下丘脑AMPK/HSF1/HSP70轴调控内质网应激和摄食环路构建在围产期母代肥胖诱发代谢异常代际传递中的作用和机制

围产期肥胖可增加后代发生肥胖及其它代谢综合征的风险，发育期瘦素信号介导下丘脑摄食环路正常构建是发挥能量稳态调控的前提条件。前期工作表明：围产期肥胖的子代（OOM）发育期下丘脑摄食调控异常，存在内质网（ER）应激及以热休克因子1介导热休克反应（HSR）激活为特征的蛋白毒性应激。OOM发育期下丘脑HSR的异常激活是否及如何影响摄食环路的构建？目前尚不明确。课题假设围产期肥胖母体不良环境可改变子代下丘脑能量感应分子AMPK的活性，诱导HSR异常激活，干扰摄食调控回路构建，从而构成个体成年期肥胖等疾病的发病基础。本课题拟以ER应激的药理学干预、基于Cre-Loxp条件性基因编辑、原位杂交和染色质免疫共沉淀等手段探讨中枢ER应激在介导围产期肥胖对子代下丘脑摄食回路构建中的作用，试图从一个新的视点阐释代谢异常代际传递发生的分子机制，为围产期肥胖所致不良结局的干预提供科学依据。

Perinatal maternal obesity can increase the risk of obesity and other metabolic syndrome in offspring. Hypothalamus is the headquarter for maintaining metabolic homeostasis, with normal arcuate nucleus of the hypothalamus (ARH) projections as the basis of body weight regulation. Leptin signaling is required for developing hypothalamic neurocircuits during critical periods of early postnatal life, which is exquisitely sensitive to and shaped by external cues from the maternal environment. Numerous evidences suggest that endoplasmic reticulum (ER) stress is the major pathway linking leptin resistance and hypothalamic energy dysregulation. Our preliminary data have identified male offspring of obese dams had significantly disordered energy homeostasis. In addition, maternal obesity caused differentially expressed genes that were significantly enriched in ER protein folding pathway with heat shock proteins 70(HSP70) upregulated remarkably in the hypothalamus of male offspring, which indicated ER stress (featured by unfolding protein response, UPR) and protein toxicity stress (characterized by heat shock response, HSR) were irritated abnormally. However, the molecular mechanism by which maternal obesity induces offspring hypothalamic UPR and HSR is not yet clear. In this regard, we hypothesize that poor maternal obese environment may change the activity of hypothalamic energy metabolic stress molecular AMPK, and induce activated heat shock factor 1(HSF1) mediating HSR extremely, resulting in absence of developed feeding circuit projection. With this regard, we intend to explore the effects of maternal obesity on ER stress/protein toxic stress and feeding circuits development in the hypothalamus of offspring through pharmacological intervention, Cre-Loxp gene-editing system, in situ hybridization and chromatin immunoprecipitation. Outcomes of this project will reveal a new mechanistic link between crosstalk of protein homeostasis and energy metabolism with abnormal metabolic intergenerational transmission, which might provide scientific basis for future intervention of adverse outcome caused by maternal perinatal obesity.