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: 9300983
• 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/9300983
• 关键词: Alanine; Antioxidants; Back; Brain; Buffers; Cardiovascular Diseases; Carnosine; 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; base; clinically relevant; diabetic; feeding; glucose tolerance; insulin sensitivity; mouse model; novel; novel therapeutics; obesogenic; 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.

肥胖是一种非常普遍的疾病，并且与 2 型肥胖风险增加相关 糖尿病（T2D）和心血管疾病。因此，了解肥胖如何发展以及 确定旨在控制肥胖及其代谢后果的新疗法至关重要 重要性。最近的研究表明，骨骼肌中的二肽肌肽已被耗尽。 T2D 患者和肌肽喂养可减少饮食引起的肥胖。肌肽（ala-his）是一种 二肽存在于骨骼肌、大脑和心脏中。它在糖酵解过程中缓冲质子，并且是一种强效的 抗氧化剂。肌肽由肌肽合成酶合成，并水解回丙氨酸 肌肽的稳态平衡也由肽维持 转运蛋白，Pept2 。尽管人类肥胖和 T2D 与肌肽水平下降有关 骨骼肌、肌肽消耗的机制及其对骨骼肌的保护作用 肥胖症尚不完全清楚。我们的初步研究表明，小鼠的高脂肪喂养会降低肌肽 水平，并且通过补充肌肽恢复这些水平限制体重增加，增加 能量消耗、胰岛素敏感性和葡萄糖耐量。基于这些观察，我们建议 慢性肌肽缺乏会降低肌肉的能量消耗和抗氧化能力，从而导致 胰岛素抵抗和氧化应激。为了验证这一假设，我们将：（1）阐明其机制 肥胖引起的肌肽消耗； 2) 测试补充肌肽是否可以预防或逆转肥胖 它的代谢后果； (3) 研究肌肽调节肥胖的机制 胰岛素敏感性。为了评估我们研究结果的临床相关性，我们还将测量肌肽和 肥胖和非肥胖儿童的肌肽酶活性。该项目的研究结果可能会导致 开发一种新颖且经过验证的抗肥胖策略，该策略还可以预防或逆转饮食引起的肥胖 胰岛素抵抗。该项目的成功完成将为以下项目奠定基础并形成理论基础： 测试肌肽对人体的抗肥胖和抗糖尿病作用。