Hypothalamic MANF and food-intake activity

项目总结 肥胖是世界范围内的一个主要健康问题，也是各种疾病的主要风险因素 疾病，包括2型糖尿病、中风和心血管疾病。因为神经元 大脑中的活动对维持全身能量平衡至关重要，异常 神经元功能可能导致肥胖的发展；因此，解开复合体 中枢控制能量稳态背后的神经元机制是一个高度优先的问题，如果我们 是了解肥胖的生物学，并最终治疗或减轻它的健康负担 强加的。中脑星形胶质细胞源性神经营养因子(MANF)是一种新发现的 神经营养因子对几种神经退行性变的保护作用已被证实 但它在大脑中的内源性功能在很大程度上仍不清楚。最近，我们 建立了一种转基因小鼠模型，其中MANF在中枢神经系统过表达 系统。令人惊讶的是，MANF转基因小鼠变得肥胖并表现出过度吞噬。此外， 我们发现内源性MANF在下丘脑中高度丰富，其表达是 与小鼠的进食状况密切相关。这些观察结果使我们假设 MANF参与下丘脑对食物摄取和能量平衡的控制。 检验这一假说的具体目的是：目的(1)通过以下方式评估小鼠的表型 增加或减少下丘脑MANF的表达。我们将使用病毒转导 和CRISPR/Cas9技术调节MANF水平，特别是在下丘脑和 评估这种调节后小鼠的代谢表型；目的(2)鉴定 下丘脑MANF参与能量稳态的调节。我们将表演亲和力 纯化层析与串联质谱联用进行综合研究 下丘脑中的MANF相互作用体以及这种相互作用如何塑造 MANF.这项研究的结果将拓宽我们对神经元功能的了解 调节能量动态平衡。了解MANF信号的分子机制将 为开发潜在的基于MANF的治疗策略提供有价值的见解 肥胖和相关的神经退行性疾病。 好了！

PROJECT SUMMARY Obesity is a major health problem worldwide and also a leading risk factor for various diseases, including type 2 diabetes, stroke, and cardiovascular diseases. Since neuronal activities in the brain are critical for maintaining systemic energy homeostasis, abnormal neuronal functions could lead to the development of obesity; thus, unraveling the complex neuronal mechanisms behind the central control of energy homeostasis is a high priority if we are to understand the biology of obesity and eventually treat or alleviate the health burdens it imposes. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified neurotrophic factor whose protective efficacy has been confirmed in several neurodegenerative diseases, but its endogenous function in the brain remains largely unknown. Recently, we generated a transgenic mouse model in which MANF is overexpressed in the central nervous system. Surprisingly, MANF transgenic mice become obese and exhibit hyperphagia. Moreover, we found endogenous MANF is highly enriched in the hypothalamus, and its expression is closely linked to the feeding status of the mice. These observations led us to hypothesize that MANF is involved in the hypothalamic control of food intake and energy homeostasis. Specific Aims for testing this hypothesis are: Aim (1) To evaluate the phenotypes of mice by increasing or reducing MANF expression in the hypothalamus. We will use virus transduction and CRISPR/Cas9 technology to modulate MANF levels specifically in the hypothalamus and evaluate the metabolic phenotypes of the mice after such modulations; Aim (2) To identify hypothalamic MANF partners in the regulation of energy homeostasis. We will perform affinity purification chromatography followed by tandem mass spectrometry to comprehensively study the MANF interactome in the hypothalamus and how such interactions shape the function of MANF. The results of this study will broaden our knowledge about the neuronal functions that regulate energy homeostasis. Understanding the molecular mechanisms of MANF signaling will yield valuable insights for developing potential MANF-based therapeutic strategies to treat obesity and related neurodegenerative disorders. !