Mechanisms of diet-induced leptin resistance in ARC and VTA

饮食诱导 ARC 和 VTA 瘦素抵抗的机制

基本信息

  • 批准号:
    8879117
  • 负责人:
  • 金额:
    $ 36.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-07-15 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

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):饮食诱导的肥胖症(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促性腺激素。然而,瘦素的作用在肥胖动物中减弱,这种活性被称为瘦素抵抗。高脂肪和蔗糖的饮食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,低脂肪饮食与高果糖导致瘦素抵抗,而没有果糖的饮食不会。瘦素通过信号转导和转录激活蛋白3(STAT 3)以及营养感测AMP激活激酶(AMPK)/乙酰辅酶A羧化酶(ACC)途径来进行信号传导。瘦素通过促进pAMPK/pACC的去磷酸化而通过后者发出信号。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,饮食导致过度消费,加剧了果糖,促进炎症,内质网(ER)的压力,和活性氧(ROS),这些特异性抑制瘦素介导的STAT 3磷酸化(P-STAT 3)。我们推测,高果糖饮食,而不是葡萄糖,削弱瘦素介导的pAMPK/pACC在下丘脑弓状核(ARC)和腹侧被盖区(VTA)的去磷酸化。此外,我们假设果糖与营养过剩协同作用,增加炎症,ER应激和ROS,从而抑制pSTAT 3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。我们将在雄性Sprague道利大鼠中通过检查食物摄入和体重的神经调节、全身能量稳态和脑区域特异性瘦素信号传导来检验这些假设。实验1将检查与膳食葡萄糖或蔗糖相比,2周膳食果糖是否抑制瘦素介导的pAMPK/pACC的去磷酸化或损害STAT 3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检查了STAT 3和AMPK瘦素信号传导途径两者的中断是否对于通过特异性抑制各个途径的瘦素抗性促进的体重增加是关键的。在实验4中,我们将检查是否过度营养加果糖(相对于葡萄糖)将诱导更大的脑炎症/ER应激/ROS,并因此导致ARC和VTA中瘦素介导的P-STAT 3信号传导的更严重抑制。实验5将通过输注这些应激源的相应抑制剂来检查炎症、ER应激或ROS产生对果糖/过度营养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一个解释瘦素抵抗的两次打击模型。对这些机制的理解将为肥胖症提供新的治疗策略,包括靶向炎症/ER应激/ROS的药物与低果糖饮食结合,以恢复瘦素的作用。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Activation of the central melanocortin system in rats persistently reduces body and fat mass independently of caloric reduction.
大鼠中枢黑皮质素系统的激活会持续减少身体和脂肪量,而与热量减少无关。
  • DOI:
    10.1139/cjpp-2017-0440
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    2.1
  • 作者:
    Côté,Isabelle;Green,SaraM;Morgan,Drake;Carter,ChristyS;Tümer,Nihal;Scarpace,PhilipJ
  • 通讯作者:
    Scarpace,PhilipJ
Fructose consumption does not worsen bone deficits resulting from high-fat feeding in young male rats.
  • DOI:
    10.1016/j.bone.2016.02.004
  • 发表时间:
    2016-04
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Yarrow JF;Toklu HZ;Balaez A;Phillips EG;Otzel DM;Chen C;Wronski TJ;Aguirre JI;Sakarya Y;Tümer N;Scarpace PJ
  • 通讯作者:
    Scarpace PJ
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

PHILIP J SCARPACE其他文献

PHILIP J SCARPACE的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('PHILIP J SCARPACE', 18)}}的其他基金

