中枢下丘脑c-Jun对机体能量和脂质代谢的调控作用与机制研究

A imbalance of nutritional homeostasis is an important factor that leads to obesity and related metabolic diseases, but the regulatory mechanism still needs to be clarified. The central nervous system (CNS) is the key part of sensing nutritional signals and regulating metabolism. Our previous studies found that both short- and long-term high-fat diet activated the protein expression and phosphorylation of central hypothalamic c-Jun in mice, suggesting that central hypothalamic c-Jun expression may be involved in the metabolic regulation of obesity induced by high-fat diet. Subsequently, we constructed the mice with c-Jun deletion in Nestin-expressing cells, found that these mice have lower body weight and fat mass, as well as higher energy expenditure, compared with control mice. Therefore, we propose that Central hypothalamic c-Jun may play an important role in regulating energy homeostasis and lipid metabolism, and it may play a key role in the process of lipid and energy metabolic disorder in mice induced by high glucose and high-fat diets. This project will use a variety of animal and cell models to study the regulatory role and mechanism of central hypothalamic c-Jun on energy and lipid metabolism. The study will deepen people's understanding of the physiological function of c-Jun and the molecular mechanism of metabolic diseases such as obesity, induced by nutritional imbalance.

营养稳态失衡是导致肥胖等代谢性疾病发生的重要因素，但具体调控机制仍需阐明。中枢是感应营养素信号变化及调控代谢的核心部位。申请人前期研究发现，短期和长期高脂饮食均可以激活小鼠中枢下丘脑c-Jun的蛋白表达及磷酸化，提示中枢下丘脑c-Jun可能参与了高脂饮食诱导肥胖的代谢调节过程。之后申请人构建了全脑敲除c-Jun的突变小鼠，发现该小鼠出现体重、脂肪块减少和能量消耗增加的表型。因此，我们提出假设：中枢下丘脑c-Jun具有调控能量和脂质代谢的重要功能，且可能在高糖、高脂等饮食导致的能量和脂质代谢紊乱过程中具有关键作用。本项目将利用全脑和特定神经元敲除c-Jun的小鼠及细胞模型，结合脑室注射手段，从多个层次研究中枢下丘脑c-Jun对机体能量和脂质代谢的调控作用与机制。该研究将加深人们对c-Jun生理功能的认识，有助于理解营养失衡诱发肥胖等代谢疾病发生发展的分子机制。

营养稳态失衡是导致肥胖等代谢性疾病发生的重要因素，但具体调控机制仍需阐明。中枢是感应营养素信号变化及调控代谢的核心部位。本项目探讨了中枢下丘脑c-Jun调控能量和脂质代谢的作用与机制。我们发现高脂饮食可激活小鼠下丘脑c-Jun的蛋白表达及磷酸化。全脑敲除c-Jun的小鼠体重和脂肪减少，能耗增加。进一步研究发现，下丘脑中重要神经元POMC中c-Jun的蛋白表达及磷酸化水平也可被高脂饮食诱导表达。POMC神经元敲除c-Jun的小鼠（c-jun ∆POMC）饲喂普通粮食时体重、脂肪含量及能耗等指标和对照小鼠比无差异。饲喂高脂饮食时，c-jun ∆POMC小鼠体重和脂肪减少，能耗增加，提示c-jun ∆POMC小鼠能够抵抗高脂饮食诱导的肥胖。机制研究表明，这可能是因为高脂时POMC神经元敲除c-Jun能够激活交感神经，从而促进白脂脂解和褐脂产热增加所致。此外，我们还发现AgRP神经元中c-Jun具有介导慢性应激诱导的焦虑和结肠炎易感作用。综上所述，我们的工作阐明了中枢c-Jun的多个生理功能，加深了人们对c-Jun蛋白及相关生理过程的理解和认识。