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: 8689004
• 负责人: PHILIP J SCARPACE
• 金额: $ 36.87万
• 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/8689004
• 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 Targeting; 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.

描述（由申请人提供）：饮食性肥胖（DIO）的一个潜在致病因素是瘦素抵抗。瘦素是大多数瘦动物体内的一种有效的厌食症激素。然而，瘦素的作用在肥胖动物中减弱，这种反射性被称为瘦素抵抗。高脂肪和高蔗糖的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，含有高果糖的低脂饮食会导致瘦素抵抗，而不含果糖的饮食则不会。瘦素通过转录蛋白3 （STAT3）的信号转导和激活因子以及营养感知amp活化激酶(AMPK)/乙酰辅酶a羧化酶（ACC）途径传递信号。瘦素通过后者通过促进pAMPK/pACC的去磷酸化来传递信号。我们证明果糖阻止瘦素介导的pAMPK/pACC去磷酸化，导致瘦素抵抗。营养过剩也会导致瘦素抵抗。我们认为，过量摄入果糖的饮食会促进炎症、内质网（ER）应激和活性氧（ROS），而这些会特异性抑制瘦素介导的STAT3磷酸化（P-STAT3）。我们假设，饮食中果糖的升高，而不是葡萄糖，会损害下丘脑弓状核（ARC）和腹侧被皮层（VTA）中瘦素介导的pAMPK/pACC的去磷酸化。此外，我们假设果糖与营养过剩协同作用，会增加炎症、内质网应激和ROS，从而抑制pSTAT3信号传导。此外，这两种途径的中断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，在雄性斯普拉格·道利大鼠身上验证这些假设。实验1将检验与葡萄糖或蔗糖相比，2周饮食中的果糖是否会抑制瘦素介导的pAMPK/pACC的去磷酸化或损害STAT3的磷酸化。实验2将确定果糖是否通过中心输注果糖或葡萄糖直接作用于中央瘦素信号通路。实验3研究了STAT3和AMPK瘦素信号通路的破坏是否对瘦素抵抗促进体重增加至关重要，这是通过对单个通路的特定抑制来实现的。在实验4中，我们将研究过度营养加果糖（与葡萄糖相比）是否会诱导更大的脑炎症/内质网应激/ROS，从而导致更严重的抑制ARC和VTA中瘦素介导的P-STAT3信号。实验5将检查炎症、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，通过输注这些应激源的各自抑制剂。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双重打击模型。了解这些机制将为肥胖提供新的治疗策略，包括针对炎症/内质网应激/活性氧的药物，再加上低果糖饮食，以恢复瘦素的作用。