Project 1 - Carnosine Metabolism in Diet-Induced Obesity

项目 1 - 饮食引起的肥胖中的肌肽代谢

• 批准号: 8711510
• 负责人: Shahid P Baba
• 金额: $ 24.96万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8711510
• 关键词: Alanine; Antioxidants; Back; Brain; Buffers; Cardiovascular Diseases; Carnosine; Child; Chronic; Development; Diabetes Mellitus; Diet; Dipeptides; Energy Metabolism; Enzymes; Equilibrium; Fatty acid glycerol esters; Glycolysis; Heart; Histidine; Human; Insulin; Insulin Resistance; Lead; Ligase; Measures; Metabolic; Metabolism; Mus; Muscle; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Patients; Peptides; Protons; Research; Risk; Role; Skeletal Muscle; Supplementation; Testing; Weight Gain; aminoacyl-histidine dipeptidase; base; clinically relevant; diabetic; feeding; glucose tolerance; insulin sensitivity; mouse model; novel; novel therapeutics; obesity in children; prevent; protective effect; restoration

Obesity is a highly prevalent condition and is associated with an increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease. As such, an understanding of how obesity develops and the identification of novel therapeutics aimed at controling obesity and its metabolic consequences are of utmost importance. Recent studies demonstrate that the dipeptide carnosine is depleted in the skeletal muscle of patients with T2D and that carnosine feeding decreases diet-induced obesity. Carnosine (ala-his) is a dipeptide present in skeletal muscle, brain, and heart. It buffers protons during glycolysis and it is a strong antioxidant. Carnosine is synthesized by the enzyme carnosine synthetase and is hydrolysed back to alanine and histidine by carnosinase.The homeostatic balance of carnosine is also maintained by the peptide transporter, Pept2 . Although obesity and T2D in humans is associated with a decrease in carnosine levels in the skeletal muscle, the mechanisms underiying carnosine depletion and its protective effects against obesity are not entirely known. Our intial studies show that high fat feeding in mice decreases carnosine levels and that restoration of these levels by carnosine supplementation restricts weight gain, increases energy expenditure, insulin senstivity and glucose tolerance. Based on these observations, we propose that chronic carnosine deficiency decreases energy expenditure and antioxidant capacity ofthe muscle, resulting in insulin resistance and oxidative stress. To test this hypothesis we will: (1) elucidate the mechanism of carnosine depletion in obesity; 2) test whether carnosine supplementation prevents or reverses obesity and its metabolic consequences; and (3) investigate the mechanism by which carnosine regulates adiposity and insulin sensitivity. To evaluate the clinical relevance of our findings, we will also measure carnosine and carnosinase activity in obese and non-obese children. The findings of this project could lead to the development of a novel and validated anti-obesity strategy that could also prevent or reverse diet-induced insulin resistance. Successful completion ofthis project would lay the foundaton and form the rationale for testing the anti-obesogenic and anti-diabetic effects of carnosine in humans.

肥胖是一种高度普遍的状况，与2型发展的风险增加有关 糖尿病（T2D）和心血管疾病。因此，了解肥胖的发展方式和 旨在控制肥胖及其代谢后果的新型治疗剂的鉴定是最大的 重要性。最近的研究表明，在 T2D患者和肉肽喂养的患者降低了饮食诱导的肥胖症。肌氨酸（Ala-His）是 骨骼肌，大脑和心脏中存在二肽。它在糖酵解过程中缓冲质子，并且是强大的 抗氧化剂。肌氨酸是由酶Carnosine合成酶合成的，并被水解回丙氨酸 和肉瘤酶的组氨酸。肌肽的稳态平衡也由肽维持 转运蛋白，pept2。尽管人类的肥胖和T2D与肌肽水平的降低有关 骨骼肌肉，肉瘤耗竭的机制及其对抗的保护作用 肥胖不是完全知道的。我们的Intial研究表明，小鼠的高脂肪进食可减少肉豆蔻素 水平以及通过补充肉肽恢复这些水平的恢复会限制体重增加，增加 能量消耗，胰岛素剂量和葡萄糖耐受性。基于这些观察，我们建议 慢性肌肽缺乏降低了肌肉的能量消耗和抗氧化能力，导致 在胰岛素抵抗和氧化应激中。为了检验该假设，我们将：（1）阐明 肥胖症中的肌氨酸耗竭； 2）测试补充肉肽是否可以防止或逆转肥胖和 它的代谢后果； （3）调查肉豆蔻调节肥胖和的机制 胰岛素灵敏度。为了评估我们发现的临床相关性，我们还将测量肉豆蔻和 肥胖儿童和非肥胖儿童中的肉推酶活性。该项目的发现可能导致 开发一种新颖且经过验证的抗肥胖策略，该策略也可以预防或逆转饮食诱导 胰岛素抵抗。成功完成此项目将奠定fintaton，并形成原理 测试肉豆蔻苷在人类中的抗肥大和抗糖尿病作用。