Hexosamine biosynthetic pathway activation and leptin resistance

己糖胺生物合成途径激活和瘦素抵抗

基本信息

批准号：
9918883
负责人：
Ruth B Harris
金额：
$ 38万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918883
关键词：
Acute Adult Animals Area Biological Models Blood Glucose Body Size Body Weight Body fat Brain Calories Cardiovascular Diseases Cell Culture Techniques Cell physiology Cells Child Chronic Chronic Disease Consumption Data Development Diet Disease Resistance Eating Energy Metabolism Enzymes Exposure to Failure Fatty acid glycerol esters Food Energy Fructose Glucose Health Hexosamines Homeostasis Hormones Human Hyperglycemia Hypothalamic structure In Vitro Insulin Resistance JAK2 gene Leptin Leptin resistance Link Liquid substance Maintenance Malignant Neoplasms Metabolic Modification Neurons Nutrient Obesity Obesity Epidemic Pathway interactions Pattern Peripheral Phosphorylation Phosphorylation Site Physiological Predisposing Factor Proteins Rattus Receptor Activation Recommendation Resistance Risk Rodent Saccharin Signal Transduction Signaling Protein Site Stat3 protein Sucrose Testing Tube Weight Work absorption adipokines detection of nutrient dietary guidelines drinking glucose metabolism in vivo leptin receptor mind control obesity in children obesity risk prevent response sugar sweetened beverage transcription factor

项目摘要

The adipokine leptin is released in proportion to the size of body fat stores and is a key contributor to the control of food intake and maintenance of metabolic homeostasis in normal weight animals and humans. A failure to fully activate leptin signaling proteins results in leptin resistance, which is a predisposing factor for obesity. Approximately 34% of US adults and 17% of children are obese and consumption of sugar sweetened beverages has been implicated in this epidemic of obesity. Rats consuming 30% sucrose solution develop peripheral and central leptin resistance faster than those fed formulated high-fat or high-sucrose diets. Leptin resistance is traditionally associated with a failure increase phosphorylation of the transcription factor signal transducer and activator of transcription 3 (pSTAT3) in areas of the brain that control food intake and energy expenditure. In leptin resistant sucrose-drinking rats basal hypothalamic pSTAT3 is increased and leptin does not increase pSTAT3 or inhibit food intake. Preliminary in vivo and in vitro data provide compelling evidence that increased glucose availability increases activity of the hexosamine biosynthetic pathway (HBP), increases pSTAT3 and causes leptin resistance. HBP activity results in O-GlcNAc modification of hundreds of proteins including enzymes and transcription factors. Basal HBP activity is crucial for many regulatory cell processes, but chronic activation disrupts signaling cascades and promotes cancer, cardiovascular disease and insulin resistance. Rats drink sucrose throughout the day and we hypothesize that the resultant surges in blood glucose chronically activate the HBP and inhibit leptin signaling due to O-GlcNAc modification of the key leptin signaling protein STAT3. Three Specific Aims will test this hypothesis. The first Aim will test whether consumption of liquid sucrose results in repeated excursions of blood glucose that stimulate the HBP, promote protein O-GlcNAc modification and cause leptin resistance. The second Aim will use in vitro studies to investigate the mechanism by which activation of the HBP modifies STAT3 phosphorylation and interferes with leptin signaling. The third Aim will use in vivo rodent studies to test the physiologic impact of HBP activation in the hypothalamus on leptin responsiveness. These Aims will provide significant new information on a mechanism that links consumption of sweetened beverages with increased risk for obesity.

脂肪因子瘦素是按人体脂肪储存大小成比例的，是关键贡献了食物摄入量和代谢稳态维持的贡献者体重动物和人类。无法完全激活瘦素信号蛋白会导致瘦素抗性，这是肥胖的诱人因素。大约34％的美国成年人和17％儿童的肥胖，糖吃甜味的饮料已经与此有关肥胖的流行。食用30％蔗糖溶液的大鼠发展周围和中央瘦素阻力比喂养配方的高脂或高血糖饮食更快。瘦素耐药性是传统上与失败增加了转录因子信号的磷酸化控制食物的大脑区域中转录3（PSTAT3）的换能器和激活剂进气和能量消耗。在耐瘦素耐蔗糖的大鼠基础下丘脑 PSTAT3增加，瘦素不会增加PSTAT3或抑制食物摄入。初步体内和体外数据提供了令人信服的证据，表明葡萄糖可用性增加增加己糖胺生物合成途径（HBP）的活性增加了PSTAT3并引起瘦素反抗。 HBP活性导致数百种蛋白质的O-GLCNAC修饰酶和转录因子。基础HBP活性对于许多调节细胞至关重要过程，但慢性激活会破坏信号级联并促进癌症，心血管疾病和胰岛素抵抗。老鼠全天喝蔗糖，我们假设由此产生的血糖逐渐激活HBP并抑制瘦素信号由于O-GLCNAC修饰引起的关键瘦素信号蛋白STAT3。三具体目标将检验这一假设。第一个目标将测试是否消耗液体蔗糖会导致刺激HBP的血糖反复偏移，促进蛋白质 O-GLCNAC修饰并引起瘦素耐药性。第二个目标将使用体外研究来研究HBP激活修饰STAT3磷酸化的机制和干扰瘦素信号传导。第三个目标将使用体内啮齿动物研究来测试 HBP激活下丘脑对瘦素反应性的生理影响。这些目标将提供有关将甜味消费联系起来的机制的重要新信息肥胖风险增加的饮料。