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.

科学文摘 虽然体重减轻 10% 可以显着降低患肥胖相关糖尿病和心脏病的风险 患有这种疾病的人中，只有不到 20% 的人能够实现并维持这种体重减轻。因此，肥胖是 占美国医疗保健费用的很大一部分。食用上述可口食物 稳态需求（基于奖励的喂养）可能是体重反弹的一个因素。腹侧被盖 区域（VTA）多巴胺神经元在基于奖励的喂养中发挥着关键作用。代谢状态影响 奖励电路。然而，这种调节背后的机制尚不清楚。侧面 下丘脑区 (LHA) 食欲素葡萄糖抑制 (GI) 神经元为神经元提供兴奋性输入 VTA 多巴胺神经元可能是代谢状态和基于奖励的喂养之间的重要联系。 例如，食欲素介导禁食引起的基于奖励的进食的增加。我们的初步 数据显示，禁食还降低了葡萄糖对 LHA 食欲素-GI 神经元的抑制作用，导致 增加低血糖下的激活。该提案检验了体重减轻增加的假设 葡萄糖缺乏激活 LHA 食欲素-GI 神经元。葡萄糖敏感性的这种变化加强了 通过引起 VTA 多巴胺上的谷氨酸信号持续变化来进行基于奖励的喂养 神经元。因此，餐前血糖降低可以增加后续膳食的摄入量。 三个具体目标将在体外和体内检验这一假设：1）确定体重是否减轻 增强食欲素胃肠神经元对葡萄糖降低的反应； 2）判断是否减肥 以葡萄糖和食欲素依赖性方式增强 VTA 多巴胺神经元的突触可塑性； 3） 确定 LHA 葡萄糖水平升高是否会减弱禁食和减肥对身体的影响 基于奖励的行为。这些研究将增加对潜在机制的理解 实现和维持减肥的困难。

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.