Mechanisms of diet-induced leptin resistance in ARC and VTA

饮食诱导 ARC 和 VTA 瘦素抵抗的机制

• 批准号: 8237621
• 负责人: PHILIP J SCARPACE
• 金额: $ 37.04万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237621
• 关键词: 5' -AMP-activated protein kinase; Acetyl-CoA Carboxylase; Acids; Acute; American; Animals; Body Weight; Brain; Brain region; Cessation of life; Chemicals; Chronic; Chronic Disease; Complex; Consumption; Coupled; Data; Diet; Dietary Sucrose; Drug Delivery Systems; Eating; Encephalitis; Endoplasmic Reticulum; Enzymes; Fat-Restricted Diet; Fatty acid glycerol esters; Fructose; Glucose; Health; Homeostasis; Hormones; Human; Hypothalamic structure; I-kappa B Proteins; Individual; Inflammation; Infusion procedures; Injection of therapeutic agent; Lead; Leptin; Leptin resistance; Malonyl Coenzyme A; Mediating; Modeling; Molecular Chaperones; Obesity; Pathway interactions; Peptides; Phosphorylation; Phosphotransferases; Physiological; Population; Production; Protein Dephosphorylation; Proteins; Rattus; Reactive Oxygen Species; Rodent Model; Role; STAT protein; Signal Pathway; Signal Transduction; Sprague-Dawley Rats; Structure of nucleus infundibularis hypothalami; Sucrose; Superoxide Dismutase; Testing; Up-Regulation; Ventral Tegmental Area; Weight; Weight Gain; detection of nutrient; disability; endoplasmic reticulum stress; feeding; inhibitor/antagonist; leptin receptor; male; mimetics; neuroregulation; novel therapeutics; nutrition; pre-clinical; prevent; research study; response; stressor; sugar; tempol; theories

DESCRIPTION (provided by applicant): One potential causative factor of diet-induced obesity (DIO) is leptin resistance. Leptin is a potent anorexic hormone in most lean animals. However, the effects of leptin are diminished in obese animals, and this refractiveness is known as leptin resistance. Diets high in fat and sucrose lead to leptin resistance and obesity, yet the causative dietary ingredient(s) remain elusive. Our data demonstrate that a low-fat diet with elevated fructose causes leptin resistance, whereas diets without fructose do not. Leptin signals via the signal transducer and activator of transcription protein 3 (STAT3) and the nutrient sensing AMP-activated kinase (AMPK)/acetyl CoA carboxylase (ACC) pathways. Leptin signals through the latter by promoting dephosphorylation of pAMPK/pACC. We demonstrated that fructose prevents leptin-mediated pAMPK/pACC dephosphorylation, leading to leptin resistance. Over-nutrition also leads to leptin resistance. We suggest that diets that lead to over-consumption, exacerbated by fructose, promote inflammation, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) and these specifically inhibit leptin-mediated STAT3 phosphorylation (P-STAT3). We postulate that elevated dietary fructose, but not glucose, impairs the leptin- mediated dephosphorylation of pAMPK/pACC in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA). Additionally, we postulate that fructose, in synergy with over-nutrition, increases inflammation, ER stress, and ROS, thus inhibiting pSTAT3 signaling. Furthermore, disruptions in both pathways are necessary to promote weight gain. We will test these hypotheses in male Sprague Dawley rats by examining the neural regulation of food intake and body weight, whole body energy homeostasis, and brain region-specific leptin signaling. Exp 1 will examine if 2-week dietary fructose inhibits the leptin-mediated dephosphorylation of pAMPK/pACC or impairs the phosphorylation of STAT3 compared with that of dietary glucose or sucrose. Exp 2 will determine if fructose acts directly on central leptin signaling pathways by central infusion of fructose or glucose. Exp 3 examines if disruptions in both the STAT3 and AMPK leptin signaling pathways are critical for the leptin-resistance promoted weight gain by specific inhibition of the individual pathways. In Exp 4, we will examine if over-nutrition plus fructose (vs. glucose) will induce a greater brain inflammation/ER stress/ROS, and consequently, result in more severe inhibition of leptin-mediated P-STAT3 signaling in the ARC and VTA. Exp 5 will examine the individual contribution of inflammation, ER stress or ROS production to fructose/over-nutrition-induced leptin resistance by infusion of respective inhibitors of these stressors. Our approach is unique because we suggest that fructose plus over-nutrition constitute a two-hit model explaining leptin resistance. An understanding of these mechanisms will provide new therapeutic strategies for obesity, including drugs that target inflammation/ER stress/ROS coupled with low fructose diets to resurrect leptin action. PUBLIC HEALTH RELEVANCE: The American population may be particularly vulnerable to dietary obesity due to chronic consumption of high sugar and fat diets, and obesity-related health complications hasten the onset of disability and death. This proposal seeks to examine the role of dietary fructose and fat in the promoting weight gain. In particular, it examines the way fructose and over-consumption prevents the hormone leptin from its normal action, thus promoting weight and fat gain. Our proposed studies will be conducted in Sprague-Dawley rats, a pre-clinical rodent model for diet-induced obesity in humans.

