Identification of sphingolipid metabolites that induce obesity via misregulation of appetite, caloric intake and fat storage in Drosophila.
Identification of sphingolipid metabolites that induce obesity via misregulation of appetite, caloric intake and fat storage in Drosophila.
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DOI：
10.1371/journal.pgen.1003970
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Harris GL
中科院分区：
文献类型：
--
作者：
Walls SM Jr;Attle SJ;Brulte GB;Walls ML;Finley KD;Chatfield DA;Herr DR;Harris GL
肥胖症的定义是过度的脂质积累。然而，脂质在其进展中发挥的积极机制作用尚不清楚。神经酰胺（鞘脂代谢的代谢中心）的蓄积与人类和模型系统中的代谢综合征和肥胖相关。在这里，我们使用果蝇基因操作，导致积累或耗尽的神经酰胺和鞘氨醇-1-磷酸（S1 P）中间体。使用液相色谱电喷雾电离串联质谱法对各种鞘脂代谢基因的突变体进行鞘脂组学特征分析。使用生化测定和显微镜检查来评估肥胖的经典标志，包括脂肪储存升高、体重增加、对饥饿诱导的死亡的抵抗、肥胖增加和脂肪细胞肥大。采用多种行为测定法评估食欲、热量摄入、膳食量和膳食频率。此外，我们利用DNA微阵列来分析这些果蝇之间的差异基因表达，这些差异基因表达映射到脂质代谢途径的变化。我们的研究结果表明，神经酰胺的积累足以通过两种不同的机制诱导肥胖表型：1）二氢神经酰胺（C14：0）和神经酰胺二烯（C14：2）积累通过降低脂肪动力学激素产生细胞的功能性降低脂肪储存动员，以及2）调节S1 P：神经酰胺（C14：1）比率通过后肠特异性神经肽样受体dNepYr抑制餐后饱腹感，导致热量摄入依赖性肥胖。肥胖症的特征是体重过度增加，增加了患II型糖尿病和心脏病等疾病的风险。众所周知，富含饱和脂肪的高热量饮食会导致体重过度增加。然而，饱和脂肪在这一过程中发挥的作用远远超出了脂肪组织中的简单储存。饱和脂肪是生物活性脂质神经酰胺的基本组成部分。神经酰胺的积累最近与肥胖有关。然而，目前尚不清楚其积累是否在诱导肥胖中起积极作用。在这里，我们利用果蝇的遗传操作来积累和消耗各种神经酰胺种类和其他相关脂质。我们的研究结果表明，神经酰胺和相关脂质的调节足以通过两种不同的机制诱导肥胖：热量摄入依赖性机制通过抑制神经肽Y饱腹感信号传导起作用，而热量摄入独立性机制通过调节调节脂肪储存的激素产生细胞起作用。这些数据暗示神经酰胺通过增加热量摄入和脂肪储存积极促进肥胖。
Obesity is defined by excessive lipid accumulation. However, the active mechanistic roles that lipids play in its progression are not understood. Accumulation of ceramide, the metabolic hub of sphingolipid metabolism, has been associated with metabolic syndrome and obesity in humans and model systems. Here, we use Drosophila genetic manipulations to cause accumulation or depletion of ceramide and sphingosine-1-phosphate (S1P) intermediates. Sphingolipidomic profiles were characterized across mutants for various sphingolipid metabolic genes using liquid chromatography electrospray ionization tandem mass spectroscopy. Biochemical assays and microscopy were used to assess classic hallmarks of obesity including elevated fat stores, increased body weight, resistance to starvation induced death, increased adiposity, and fat cell hypertrophy. Multiple behavioral assays were used to assess appetite, caloric intake, meal size and meal frequency. Additionally, we utilized DNA microarrays to profile differential gene expression between these flies, which mapped to changes in lipid metabolic pathways. Our results show that accumulation of ceramides is sufficient to induce obesity phenotypes by two distinct mechanisms: 1) Dihydroceramide (C14:0) and ceramide diene (C14:2) accumulation lowered fat store mobilization by reducing adipokinetic hormone- producing cell functionality and 2) Modulating the S1P: ceramide (C14:1) ratio suppressed postprandial satiety via the hindgut-specific neuropeptide like receptor dNepYr, resulting in caloric intake-dependent obesity. Obesity is characterized by excessive weight gain that increases one's risk for pathologies such as Type II diabetes and heart disease. It is well-known that a high calorie diet rich in saturated fats contributes to excessive weight gain. However, the role that saturated fats play in this process goes far beyond simple storage in fat tissue. Saturated fats are essential building blocks for the bioactive lipid ceramide. Accumulation of ceramide has recently been associated with obesity. However, it is not known whether its accumulation plays an active role in the induction of obesity. Here, we utilized genetic manipulation in Drosophila to accumulate and deplete a variety of ceramide species and other related lipids. Our results showed that modulation of ceramide and related lipids is sufficient to induce obesity through two distinct mechanisms: a caloric intake-dependent mechanism works through suppression of neuropeptide Y satiety signaling, while a caloric intake-independent mechanism works through regulation of hormone producing cells that regulate fat storage. These data implicate ceramides in actively promoting obesity by increasing caloric intake and fat storage.
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DOI：
10.1073/pnas.0702726104
发表时间：
2007-05-15
影响因子：
11.1
作者：
Ja, William W.;Carvalho, Gil B.;Benzer, Seymour
通讯作者：
Benzer, Seymour
DOI：
10.1152/ajpendo.91014.2008
发表时间：
2009-07-01
影响因子：
5.1
作者：
Yang, Guang;Badeanlou, Leylla;Samad, Fahumiya
通讯作者：
Samad, Fahumiya
影响因子：
9.8
作者：
Grönke S;Müller G;Hirsch J;Fellert S;Andreou A;Haase T;Jäckle H;Kühnlein RP
通讯作者：
Kühnlein RP
影响因子：
3.5
作者：
McCampbell, A;Truong, D;Brown, RH
通讯作者：
Brown, RH
影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR