Hypothalamic lipid signaling in metabolism regulation

代谢调节中的下丘脑脂质信号传导

• 批准号: 10745160
• 负责人: Sabrina Diano
• 金额: $ 69.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745160
• 关键词: Acute; Affect; Anabolism; Appetite Stimulants; Behavior; Catabolic Process; Catabolism; Ceramides; Chimeric Proteins; Chronic; Data; Development; Disinhibition; Down-Regulation; Eating; Elements; Endoplasmic Reticulum; Energy Metabolism; Enzymes; Etiology; Fasting; Fatty Acids; Feeding behaviors; Food deprivation (experimental); Generations; Genes; High Fat Diet; Hypothalamic structure; Link; Lipids; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Neurons; Obese Mice; Pathway interactions; Phenotype; Physiological Processes; Play; Production; Protein Family; Proteins; RTN4 gene; Regulation; Role; Signal Transduction; Site; Sphingolipids; Sphingosine-1-Phosphate Receptor; Structure of nucleus infundibularis hypothalami; Testing; Up-Regulation; diet-induced obesity; fatty acid metabolism; feeding; in vivo calcium imaging; insight; lipid metabolism; long chain fatty acid; member; motivated behavior; novel; oxidation; parabrachial nucleus; sphingosine 1-phosphate

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).

我们最近的研究表明，线粒体裂变与脂质代谢和 更具体地说，线粒体裂变是长链脂肪酸氧化的固有元素 甲状腺素AGRP神经元（Jin等，2021）。有趣的是，线粒体裂变与脂质有关 分解代谢过程，线粒体融合与脂质合物相关。更具体地说，丝线2，关键 线粒体融合蛋白，在内质网（ER） - 松粒的形成中起关键作用 接触部位，脂质代谢的相关位点，将完整的脂肪酸用作代理的前体 例如，鞘脂。除了丝线反蛋白2外，还显示其他蛋白质可以调节ER- 线粒体相互作用。其中，神经突生长抑制剂（Nogo），是网状家族的成员 位于ER上的蛋白质（网状4基因； RTN4）的蛋白质，在调节鞘脂中起着至关重要的作用 生产（Cantalupo等，2015）。在鞘脂中，鞘氨醇1-磷酸（S1P）已显示为 在大量生理过程中起着至关重要的作用，包括最近通过其喂养行为 下丘脑的作用。但是，在下丘脑内的S1P合成及其靶标的特定位点 尚未确定。我们的初步数据表明，AGRP神经元富含所涉及的酶 在S1P de从头生物合成及其mRNA水平受到代谢状态的调节，禁食 上调Nogo mRNA水平，同时下调与S1P合成的所有酶。排队 因此，我们观察到弓形核中的S1P水平在食物剥夺过程中被下调。作为 多种不同的S1P介导的作用与其分泌能力有关，我们发现S1P受体 在邻近的厌食POMC神经元中表达，其中S1P显着诱导了它们的激活 通过体内钙成像。有趣的是，我们还观察到Nogo的表达和几个 饮食诱导的肥胖症中，参与从头合成的S1P de从头合成的酶也改变了 （dio）。我们的数据完全推动了nogo是AGRP的关键调节剂的中心假设 神经元功能和喂养行为通过调节脂肪酸代谢途径（分解代谢与 代谢）和高脂肪饮食（HFD）期间脂肪酸代谢的失调在DIO中起作用。 具体而言，我们假设在AGRP神经元中禁食期间激活时，Nogo抑制S1P DE NOVO生物合成将通过线粒体（分解代谢途径）将脂肪酸引导为氧化，因此激活 AGRP神经元和诱导喂养行为（AIM 1）。另一方面，AGRP中的Nogo下调 联邦状态期间的神经元将抑制从头生物合成（从而促进合成代谢途径），并通过 通过其受体作用，S1P会影响AGRP靶神经元，导致食物摄入量减少（AIM 2）。最后， 该途径的失调和鞘脂代谢的导致不平衡（神经酰胺增加 HFD期间的生产但S1P生成降低）在DIO中起作用（AIM 3）。