Kansas Center for Metabolism and Obesity REsearch (KC-MORE) - Project 2

堪萨斯代谢和肥胖研究中心 (KC-MORE) - 项目 2

• 批准号: 10598046
• 负责人: E Matthew Morris
• 金额: $ 29.71万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598046
• 关键词: Acute; Biogenesis; Body Weight; Brain; Cardiovascular Diseases; Cell Nucleus; Chronic; Complex; Consumption; Data; Dependovirus; Diet; Eating; Energy Intake; Energy Metabolism; Energy Metabolism Pathway; Environment; Exposure to; Fasting; Fatty acid glycerol esters; Feeding behaviors; Food; Food Intake Regulation; Gene Expression; Genetic Transcription; Goals; Homeostasis; Hormonal; Hormones; Hypothalamic structure; Insulin; Kansas; Knock-out; Leptin; Link; Lipids; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Obesity; Pathway interactions; Peripheral; Peroxisome Proliferator-Activated Receptors; Pharmacologic Substance; Regulation; Research; Research Project Grants; Respiratory physiology; Role; Satiation; Seasons; Signal Pathway; Signal Transduction; Stimulus; Structure; Structure of nucleus infundibularis hypothalami; Sucrose; Sum; Testing; Thermogenesis; Time; Tissues; Transcriptional Activation; Transcriptional Regulation; Weight Gain; energy balance; fatty acid oxidation; feeding; food restriction; ghrelin; hormonal signals; improved; interest; lipid metabolism; mRNA Expression; metabolic rate; mouse model; neural; neurotransmission; nrf1 protein; obesogenic; overexpression; pharmacologic; reduced food intake; response; tool; total energy expenditure

PROJECT 2 (MORRIS): PROJECT SUMMARY Obesity is the strongest independent predictor for the onset and progression of metabolic diseases, such as type 2 diabetes and cardiovascular disease. Weight gain occurs due combination of increased food/energy intake and decreased total energy expenditure to create a positive energy balance. Energy balance is not constant or consistent, and therefore long-term weight gain occurs as a sum of numerous, small positive fluctuations over time scales ranging from days to seasons. These acute episodes of positive energy balance occur as a complex interaction of the current obesogenic environment and inappropriate regulation of energy homeostasis. Energy homeostasis is regulated through the integration of peripheral neural, hormonal and nutrient signals by a complex, interconnected central network, including the ventromedial nucleus of the hypothalamus (VMH). The VMH has been observed as involved in the regulation of both components of energy balance, energy expenditure and energy intake, making it an important component of body weight regulation. The main goal of the proposed 3-year research plan is to establish an independent research line investigating the role of mitochondrial lipid metabolism in ventromedial hypothalamus neurons on the regulation of energy homeostasis. Activation of pathways involved in sensing reduced cellular energy state in the VMH have been proposed to increase food intake through acute activation of neuron lipid metabolism. Further, inhibition of these same pathways has been observed to increase whole-body energy expenditure. However, it is unknown whether regulation of these two components of energy homeostasis is dependent upon mitochondrial lipid metabolism in VMH neurons. The central hypothesis of this proposal is that neuronal mitochondrial lipid metabolism in the VMH modulates systemic energy homeostasis regulation during exposure to energy dense diets through control of 1) food intake and 2) energy expenditure. In this proposal, we will use a VMH-specific, PGC-1α knockout (VPGC1a- /-) mouse model to study the role of neuron mitochondrial fatty acid oxidation and respiratory function on food intake regulation during fasting and satiety hormone exposure. Additional studies will examine whether modulation of neuronal mitochondria lipid metabolism impacts high-fat/high-sucrose-induced weight gain. As a corollary, both sets of studies will utilize adeno-associated virus to increase mitochondrial lipid metabolism in VMH neurons through overexpression of PGC1a.

项目2 (morris)：项目总结