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，但依从性差，骨骼肌收缩如何降低代谢性疾病的风险知之甚少。脂质代谢异常有助于2型糖尿病的病理生理学，但对于脂质、肌肉功能和代谢失代偿之间的关系尚无一致的解释。出乎意料的是，在动物和人类中，高脂肪喂养和肥胖在骨骼肌中诱导脂肪酸合酶（FAS）。肌浆网/内质网钙ATP酶（SERCA）对正常肌肉功能至关重要。骨骼肌FAS缺乏导致高脂饮食诱导的肌无力，因为FAS是通过决定肌浆网（SR）的磷脂组成来维持SERCA活性所必需的。在年轻的老鼠中，需要高脂肪饮食来引起虚弱。由于相同的机制，相同的表型发生在吃低脂食物的肌肉FAS缺乏的衰老小鼠中。FAS与磷脂合成酶胆碱/乙醇胺磷酸转移酶1（CEPT 1）连接。高脂喂养诱导骨骼肌中的CEPT 1。骨骼肌CEPT 1缺乏通过与FAS缺乏相同的机制引起高脂肪饮食诱导的肌无力：改变SR磷脂组成，导致SERCA活性降低。肌肉中的FAS和CEPT 1似乎主要将脂质引导至SR，因为在FAS缺陷或CEPT 1缺陷的肌肉中对线粒体功能、PPAR活化、ER应激或其他过程没有影响。FAS也与过氧化物酶体脂质合成有关。这一过程的最后一步是由过氧化物酶体还原酶激活过氧化物酶体增殖体激活体（PexRAP）介导的，克隆和命名的基础上，其性质在非肌肉组织。PexRAP是一种能够进行常规磷脂合成的多功能酶，PexRAP缺陷小鼠肌肉SR的磷脂组成反映了FAS和CEPT 1缺陷小鼠肌肉SR的磷脂组成。在肥胖人群中，FAS和CEPT 1受到协调调节。这一途径受体重减轻的动态调节，并与胰岛素刺激的葡萄糖处置有关。质谱分析表明，在FAS缺陷型、CEPT 1缺陷型和PexRAP缺陷型小鼠的肌肉中，以及在人代谢综合征中，SR磷脂特征受到类似的影响。本申请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联系，以改善肥胖和糖尿病患者的健康。我们将测试的假设，内源性磷脂合成途径涉及FAS，PexRAP，和CEPT 1在骨骼肌通道脂质，以维持肌肉功能的代谢应激的设置。这一假设将通过解决以下四个目标进行检验：（1）确定小鼠骨骼肌肌浆网和钙处理中脂肪生成介导的变化对饮食和运动变化的响应动力学。(2)提示FAS、PexRAP和CEPT 1参与导致培养细胞中肌浆网组成和功能改变的常见磷脂合成途径。(3)确定小鼠骨骼肌中PexRAP基因失活是否改变肌浆网的组成和功能，从而影响力量和葡萄糖代谢。(4)通过确定代谢综合征患者肌浆网的组成和功能是否改变，将这些观察结果转化为人类。实现这一应用的目标可以提供对有效治疗的生化障碍的新理解，在其他健康的肥胖人群中提供新的进展代谢妥协的生物标志物，并通过重新定位国家推进转化科学中心（NCATS）药物收藏（NPC）提供治疗糖尿病的可行目标。