描述（由申请人提供）：饮食引起的肥胖（DIO）的一种潜在致病因素是瘦素抵抗。对于大多数瘦动物来说，瘦素是一种有效的厌食激素。然而，瘦素的作用在肥胖动物中减弱，这种折射被称为瘦素抵抗。高脂肪和高蔗糖饮食会导致瘦素抵抗和肥胖，但致病的饮食成分仍然难以捉摸。我们的数据表明，果糖含量升高的低脂饮食会导致瘦素抵抗，而不含果糖的饮食则不会。瘦素通过信号转导器和转录蛋白 3 (STAT3) 激活剂以及营养感应 AMP 激活激酶 (AMPK)/乙酰辅酶 A 羧化酶 (ACC) 途径发出信号。瘦素通过后者通过促进 pAMPK/pACC 去磷酸化来发出信号。我们证明果糖可以阻止瘦素介导的 pAMPK/pACC 去磷酸化，从而导致瘦素抵抗。营养过剩也会导致瘦素抵抗。我们认为，导致过度消费并因果糖而加剧的饮食会促进炎症、内质网 (ER) 应激和活性氧 (ROS)，并且这些饮食会特异性抑制瘦素介导的 STAT3 磷酸化 (P-STAT3)。我们假设膳食果糖升高，而非葡萄糖，会损害下丘脑弓状核 (ARC) 和腹侧被盖区 (VTA) 中瘦素介导的 pAMPK/pACC 去磷酸化。此外，我们假设果糖与营养过剩协同作用，会增加炎症、ER 应激和 ROS，从而抑制 pSTAT3 信号传导。此外，这两种途径的破坏对于促进体重增加是必要的。我们将通过检查食物摄入和体重的神经调节、全身能量稳态和大脑区域特异性瘦素信号传导，在雄性斯普拉道利大鼠中测试这些假设。实验 1 将检查与膳食葡萄糖或蔗糖相比，2 周膳食果糖是否会抑制瘦素介导的 pAMPK/pACC 去磷酸化或损害 STAT3 的磷酸化。实验 2 将确定果糖是否通过果糖或葡萄糖的中枢输注直接作用于中枢瘦素信号通路。实验 3 检查 STAT3 和 AMPK 瘦素信号通路的破坏是否对于通过特定抑制各个通路而促进体重增加的瘦素抵抗至关重要。在实验 4 中，我们将检查营养过剩加果糖（相对于葡萄糖）是否会诱发更大的脑部炎症/ER 应激/ROS，从而导致 ARC 和 VTA 中瘦素介导的 P-STAT3 信号传导受到更严重的抑制。实验 5 将通过输注这些应激源的相应抑制剂来检查炎症、内质网应激或 ROS 产生对果糖/营养过剩诱导的瘦素抵抗的个体贡献。我们的方法是独特的，因为我们认为果糖加上营养过剩构成了解释瘦素抵抗的两次打击模型。了解这些机制将为肥胖症提供新的治疗策略，包括针对炎症/内质网应激/活性氧的药物与低果糖饮食相结合，以恢复瘦素的作用。 公共卫生相关性：由于长期食用高糖和高脂肪饮食，美国人口可能特别容易受到饮食性肥胖的影响，而与肥胖相关的健康并发症会加速残疾和死亡的发生。该提案旨在研究膳食果糖和脂肪在促进体重增加中的作用。特别是，它研究了果糖和过度消费如何阻止瘦素激素的正常作用，从而促进体重和脂肪增加。我们提出的研究将在斯普拉格-道利大鼠中进行，这是一种针对人类饮食引起的肥胖的临床前啮齿动物模型。