Central control of body weight and satiety regulation

在工业国家和中低收入国家，肥胖症的发展给患者和保健系统带来了沉重的负担，其基础是心血管疾病和2型糖尿病等相关并存疾病。因此，了解其潜在的分子机制具有重要意义。在这里，罕见的单基因肥胖症动物模型和患者的识别导致了对体重中枢调节的基本新见解。到目前为止，大多数突变都是在所谓的瘦素黑素皮质素信号通路中嵌入的基因中观察到的，并会导致吞噬功能亢进和早发性肥胖。脂肪组织中分泌的瘦素激素会激活下丘脑的瘦素受体，进而激活POMC(阿片黑素皮质素原)表达的神经元，从而导致黑素细胞刺激素(α-和β-MSH)的产生。α-MSH和β-MSH能够激活黑素皮质素4受体(MC4R)，诱导饱腹感。在这一途径中有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是必不可少的。除了其他临床方面，吞噬功能亢进和肥胖是主要症状，不幸的是，保守治疗方案，在大多数情况下，甚至减肥手术都不能成功确保这些特殊患者的体重减轻。因此，确定新的治疗方案是很重要的。最近，我用一种MC4R激动剂进行了一项由研究人员发起的试验，该试验导致POMC和LEPR缺陷患者持续体重减轻，说明了药物治疗方案的医学需求。通过这一应用，我想利用患者的诱导多能干细胞(IPSC)来阐明瘦素黑素皮质素途径中的基因突变对功能的影响，这些干细胞被分化为下丘脑神经元。此外，这种方法将伴随着患者的详细临床特征，以阐明受影响的基因在人类生理学中的作用。最后，建立的基于干细胞的体外系统允许研究不同的化合物，如瘦素增敏剂，这可能会改善这些罕见疾病患者的药物治疗策略。通过这种方法，我希望在对罕见形式的肥胖进行分析的基础上，对体重的中央调节获得新的基本见解，这可能会导致新的治疗选择，并可能转移到常见肥胖形式中有更频繁基因变异的患者身上。

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.