Role for Glucose-Inhibited Orexin Neurons in Weight Regain Following Dieting

葡萄糖抑制食欲素神经元在节食后体重恢复中的作用

• 批准号: 9977162
• 负责人: Kevin D. Beck
• 金额: $ 47.39万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977162
• 关键词: Acute; Attenuated; Behavior; Body Weight; Body Weight decreased; Brain; Cardiovascular Diseases; Consumption; Data; Developed Countries; Diabetes Mellitus; Diet; Dopamine; Eating; Electrophysiology (science); Energy Intake; Ensure; Exposure to; Fasting; Fatty acid glycerol esters; Food; Food Supply; Glucose; Glutamates; Green Fluorescent Proteins; Health; Health Care Costs; Heart Diseases; High Fat Diet; Hormonal; Hormonal Change; Hormones; In Vitro; Individual; Ingestion; Intake; Lateral Hypothalamic Area; Lead; Leptin; Leptin resistance; Life; Link; Macronutrients Nutrition; Maintenance; Mediating; Metabolic; Microdialysis; Modernization; Mus; Neurons; Nucleus Accumbens; Obesity; Obesity Epidemic; Obesity associated disease; Palate; Pathway interactions; Peripheral; Play; Postabsorptive Hypoglycemia; Preparation; Psychological reinforcement; Rattus; Regulation; Rewards; Role; Satiation; Signal Pathway; Signal Transduction; Slice; Stomach; Synaptic plasticity; Testing; Tracer; Tyrosine 3-Monooxygenase; United States; Ventral Tegmental Area; Weight; base; cardiovascular risk factor; comorbidity; conditioned place preference; designer receptors exclusively activated by designer drugs; dopaminergic neuron; feeding; food restriction; ghrelin; glutamatergic signaling; healthy weight; hypocretin; improved; in vivo; indexing; male; mind control; motivated behavior; neural circuit; novel; obesity risk; prevent; reinforced behavior; response; reward circuitry; sugar; therapy development

Scientific Abstract Although a 10% weight loss significantly reduces the risk of obesity-associated diabetes and heart disease, fewer than 20% of individuals achieve and maintain this weight loss. Thus, obesity underlies a large portion of health care costs in the United States. Consumption of palatable foods above homeostatic needs (reward-based feeding) is a likely contributor to weight regain. Ventral tegmental area (VTA) dopamine neurons play a key role in reward-based feeding. Metabolic state influences reward circuitry. However the mechanisms underlying this regulation are unclear. The lateral hypothalamic area (LHA) orexin glucose-inhibited (GI) neurons which provide excitatory input to the VTA dopamine neurons may be an important link between metabolic status and reward-based feeding. For example, orexin mediates the fasting-induced increase in reward-based feeding. Our preliminary data show that fasting also reduces the inhibitory effect of glucose on LHA orexin-GI neurons leading to increased activation in low glucose. This proposal tests the hypothesis that weight loss increases activation of LHA orexin-GI neurons by glucose deficit. This change in glucose sensitivity reinforces reward-based feeding by causing persistent changes in glutamate signaling onto the VTA dopamine neurons. As a result pre-prandial glucose decreases could enhance intake of the subsequent meal. Three Specific Aims will test this hypothesis in vitro and in vivo: 1) Determine whether weight loss enhances the response of orexin GI neurons to decreased glucose; 2) Determine whether weight loss enhances synaptic plasticity in VTA dopamine neurons in a glucose and orexin dependent manner; 3) Determine whether increased LHA glucose level attenuates the effects of fasting and weight loss on reward based behavior. These studies will increase understanding of the mechanisms underlying difficulties in achieving and maintaining weight loss.

科学摘要 尽管体重减轻10％可显着降低肥胖相关糖尿病和心脏的风险 疾病，不到20％的个体实现并维持这种体重减轻。因此，肥胖是基础 美国很大一部分医疗保健费用。上面的可口食品的消费 稳态需求（基于奖励的喂养）可能是重新获得体重的原因。腹侧盖 区域（VTA）多巴胺神经元在基于奖励的喂养中起关键作用。代谢状态的影响 奖励电路。但是，该法规的基础机制尚不清楚。横向 下丘脑区域（LHA）抑制葡萄糖（GI）神经元，可为兴奋性输入 VTA多巴胺神经元可能是代谢状态与基于奖励的喂养之间的重要联系。 例如，Orexin介导了禁食引起的基于奖励的喂养的增加。我们的初步 数据表明，禁食还降低了葡萄糖对LHA Orexin-GI神经元领先的抑制作用 在低葡萄糖中的激活增加。该建议检验了体重减轻增加的假设 通过葡萄糖不足激活LHA Orexin-GI神经元。葡萄糖敏感性的这种变化增强了 基于奖励的喂养是通过导致谷氨酸信号的持续变化到VTA多巴胺 神经元。结果，餐前葡萄糖的降低可能会增强随后的餐食的摄入量。 三个具体目标将在体外和体内检验该假设：1）确定体重是否减轻 增强了Orexin Gi神经元对葡萄糖降低的反应； 2）确定是否减肥 以葡萄糖和蛋白质依赖性方式增强VTA多巴胺神经元中的突触可塑性； 3） 确定升高的LHA葡萄糖水平是否减弱了禁食和体重减轻对 基于奖励的行为。这些研究将增加对基本机制的理解 实现和维持体重减轻的困难。

项目成果

Lateral hypothalamic orexin glucose-inhibited neurons may regulate reward-based feeding by modulating glutamate transmission in the ventral tegmental area.

• DOI: 10.1016/j.brainres.2018.05.025
• 发表时间: 2020-03-15
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Teegala SB;Sheng Z;Dalal MS;Hirschberg PR;Beck KD;Routh VH
• 通讯作者: Routh VH

Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry.

• DOI: 10.1016/j.mcn.2014.08.001
• 发表时间: 2014-09
• 期刊: Molecular and cellular neurosciences
• 作者: Sheng Z;Santiago AM;Thomas MP;Routh VH
• 通讯作者: Routh VH

Lateral hypothalamus hypocretin/orexin glucose-inhibited neurons promote food seeking after calorie restriction.

• DOI: 10.1016/j.molmet.2023.101788
• 发表时间: 2023-10
• 期刊: MOLECULAR METABOLISM
• 影响因子: 8.1
• 作者: Teegala, Suraj B.;Sarkar, Pallabi;Siegel, Dashiel M.;Sheng, Zhenyu;Hao, Lihong;Bello, Nicholas T.;De Lecea, Luis;Beck, Kevin D.;Routh, Vanessa H.
• 通讯作者: Routh, Vanessa H.

Ventromedial hypothalamus glucose-inhibited neurones: A role in glucose and energy homeostasis?

• DOI: 10.1111/jne.12773
• 发表时间: 2020-01-01
• 期刊: JOURNAL OF NEUROENDOCRINOLOGY
• 影响因子: 3.2
• 作者: Hirschberg, Pamela R.;Sarkar, Pallabi;Routh, Vanessa H.
• 通讯作者: Routh, Vanessa H.