果蝇神经内分泌细胞感受氨基酸水平进而调控脂肪组织氨基酸代谢的分子机制

生物体的一个基本功能是感受摄入的营养类型和数量，进而调节自身的代谢状态。因此发现特定营养的感受原理及其生物效应的分子机制，不仅可以理解营养感受细胞和效应细胞的工作原理，也为特异地改变代谢状态，进而调控生理和病理过程提供了可能。本课题组通过前期实验，发现果蝇脂动激素（Akh）分泌细胞是一个之前未被认识的氨基酸感受器。这些细胞被特定氨基酸激活后释放Akh（胰高血糖素类似物），进而诱发脂肪体细胞的钙离子震荡和代谢变化。我们还发现，苏氨酸与甲硫氨酸对于快速发育中的果蝇幼虫具有依赖于Akh信号的生物毒性，这一发现显示氨基酸感受通路可能参与了特定营养对发育的调控。本项目拟在现有发现基础上，进一步阐明Akh分泌细胞感知特定氨基酸的分子机制，明确Akh信号对脂肪细胞氨基酸代谢的影响，并揭示特定氨基酸产生激素依赖的发育毒性的原因。本研究将从多细胞通信的角度促进对生物体氨基酸感知及其调控作用的深入理解。

One fundamental function of most living organisms is to sense the type and quantity of nutrients ingested, such that to further regulate their metabolic state. Therefore, understanding the molecular mechanism of how a specific nutrition can be detected and its subsequent metabolic effects, will not only provide knowledge about the mechanisms of how nutritional sensor and effector cells function but also offer opportunities to precisely manipulate the metabolic states and to control different physiological and pathological processes. Through functional live-cell imaging of fruit fly larvae, our team found that Akh-producing cells are a previously unidentified amino acid sensor. These neuroendocrine cells can be activated by specific amino acids, then release a peptide hormone Akh, a functional analogue of human glucagon, which will induce Ca2+ oscillation and metabolic change in the fat body cells. We further found that particular amino acids (threonine and methionine) show significant Akh-dependent toxicity in the fast-growing fly larvae, suggesting that this amino acid-sensing mechanism may be involved in the nutrient-dependent development regulation. Based on our current findings, we will investigate: the molecular mechanism of how Akh-producing cells perceive specific amino acids, the effect of Akh signaling on the amino acid metabolism in adipocytes, and how specific amino acids generate hormone-dependent developmental toxicity. This study will provide in-depth knowledge about the perception and biological effects of amino acid from an intercellular communication perspective.