MODULATING PHYSIOLOGIC EFFECTS OF PHOSPHOLIPID METABOLISM IN OBESITY AND DIABETES

调节磷脂代谢对肥胖和糖尿病的生理影响

• 批准号: 9221327
• 负责人: Clay F. Semenkovich
• 金额: $ 42.4万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221327
• 关键词: 5' -AMP-activated protein kinase; Address; Adipose tissue; Adult; Affect; Aging; Animals; Biochemical; Blindness; Blood coagulation; Body Weight decreased; Ca(2+)-Transporting ATPase; Calcium; Choline; Collection; Complications of Diabetes Mellitus; Consensus; Cultured Cells; Degenerative polyarthritis; Diabetes Mellitus; Diet; Dietary Fats; Disease; Eating; Endoplasmic Reticulum; Enzymes; Ethanolamines; Exercise; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fatty-acid synthase; Functional disorder; Gap Junctions; Gastric Bypass; Genes; Genetic; Goals; Health; Healthcare Systems; High Fat Diet; Human; Impairment; Insulin Resistance; Knock-out; Knockout Mice; Lecithin; Life; Link; Lipids; Liver; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Mediating; Mental Depression; Metabolic; Metabolic Diseases; Metabolic stress; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Mus; Muscle; Muscle Contraction; Muscle Weakness; Muscle function; Myocardial Infarction; Names; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obstructive Sleep Apnea; Oxidoreductase; Pathway interactions; Patients; Peripheral Vascular Diseases; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Phosphatidylethanolamine; Phospholipid Metabolism; Phospholipids; Phosphotransferases; Physiological; Plasma; Process; Property; Public Health; Publishing; Research Infrastructure; Role; Sarcoplasmic Reticulum; Signal Transduction; Skeletal Muscle; Source; Stress; Stroke; Testing; Tissues; Translating; Translational Research; Weight; Work; base; cost; diabetes mellitus therapy; diet and exercise; disorder risk; effective therapy; feeding; glucose disposal; glucose metabolism; glucose tolerance; glucose uptake; improved; insulin sensitivity; juvenile animal; lipid biosynthesis; lipid metabolism; muscle aging; muscle strength; novel; novel marker; potential biomarker; public health relevance; release of sequestered calcium ion into cytoplasm; response; synthetic enzyme; tool

DESCRIPTION (provided by applicant): Exercise is an ideal therapy for diabetes and obesity, but compliance is poor and how skeletal muscle contraction decreases metabolic disease risk is poorly understood. Abnormal lipid metabolism contributes to the pathophysiology of type 2 diabetes, but there is no consensus explanation for the relationship between lipids, muscle function, and metabolic decompensation. Unexpectedly, fatty acid synthase (FAS) is induced in skeletal muscle by high fat feeding and obesity in both animals and humans. Sarco/endoplasmic reticulum calcium ATPase (SERCA) is critical for normal muscle function. Skeletal muscle FAS deficiency causes high fat diet-induced muscle weakness because FAS is required to maintain SERCA activity by determining the phospholipid composition of the sarcoplasmic reticulum (SR). In young mice, a high fat diet is required to elicit weakness. The same phenotype due to the same mechanism occurs in aging mice with muscle FAS deficiency eating a low fat chow diet. FAS is linked to the phospholipid synthetic enzyme choline/ethanolamine phosphotransferase 1 (CEPT1). High fat feeding induces CEPT1 in skeletal muscle. Skeletal muscle CEPT1 deficiency causes high fat diet-induced muscle weakness through the same mechanism as FAS deficiency: altered SR phospholipid composition leading to decreased SERCA activity. FAS and CEPT1 in muscle appear to channel lipids predominantly to the SR since there is no effect on mitochondrial function, PPAR activation, ER stress or other processes in either FAS-deficient or CEPT1-deficient muscle. FAS is also linked to peroxisomal lipid synthesis. The final step in this process is mediated by Peroxisomal Reductase Activating PPAR (PexRAP), cloned and named based on its properties in nonmuscle tissue. PexRAP is a multifunctional enzyme capable of conventional phospholipid synthesis, and the phospholipid composition of muscle SR in PexRAP-deficient mice mirrors that of muscle SR in FAS and CEPT1 deficiency. In obese humans, FAS and CEPT1 are coordinately regulated. This pathway is dynamically modulated by weight loss, and related to insulin stimulated glucose disposal. Mass spectrometry analyses indicate that the SR phospholipid signature is similarly affected in muscle in FAS-deficient, CEPT1-deficient, and PexRAP- deficient mice, and in human metabolic syndrome. The long-term objective of this application is to characterize this novel link between diet, obesity, aging, and muscle function to improve the health of people with obesity and diabetes. We will test the hypothesis that an endogenous phospholipid synthetic pathway involving FAS, PexRAP, and CEPT1 in skeletal muscle channels lipids to maintain muscle function in the setting of metabolic stress. This hypothesis will be tested by addressing four aims: (1) To define the dynamics of lipogenic-mediated changes in skeletal muscle sarcoplasmic reticulum and calcium handling in response to changes in diet and exercise in mice. (2) To implicate FAS, PexRAP, and CEPT1 in a common phospholipid synthetic pathway leading to altered sarcoplasmic reticulum composition and function in cultured cells. (3) To determine if genetic inactivation of PexRAP in the skeletal muscle of mice alters the composition and function of the sarcoplasmic reticulum to affect strength and glucose metabolism. (4) To translate these observations to humans by determining if the composition and function of the sarcoplasmic reticulum is altered in people with the metabolic syndrome. Achieving the goals of this application could deliver new understanding of biochemical impediments to effective treatments, deliver novel biomarkers of progression to metabolic compromise in otherwise healthy obese people, and deliver viable targets for treating diabetes by repositioning drugs available through the National Center for Advancing Translational Sciences (NCATS) Pharmaceutical Collection (NPC).

