液素的内分泌作用，最初被认为仅限于肠道系统。与此同时，有关促胰液素在其他器官中的各种作用也有报道。我们发现肠道激素是棕色脂肪组织(BAT)中与膳食相关的产热的生理介质。每餐分泌素的释放刺激蝙蝠产热，从而导致食物终止，从而在调节饥饿和饱足方面发挥作用，表明蝙蝠的调节功能不仅仅是作为分解代谢的加热器官。促胰液素对食物摄取的影响依赖于功能性BAT，即UCP1。反之亦然，基于抗体的内源性促胰液素中和导致减弱进食诱导的蝙蝠体温升高，以及增加食物摄入量，从而建立肠道-蝙蝠-脑轴。这与以前的一项研究相矛盾，该研究认为促胰液素的厌食作用是通过下丘脑前阿片黑质皮质能神经元上的促胰液素受体在大脑中的中枢作用来实现的。因此，我们的目标是通过有条件地敲除促胰液素受体，确定促胰液素在与膳食相关的蝙蝠产热和随后的饱食中的中央和直接作用的相对贡献。这一方法将使我们能够比较BAT或下丘脑POM神经元中细胞特异性分泌素受体切除对摄食行为、能量平衡和肥胖参数的影响。关于分泌素介导的蝙蝠激活，与蝙蝠到大脑的通讯机制有关的另一个关键部分缺失了。揭示蝙蝠-脑交流的传入通路将补充对肠道-蝙蝠-脑轴的理解。原则上，信号可以通过三种不同的机制运作：通过血液循环从蝙蝠到大脑的对流热量传递，从蝙蝠到大脑的神经元传递和内分泌巴托克信号。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往往控制着生理过程。除了热传递，几条证据也表明传入感觉神经和巴托酮参与其中。我们在这里的目标是破译这些途径的参与。分泌素在蝙蝠激活和控制食物摄入量方面的作用在人类身上也很明显。分泌素介导的BAT激活与饱腹感增加、恢复进食的动机延迟以及对开胃食物的中枢反应减少有关。因此，促胰液素影响食物摄入量的动态平衡和享乐调节。虽然体内平衡系统对能量储备的耗尽做出反应，但享乐系统是由高度美味的食物的奖励价值驱动的。因此，我们的目标是加深我们对促胰液素在动态平衡和享乐主义驱动的食物摄入中的作用的理解。

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.