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시상하부 에너지대사 조절 뉴론의 활성 조절 기전 연구

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Abstract
Chapter 1.
A growing body of evidences has been made identifying the hypothalamic inflammation that leads to the initiation of obesity development. In particular, the reactive gliosis accompanied with the inflammatory responses in hypothalamus is the pivotal cellular event that elicits the metabolic abnormalities. In this study, I evaluated whether MyD88 signaling in hypothalamic astrocytes is deeply involved in the obesity pathogenesis through mediating inflammatory responses utilizing a mouse line bearing ablation of MyD88 gene in astrocyte specifically. The mice displayed reduced hypothalamic inflammation in response to treatment of a saturated free fatty acid and a long-term exposure to fat rich diet. In line with these observations, I successfully blunted obesity development in astrocyte-specific MyD88 deficient mice. Intriguingly, I further identified that the mice displayed improved the leptin resistance induced by a long-term HFD treatment. Collectively, current study suggested that MyD88 signaling in hypothalamic astrocytes is a critical molecular mediator on obesity pathogenesis triggered by hypothalamic inflammation.|Chapter 2.
Regulation of protein synthesis is a rapid and effective means to respond to changes in the cellular environment. A central mechanism for protein synthesis involves phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which reduces protein synthesis and is associated with various cellular stresses such as endoplasmic reticulum (ER) stress. However, the function of eIF2α signaling in the hypothalamus that controls whole-body energy metabolism is largely unknown. Here, I demonstrate the role of eIF2α phosphorylation in hypothalamic AgRP neurons in the regulation of feeding and energy balance. The neuronal activity in hypothalamic arcuate nucleus and feeding behavior were significantly attenuated in AgRP neuron-specific eIF2α phosphorylation deficient mice (AgRPeIF2αA/A mice). Also, AgRPeIF2αA/A mice displayed a greater increase in energy expenditure and stronger sensitivity to leptin than control mice. Intriguingly, I further identified that the deficiency of eIF2α phosphorylation in AgRP neurons decreased the ER stress-induced unfolded protein response (UPR) signaling as well as the expression of genes for autophagy and mitochondrial dynamics in the AgRP neurons after overnight fasting. Collectively, these findings suggest that eIF2α signaling in hypothalamic AgRP neurons as an energy sensor controls activation of AgRP neurons through regulation of the UPR signaling and cellular responses in AgRP neurons, and affects the feeding behavior and whole-body energy balance.|Chapter 3.
The hypothalamus integrates various neuronal circuits to regulate feeding and whole-body energy metabolism. The small molecule guanabenz reduces the central sympathetic outflow through stimulation of central α2A-adrenergic receptor and is used as an antihypertensive drug. However, the function of guanabenz in feeding and energy balance is largely unknown. In this study, I evaluated whether the central administration of guanabenz is involved in feeding behavior and energy expenditure. The metabolic parameters, including food intake, body weight and energy expenditure, were acutely increased by administration of guanabenz. Intriguingly, I further identified that hypothalamic dopaminergic neurons were significantly activated by guanabenz. Collectively, the current study suggested that the central administration of guanabenz affects the hypothalamic dopaminergic neuronal activity and regulates feeding and whole-body energy balance.
Author(s)
김광곤
Issued Date
2020
Awarded Date
2020-08
Type
Dissertation
Keyword
HypothalamusAgRP neuronPOMC neuronAsrocyteEnergy balance
URI
https://oak.ulsan.ac.kr/handle/2021.oak/6800
http://ulsan.dcollection.net/common/orgView/200000332867
Alternative Author(s)
Kim, Kwang Kon
Affiliation
울산대학교
Department
일반대학원 생명과학과
Advisor
이병주
Degree
Doctor
Publisher
울산대학교 일반대학원 생명과학과
Language
eng
Rights
울산대학교 논문은 저작권에 의해 보호받습니다.
Appears in Collections:
Life Science > 2. Theses (Ph.D)
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