描述（由申请人提供）：运动是糖尿病和肥胖症的理想疗法，但依从性很差，骨骼肌收缩如何降低代谢疾病的风险是很差的。异常脂质代谢有助于2型糖尿病的病理生理学，但是对于脂质，肌肉功能和代谢代谢失去的关系尚无共识解释。出乎意料的是，动物和人类的高脂肪进食和肥胖症在骨骼肌中诱导脂肪酸合酶（FAS）。 Sarco/内质网钙ATPase（SERCA）对于正常肌肉功能至关重要。骨骼肌FAS缺乏会导致高脂肪饮食引起的肌肉无力，因为FAS需要通过确定肌胞浆网（SR）的磷脂组成来维持SERCA活性。在年轻小鼠中，需要高脂饮食才能引起无力。在肌肉FAS缺乏症的老化小鼠中，由于相同的机制而引起的相同表型，食用低脂饮食。 FAS与磷脂合成酶胆碱/乙醇胺磷酸转移酶1（CEPT1）有关。高脂肪进食会在骨骼肌中诱导CEPT1。骨骼肌CEPT1缺乏通过与FAS缺乏相同的机制引起高脂肪饮食引起的肌肉无力：SR磷脂组成改变，导致SERCA活性降低。肌肉中的FAS和CEPT1似乎主要将脂质引导至SR，因为对线粒体功能，PPAR激活，ER应激或其他FAS缺陷型肌肉的影响没有影响。 FAS还与过氧化物酶体脂质合成有关。该过程的最后一步是由过氧化物酶体还原酶激活PPAR（PEXRAP）基于其在非肌肉组织中的特性进行克隆和命名的。 PEXRAP是一种能够传统的磷脂合成的多功能酶，并且缺乏PEXRAP缺陷的小鼠中肌肉SR的磷脂组成反映了FAS和​​CEPT1缺乏症中肌肉SR的磷脂组成。在肥胖的人类中，FAS和CEPT1进行了协调的调节。该途径是通过体重减轻动态调节的，并且与胰岛素刺激的葡萄糖处置有关。质谱分析表明，SR磷脂特征在FAS缺乏，CEPT1缺陷型和PEXRAP缺乏的小鼠以及人类代谢综合征中类似地受到肌肉的影响。该应用的长期目标是表征饮食，肥胖，衰老和肌肉功能之间的这种新型联系，以改善肥胖和糖尿病患者的健康。我们将检验以下假设：骨骼肌通道中涉及FAS，PEXRAP和CEPT1的内源性磷脂合成途径在代谢应激的情况下保持肌肉功能。该假设将通过解决四个目的来检验：（1）定义脂肪生成介导的骨骼肌肌肉质质网和钙处理的动力学，以应对小鼠饮食和运动的变化。 （2）将FAS，PEXRAP和CEPT1牵涉到常见的磷脂合成途径中，从而导致核质网的组成和功能改变了培养细胞的功能。 （3）确定小鼠骨骼肌中PEXRAP的遗传失活是否改变了肌质网的组成和功能，以影响强度和葡萄糖代谢。 （4）通过确定代谢综合征患者的核质网的组成和功能是否改变了这些观察结果。实现此应用程序的目标可以使对有效治疗的生化障碍有新的了解，在原本健康的肥胖者中提供新的生物标志物，从而提供新的生物标志物，以使其在其他健康的肥胖者中妥协妥协，并提供可行的靶标，可通过重新定位糖尿病来治疗糖尿病，通过重新定位通过国家发展的转化科学中心（NCATS）Pharmaceutical Pharmaceutical Collection（NCATS）收集（NCATS）（NPC）。