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Integration of Lepr circuits for thermoregulation and energy status

集成 Lepr 电路以实现温度调节和能量状态

基本信息

批准号：
10425453
负责人：
Heike Muenzberg-Gruening
金额：
$ 37万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
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：
2012-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10425453
关键词：
Affect Anatomy Animals Award Body Temperature Body Weight Body Weight Changes Body Weight decreased Brain Brown Fat Data Dependence Disease Dissociation Eating Energy Metabolism Ensure Fasting Food Energy Glutamates Goals Health Histologic Homeostasis Hormones Human Hypothalamic structure Knowledge Leptin Leptin resistance Maintenance Mediating Melanocortin 4 Receptor Metabolic Metabolic Control Methods Modeling Neurons Obesity Obesity Epidemic Pathologic Peptides Peripheral Pharmaceutical Preparations Physiologic Thermoregulation Physiological Physiological Adaptation Play Population Preoptic Areas Pro-Opiomelanocortin Regulation Research Rodent Role Site Structure of nucleus infundibularis hypothalami Temperature Temperature Sense Testing Weight Work anorexic cohesion dieting experimental study food restriction improved leptin receptor lifestyle intervention metabolic abnormality assessment neuronal circuitry novel obese patients physiologic model prevent response treatment strategy weight maintenance

项目摘要

Despite intense obesity research and growing knowledge of central and peripheral mechanisms that modulate food intake and energy expenditure, lifestyle interventions to treat obesity have been consistently unsuccessful in the long-term. Powerful physiological adaptations to fasting and food restriction oppose weight loss and are thought to be the culprit that prevents long-term maintenance of weight loss. Yet, our understanding of these physiological adaptations and the neuronal circuits involved is insufficient. Our work on leptin responsive neurons in the hypothalamus (POALepr and DMHLepr neurons) has indicated that temperature sensing and energy sensing integrate in the same neuronal circuits that modulate energy expenditure (EE) and food intake (FI). Furthermore, our data indicate that EE and FI are regulated independent circuits. In line with this, we show compelling evidence that temperature and energy state greatly impact each other due to explicit changes in neuronal activity within these circuits. Our working hypothesis integrates known energy sensing circuits with temperature sensing circuits and highlights important changes in leptin sensitivity that are not only impacted by energy sensing but also with ambient temperature, highlighting leptin resistance as a physiological, rather than pathological condition. This novel view is an important progress for our understanding of physiological adaptations that will be important for human and animal studies of metabolism in health and disease. The proposed experiments focus on the neuronal circuit integration of temperature-dependent and energy state dependent changes in EE and FI. In Aim 1 we will investigate warm-sensing POALepr neurons that project to the DMH and their role to suppress EE via cold-sensing DMHLepr. Furthermore, we will show that cold-sensing DMHLepr are also regulated by energy sensing ARC neurons. In Aim 2 we will investigate warm-sensing POALepr neurons that project to the ARC and their role to suppress FI via anorexigenic ARCPOMC neurons. In Aim 3 we will investigate the role of leptin and dynamic changes in leptin sensitivity to selectively regulate EE via DMH-projecting Lepr neurons, while FI is regulated via PVN projecting Lepr neurons.

尽管对肥胖的研究越来越深入，对中枢和外周机制的了解也越来越多