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， 更具体地说，线粒体分裂是长链脂肪酸氧化的固有因素， 食欲原性AgRP神经元（Jin等人，2021年）。有趣的是，虽然线粒体分裂与脂质 在分解代谢过程中，线粒体融合与脂质代谢有关。更具体地说，线粒体融合蛋白2， 线粒体融合蛋白，在内质网（ER）-线粒体的形成中起关键作用 接触位点，脂质代谢的相关位点，其中完整脂肪酸用作生成的前体， 例如鞘脂。除了丝裂融合蛋白2，其他蛋白质也被证明可以调节ER-1的表达。 线粒体相互作用其中，神经突生长抑制剂（Nogo），是reticulon家族的一员， 位于ER上的蛋白质（Reticulon 4基因; Rtn 4）在调节鞘脂中也起着关键作用 生产（Cantalupo等人，2015年）。在鞘脂中，鞘氨醇-1-磷酸（S1 P）已被证明 在大量的生理过程中起着至关重要的作用，包括最近的摄食行为， 下丘脑的作用。然而，合成S1 P的特定位点及其在下丘脑内的靶点 尚未被确认。我们的初步数据表明，AgRP神经元富含相关酶， 在S1 P从头生物合成和它们的mRNA水平调节的代谢状态，与禁食 上调Nogo mRNA水平，同时下调参与S1 P合成的所有酶。一致 由此，我们观察到弓状核中的S1 P水平在食物剥夺期间下调。为 许多不同的S1 P介导的作用与其分泌能力有关，我们发现S1 P受体 在邻近的促凋亡POMC神经元中表达，其中S1 P显著诱导其激活 通过体内钙成像。有趣的是，我们还观察到Nogo和几种细胞因子的表达， 参与S1 P从头合成的酶以及S1 P水平在饮食诱导的肥胖中发生改变 （DIO）。总之，我们的数据推动了核心假设，即Nogo是AgRP的关键调节因子 通过调节脂肪酸代谢途径（catalysts vs. 高脂饮食（HFD）期间脂肪酸代谢的失调在DIO中起作用。 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S1 P的表达， 新的生物合成将引导脂肪酸通过线粒体氧化（分解代谢途径），从而激活 AgRP神经元和诱导摄食行为（目的1）。另一方面，Nogo下调AgRP 进食状态下的神经元将解除S1 P从头生物合成的抑制（从而促进合成代谢途径）， 通过其受体作用，S1 P将影响AgRP靶神经元，导致食物摄入减少（目的2）。最后， 这一途径的失调和由此导致的鞘脂代谢失衡（神经酰胺增加 HFD过程中S1 P的产生（但S1 P的产生减少）在DIO中起作用（目的3）。

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).