Central control of body weight and satiety regulation

体重和饱腹感调节的中央控制

• 批准号: 430970922
• 负责人: Professor Dr. Peter Kühnen
• 金额: --
• 依托单位: Institut für Experimentelle Pädiatrische Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/430970922?language=en
• 关键词: Central; control; body; weight; satiety

The development of obesity in industrial and low- and middle-income countries is leading to a severe burden for patients and health care systems based on associated comorbidities as cardiovascular diseases and type 2 diabetes mellitus. For this reason, it is of importance to understand the underlying molecular mechanism. Here, the identification of animal models and patients with rare monogenic forms of obesity has led to fundamental new insights into central regulation of body weight. So far, the majority of mutations are observed in genes embedded in the so-called leptin melanocortin signaling pathway and are leading to hyperphagia and early onset obesity. The hormone leptin, secreted in the adipose tissue, activates leptin receptors in the hypothalamus, which in turn activates POMC (pro-opiomelanocortin) expressing neurons and this is leading to the production of melanocyte stimulating hormone (alpha- and beta-MSH). Alpha- and beta-MSH are able to activate the melanocortin 4 receptor (MC4R) and induction of satiety. Obese patients with a mutation within this pathway exhibit frequently additional clinical features as e.g. impaired pubertal development. However, the complete phenotypic spectrum and functional impact of certain gene mutations remain unclear, though this would be essential to elucidate the overall functions of these genes. Apart from additional clinical aspects, hyperphagia and obesity are the main symptoms and unfortunately, conservative treatment options and in most cases even bariatric surgery are not successful to ensure reduction of body weight in these particular patients. For this reason, it is of importance to identify new treatment options. Recently, I have performed an investigator-initiated trial with a MC4R agonist, which led in POMC and LEPR deficient patients to sustained weight loss, illustrating this medical need for pharmacological treatment options. With this application, I want to elucidate the functional impact of gene mutations within the leptin melanocortin pathway using induced pluripotent stem cells (iPSC) from patients which are differentiated into hypothalamic neurons. Furthermore, this approach will be accompanied by a detailed clinical characterization of the patients to clarify the role of the affected genes in human physiology. Finally, the established stem cell based in vitro system allows the investigation of different compounds like leptin sensitizers, which might improve pharmacological treatment strategies of patients with these rare diseases. By this approach, I want to gain new fundamental insights into the central regulation of body weight based on the analysis of rare forms of obesity, which could lead to new therapeutic options and which could potentially be transferred to patients with more frequent genetic variants in common forms of obesity.

工业化国家和低收入和中等收入国家肥胖的发展给患者和医疗保健系统带来了严重的负担，这些负担包括心血管疾病和2型糖尿病等相关合并症。因此，了解潜在的分子机制非常重要。在这里，对罕见单基因肥胖的动物模型和患者的鉴定，为体重的中枢调节带来了根本性的新见解。到目前为止，大多数突变是在所谓的瘦素黑皮质素信号通路中嵌入的基因中观察到的，并导致食欲亢进和早发性肥胖。脂肪组织中分泌的瘦素激素会激活下丘脑中的瘦素受体，进而激活表达 POMC（阿片黑皮质素原）的神经元，从而导致黑素细胞刺激激素（α-和 β-MSH）的产生。 α-和 β-MSH 能够激活黑皮质素 4 受体 (MC4R) 并诱导饱腹感。该途径内发生突变的肥胖患者经常表现出额外的临床特征，例如青春期发育受损。然而，某些基因突变的完整表型谱和功能影响仍不清楚，尽管这对于阐明这些基因的整体功能至关重要。除了其他临床方面外，食欲过盛和肥胖是主要症状，不幸的是，保守治疗选择，在大多数情况下，甚至减肥手术都不能成功地确保这些特定患者的体重减轻。因此，确定新的治疗方案非常重要。最近，我用 MC4R 激动剂进行了一项由研究者发起的试验，该试验导致 POMC 和 LEPR 缺陷患者持续体重减轻，这说明了对药物治疗方案的医疗需求。通过此应用，我想使用来自分化为下丘脑神经元的患者的诱导多能干细胞 (iPSC) 来阐明瘦素黑皮质素通路内基因突变的功能影响。此外，这种方法还将伴随着患者的详细临床特征，以阐明受影响基因在人类生理学中的作用。最后，所建立的基于干细胞的体外系统允许研究瘦素敏化剂等不同化合物，这可能会改善患有这些罕见疾病的患者的药物治疗策略。通过这种方法，我希望基于对罕见肥胖形式的分析，获得关于体重中央调节的新的基本见解，这可能会带来新的治疗选择，并且有可能转移到常见肥胖形式中具有更频繁遗传变异的患者身上。