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
  • 财政年份:
    2012
  • 资助金额:
    $ 36.87万
  • 项目类别:
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:
    8510637
  • 财政年份:
    2012
  • 资助金额:
    $ 36.87万
  • 项目类别:
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
  • 财政年份:
    2012
  • 资助金额:
    $ 36.87万
  • 项目类别:
Leptin resistance: 1 mechanism underlying age-related ob
瘦素抵抗:年龄相关性肥胖的潜在机制之一
  • 批准号:
    6948924
  • 财政年份:
    2004
  • 资助金额:
    $ 36.87万
  • 项目类别:
Leptin resistance: 1 mechanism underlying age-related obesity
瘦素抵抗:年龄相关性肥胖的一种潜在机制
  • 批准号:
    7277665
  • 财政年份:
    2004
  • 资助金额:
    $ 36.87万
  • 项目类别:
Leptin resistance: 1 mechanism underlying age-related obesity
瘦素抵抗:年龄相关性肥胖的一种潜在机制
  • 批准号:
    7475658
  • 财政年份:
    2004
  • 资助金额:
    $ 36.87万
  • 项目类别:
Leptin resistance: 1 mechanism underlying age-related ob
瘦素抵抗:年龄相关性肥胖的潜在机制之一
  • 批准号:
    7095127
  • 财政年份:
    2004
  • 资助金额:
    $ 36.87万
  • 项目类别:
Leptin resistance: 1 mechanism underlying age-related ob
瘦素抵抗:年龄相关性肥胖的潜在机制之一
  • 批准号:
    6932876
  • 财政年份:
    2004
  • 资助金额:
    $ 36.87万
  • 项目类别:
Age-related Obesity: Interventions with Gene Delivery
与年龄相关的肥胖:基因传递干预措施
  • 批准号:
    7106641
  • 财政年份:
    2003
  • 资助金额:
    $ 36.87万
  • 项目类别:
Age-related Obesity: Interventions with Gene Delivery
与年龄相关的肥胖:基因传递干预措施
  • 批准号:
    6606859
  • 财政年份:
    2003
  • 资助金额:
    $ 36.87万
  • 项目类别:

相似海外基金

Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes
AMP 激活蛋白激酶对 1 型糖尿病免疫细胞调节的药理学靶向
  • 批准号:
    2867610
  • 财政年份:
    2023
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Studentship
Establishing AMP-activated protein kinase as a regulator of adipose stem cell plasticity and function in health and disease
建立 AMP 激活蛋白激酶作为脂肪干细胞可塑性和健康和疾病功能的调节剂
  • 批准号:
    BB/W009633/1
  • 财政年份:
    2022
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Fellowship
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2021
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Postdoctoral Fellowships
Metabolic control of integrin membrane traffic by AMP-activated protein kinase controls cell migration.
AMP 激活的蛋白激酶对整合素膜运输的代谢控制控制着细胞迁移。
  • 批准号:
    459043
  • 财政年份:
    2021
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Studentship Programs
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2020
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Postdoctoral Fellowships
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10561642
  • 财政年份:
    2019
  • 资助金额:
    $ 36.87万
  • 项目类别:
Determining the role of AMP-activated protein kinase in the integration of skeletal muscle metabolism and circadian biology
确定 AMP 激活蛋白激酶在骨骼肌代谢和昼夜节律生物学整合中的作用
  • 批准号:
    532989-2019
  • 财政年份:
    2019
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Postdoctoral Fellowships
Treating Diabetic Inflammation using AMP-Activated Protein Kinase Activators
使用 AMP 激活的蛋白激酶激活剂治疗糖尿病炎症
  • 批准号:
    2243045
  • 财政年份:
    2019
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Studentship
The Role of AMP-activated Protein Kinase in GVHD-causing T Cells
AMP 激活的蛋白激酶在引起 GVHD 的 T 细胞中的作用
  • 批准号:
    10359032
  • 财政年份:
    2019
  • 资助金额:
    $ 36.87万
  • 项目类别:
Investigating the therapeutic potential of AMP-activated protein kinase in myotonic dystrophy type 1
研究 AMP 激活蛋白激酶在 1 型强直性肌营养不良中的治疗潜力
  • 批准号:
    428988
  • 财政年份:
    2019
  • 资助金额:
    $ 36.87万
  • 项目类别:
    Studentship Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了