PDF(Pubmed)
Abstract：
In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions.
摘要：
在C.elegans机制中，外周器官将内部状态信息传递给神经系统仍然未知，尽管强有力的证据表明这种信号确实存在。在这里，我们报告了一种称为INS-7的祖先胰岛素超家族的肽的发现，该肽充当肠内分泌肽，并由肠道的特化细胞分泌。INS-7分泌受到食物戒断的刺激,在禁食期间增加，并作为真正的肠-脑肽，减弱神经肽的释放，该神经肽驱动外周脂肪损失。因此，INS-7作为来自肠道的稳态信号起作用，在食物短缺期间控制神经元驱动以刺激脂肪损失。机械上,INS-7作为典型DAF-2受体的拮抗剂起作用,并通过ASI神经元中的FOXO和AMPK信号传导起作用。系统发育分析表明，与常规哺乳动物胰岛素和IGF肽相比，INS-7与广泛的胰岛素/松弛素超家族成员具有更大的相似性。由具有肠内分泌功能的特化肠细胞分泌的内源性胰岛素拮抗剂的发现表明肠的意想不到的和重要的特性及其在指导神经元功能中的作用。
