Hypothalamic lipid signaling in metabolism regulation

我们最近的研究表明，线粒体分裂与脂质代谢密切相关，而且 更具体地说，线粒体裂变是长链脂肪酸氧化的内在因素。 食欲性AgRP神经元(金等人，2021)。耐人寻味的是，虽然线粒体分裂与脂质有关 分解代谢过程中，线粒体融合与脂质合成代谢有关。更具体地说，丝裂原2，危急 线粒体融合蛋白在内质网(ER)-线粒体的形成中起关键作用 接触部位，使用完整脂肪酸作为世代前体的脂肪代谢的相关部位， 例如，神经鞘脂类。除了丝裂原蛋白2外，其他蛋白质也被证明可以调节ER- 线粒体相互作用。其中，轴突生长抑制因子(Nogo)是网状蛋白家族的成员 位于内质网上的Rtn4基因也在调节鞘磷脂中起着关键作用 制作(坎塔卢波等人，2015年)。在鞘磷脂中，鞘氨醇-1-磷酸(S1P)已被证明是 在许多生理过程中起着至关重要的作用，包括最近通过其 下丘脑的活动。然而，S1P合成的特定部位及其靶点在下丘脑 还没有确定身份。我们的初步数据表明，AgRP神经元富含相关的酶。 在S1P中，新生物合成及其mRNA水平受代谢状态的调节，其中禁食 上调Nogo mRNA水平，同时下调参与S1P合成的所有酶。排队 据此，我们观察到在食物剥夺过程中，弓状核中S1P水平下调。作为 S1P介导的多种不同的作用与其分泌能力有关，我们发现S1P受体 在邻近的厌食性POMC神经元中表达，S1P显著诱导其激活 通过活体钙成像。有趣的是，我们还观察到Nogo和几个 在饮食诱导的肥胖中，参与S1P从头合成的酶与S1P水平一起发生变化 (Dio)。总之，我们的数据支持了NOGO是AgRP的关键调节因子这一中心假设 调节脂肪酸代谢途径的神经元功能和摄食行为(分解代谢与 高脂饮食(HFD)过程中脂肪酸代谢的失调在DIO中起一定作用。 具体地说，我们假设，当在禁食期间激活AgRP神经元时，NOGO通过抑制S1P de 新的生物合成将引导脂肪酸通过线粒体(分解代谢途径)氧化，从而激活 AgRP神经元和诱导摄食行为(目标1)。另一方面，NOGO下调了AgRP的调控 处于FED状态的神经元将不抑制S1P的新生物合成(从而促进合成代谢途径)，并通过 S1P通过其受体作用，影响AgRP靶神经元，导致食物摄入量减少(目标2)。最后， 这一途径的失调以及由此导致的鞘磷脂代谢失衡(神经酰胺增加 HFD期间的S1P生成减少)在DIO(目标3)中起作用。

Our recent studies have demonstrated that mitochondrial fission is tightly connected to lipid metabolism and more specifically, that mitochondrial fission is an inherent element in oxidation of long chain fatty acids by the orexigenic AgRP neurons (Jin et al., 2021). Intriguingly, while mitochondrial fission is associated with lipid catabolic processes, mitochondrial fusion is associated with lipid anabolism. More specifically, mitofusin 2, critical mitochondrial fusion protein, plays a critical role in the formation of the endoplasmic reticulum (ER)-mitochondria contact sites, relevant sites of lipid metabolism where intact fatty acids are used as precursors for the generation, for example, of sphingolipids. Besides mitofusin 2, other proteins have been shown to regulate the ER- mitochondria interaction. Among those, the Neurite OutGrowth inhibitor (Nogo), a member of the reticulon family of proteins (Reticulon 4 gene; Rtn4) located on the ER, plays also a critical role in regulating sphingolipids production (Cantalupo et al., 2015). Among sphingolipids, Sphingosine-1-phosphate (S1P) has been shown to play a crucial role in a large number of physiological processes including most recently feeding behavior via its action in the hypothalamus. However, the specific site of synthesis of S1P and its target within the hypothalamus have not been identified. Our preliminary data have shown that AgRP neurons are enriched of enzymes involved in the S1P de novo biosynthesis and their mRNA levels are regulated by the metabolic state, with fasting upregulating Nogo mRNA levels while downregulating all the enzymes involved in the synthesis of S1P. In line with this, we observed that S1P levels in the arcuate nucleus are downregulated during food deprivation. As the multitude of different S1P-mediated actions is linked to its capacity to be secreted, we found that S1P receptors are expressed in the neighboring anorexigenic POMC neurons where S1P significantly induced their activation by in vivo calcium imaging. Interestingly, we also observed that the expression of Nogo and several of the enzymes involved in the S1P de novo synthesis, together with S1P levels, are altered in diet-induced obesity (DIO). Altogether our data gave impetus to the central hypothesis that Nogo is a critical regulator of AgRP neuronal function and feeding behavior by regulating fatty acid metabolic pathways (catabolism versus anabolism) and that dysregulation of fatty acid metabolism during high fat diet (HFD) plays a role in DIO. Specifically, we hypothesize that when activated during fasting in AgRP neurons, Nogo by inhibiting S1P de novo biosynthesis will direct fatty acids to oxidation by the mitochondria (catabolic pathway) thus, activating AgRP neurons and inducing feeding behavior (Aim 1). On the other hand, Nogo downregulation in AgRP neurons during fed state will disinhibit S1P de novo biosynthesis (thus promoting the anabolic pathway), and by acting via its receptors, S1P will affect AgRP target neurons resulting in decreased food intake (Aim 2). Finally, dysregulation of this pathway and the resulting imbalance in sphingolipid metabolism (increased ceramides production but decreased S1P generation) during HFD plays a role in DIO (Aim 3).