Sphingolipid-Mediated Dysregulation of Glucose and Energy Homeostasis in the CNS

鞘脂介导的中枢神经系统葡萄糖和能量稳态失调

基本信息

批准号：
9077406
负责人：
WILLIAM L HOLLAND
金额：
$ 36.4万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9077406
关键词：
1-Phosphatidylinositol 3-Kinase Acute Adult Apoptosis Appetite Stimulants Atherosclerosis Beta Cell Biological Assay Blood Glucose Body Weight Body Weight Changes Body Weight decreased Brain Cells Ceramide glucosyltransferase Ceramides Clinical Complement Cues Deposition Diabetes Mellitus Diet Eating Energy Metabolism Enzymes Fatty Acids Food Intake Regulation Functional disorder G(M3) Ganglioside Genetic Glial Fibrillary Acidic Protein Glucose Glucose Intolerance Glucosylceramides Grant Heart failure Hepatic High Fat Diet Homeostasis Hormonal Hormones Human Hypothalamic structure In Vitro Individual Insulin Insulin Resistance Ion Channel Knockout Mice Leptin Lipids Liver Mediating Mediator of activation protein Melanocyte stimulating hormone Metabolism Mus Nature Neuroglia Neurons Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutritional Obesity Pathogenesis Peptides Peripheral Play Pro-Opiomelanocortin Process Regulation Resistance Rodent Role Satiation Saturated Fatty Acids Serotonin Serum Signal Pathway Signal Transduction Sphingolipids Structure of nucleus infundibularis hypothalami Supporting Cell Testing Tetanus Helper Peptide Tetracyclines Tissues Transgenic Mice Transgenic Organisms Weight Gain Work attenuation blood glucose regulation cell type diabetic feeding galactosylgalactosylglucosylceramidase glycemic control impaired glucose tolerance improved insulin sensitivity insulin sensitizing drugs insulin signaling interest loss of function melanocortin receptor metabolic rate mouse model myelination neuronal excitability new therapeutic target novel overexpression prevent promoter public health relevance response

项目摘要

DESCRIPTION (provided by applicant): This grant evaluates hypothalamic accumulation of the sphingolipids ceramide or glucosylceramide can drive attenuation of hypothalamic leptin, insulin, or serotonin action in POMC and AgRP neurons. Overaccumulation of sphingolipids can drive insulin resistance in a number of peripheral tissues. AgRP and POMC neurons within the hypothalamus are two distinct subpopulations of neurons that are known to regulate both body weight and glucose homeostasis in response to insulin or leptin. The hypothesis that POMC neurons accumulate ceramide and glucosylceramides in the obese state, and these sphingolipids drive resistance of these cells to leptin and insulin's glucoregulatory signals will e investigated. To test this, triggered overexpression of an inducible enzyme which degrades ceramides, acid ceramidase, will be promoted in POMC or AgRP neurons of adult mice. This will be complemented with similar mice which prevent glucosylation of ceramide via gain or loss of function of glucosylceramide synthase. These mice will be used to interrogate whether ceramides, glucosylceramides, or both have a causative role in the pathogenesis of obesity and insulin resistance. Moreover, we will promote degradation of ceramides within glial cells, which we hypothesize will exacerbate sphingolipid oversupply to hypothalamic neurons during obesity. Of particular interest in each mouse model, evaluating if and how sphingolipid reduction in POMC neurons can improve whole-body insulin sensitivity independently of weight change will be assessed. This work will thus demonstrate a possible novel drug targets to decrease both body weight gain and blood glucose in obese or diabetic individuals, respectively. SA 1) Examine whether ceramide or glucosylceramide overaccumulation in POMC neurons contributes to high fat diet-induced obesity, insulin resistance, and impaired glucose tolerance. In order to determine the importance of abnormal sphingolipid accumulation in POMC neurons as mediators of diet-induced weight gain and insulin resistance we will force sphingolipid degradation (which lowers ceramide and glucosylceramides) or prevent glucosylceramide synthesis. SA 2) Determine if acid ceramidase overexpression in glial cells opposes high fat diet-induced obesity, insulin resistance, and impaired glucose tolerance. Novel tetracycline-inducible transgenic mice have been generated which overexpress acid ceramidase in glial cells. SA3) Examine whether sphingolipid overaccumulation in AgRP neurons contributes to high fat diet-induced obesity, insulin resistance, and impaired glucose tolerance. We will use tet-on transgenic lines overexpressing the ceramide degrading enzymes, acid ceramidase, to decrease AgRP sphingolipid. AgRP-specific glucosylceramide synthase knockout mice will be evaluated for their propensity for weight gain and impaired glycemic control. We will evaluate the importance of neuronal sphingolipids to both the initiation and reversal of obesity, insulin resistance, and glucose intolerance in each of these inducible mouse models.

描述（由申请人提供）：该资助评估了下丘脑神经酰胺或葡萄糖神经酰胺的积累可导致 POMC 和 AgRP 神经元中下丘脑瘦素、胰岛素或血清素作用的减弱。鞘脂的过度积累可导致许多外周组织中的胰岛素抵抗。下丘脑内的 AgRP 和 POMC 神经元是两个不同的神经元亚群， POMC 神经元在肥胖状态下会积累神经酰胺和葡萄糖神经酰胺，并且这些鞘脂会驱动这些细胞对瘦素和胰岛素的葡萄糖调节信号产生抵抗，这一假设将被研究。这触发了一种可降解神经酰胺的诱导酶（酸性神经酰胺酶）的过度表达，将在成人 POMC 或 AgRP 神经元中得到促进这将与通过葡萄糖神经酰胺合酶功能的获得或丧失来防止神经酰胺的葡萄糖基化的类似小鼠进行补充。这些小鼠将被用来探究神经酰胺、葡萄糖神经酰胺或两者是否在肥胖和胰岛素抵抗的发病机制中具有致病作用。此外，我们将促进神经胶质细胞内神经酰胺的降解，这将加剧肥胖期间下丘脑神经元的鞘脂过剩。对每种小鼠模型特别感兴趣的是，将评估 POMC 神经元中鞘脂的减少是否以及如何能够独立于体重变化而改善全身胰岛素敏感性，因此这项工作将证明一种可能的新药物靶点，以减少体重增加和血液。 SA 1) 检查 POMC 神经元中神经酰胺或葡萄糖神经酰胺的过度积累是否会导致高脂肪饮食诱导的肥胖、胰岛素抵抗和糖耐量受损。 POMC 神经元中的鞘脂积累作为饮食引起的体重增加和胰岛素抵抗的介质，我们将强制鞘脂降解（从而降低神经酰胺和葡萄糖神经酰胺）或阻止葡萄糖神经酰胺合成 SA 2）确定神经胶质细胞中酸性神经酰胺酶的过度表达是否会对抗异常的高脂肪饮食。已经产生了过度表达酸的新型四环素诱导的转基因小鼠。 SA3) 检查 AgRP 神经元中鞘脂过度积累是否会导致高脂肪饮食诱导的肥胖、胰岛素抵抗和葡萄糖耐量受损。我们将使用过度表达神经酰胺降解酶（酸性神经酰胺酶）的 tet-on 转基因系来减少。 AgRP 鞘脂。AgRP 特异性葡萄糖神经酰胺合酶敲除小鼠将评估其体重增加和体重倾向。我们将评估神经鞘脂对这些诱导小鼠模型中肥胖、胰岛素抵抗和葡萄糖耐受不良的发生和逆转的重要性。