The role of the PNPLA3 I148M polymorphism for adipose tissue function in health and disease

肥胖是代谢综合征及其并发症的主要危险因素，如糖尿病、心血管疾病和非酒精性脂肪性肝炎(NASH)。营养过剩，但也有遗传因素导致疾病的发生和发展。这使得代谢综合征成为一种全身疾病，多个器官都会受到影响。脂肪组织(AT)包括皮下、内脏和棕色三个主要部分，在代谢综合征中起着关键作用，近年来受到越来越多的重视。它具有能量储存和消耗、胰岛素敏感性和内分泌器官的作用，通过分泌脂肪因子来调节多种生理过程。最近，磷脂酶PNPLA3基因的多态性被确认为一种遗传危险因素，存在于大约20%的高加索人中。PNPLA3的脂肪酶活性降低会导致NASH的发生和发展，并导致其他肝病的加重，如酒精性肝病和病毒性肝炎。PNPLA3在其他器官中的作用目前尚不清楚。有趣的是，携带这种多态的个体表现出身体成分的改变，具有有利的AT分布。然而，其他报告显示，肥胖会增加患代谢综合征的风险。到目前为止，PNPLA3在代谢综合征中的作用尚不清楚。最近，一个与PNPLA3基因多态性相似的小鼠模型已经建立，并导致NASH。作为额外的对照，该模型包括一个带有脂肪酶死亡突变体的小鼠品系。然而，我们有一个很好的模型来研究这个重要的人类危险因素的功能和生理。在这个项目中，我们的目标是研究PNPLA3在AT中在NASH和代谢综合征发生中的作用。首先，我们将研究PNPLA3的调节及其对瘦肉和肥胖动物主要AT功能的影响。这包括葡萄糖和脂肪代谢、间接量热法和身体成分分析。在细胞水平上，我们将描述脂肪代谢和棕色AT的功能，特别是产热作用。在下一步，我们计划确定可以作为脂肪因子的因素，并可能在AT之外发挥中介作用，例如在肝脏中。最后，我们将评估我们在一组已知PNPLA3状态的肥胖患者的组织和血清中的数据。综上所述，该项目将有助于了解PNPLA3在AT中的作用及其对代谢性疾病和肝脏疾病的影响。这将有助于为代谢综合征患者开发新的治疗策略，并识别疾病发生和发展的风险。

Obesity is a major risk factor for metabolic syndrome and its complications, such as diabetes, cardiovascular disease and nonalcoholic steatohepatitis (NASH). Hyperalimentation but also genetic factors contribute to disease onset and progression. This makes the metabolic syndrome a systemic disease with multiple organs affected. The adipose tissue (AT) with its three major compartments, subcutaneous-, visceral- and brown AT is a key player in metabolic syndrome and has been increasingly recognized in the past years. It has a role in energy -storage and –expenditure, Insulin sensitivity and as an endocrine organ, mediating multiple physiological processes through the secretion of factors termed adipokines.Recently, a polymorphism of the phospholipase PNPLA3 has been identified as a genetic risk factor, present in approximately 20% of the Caucasian population. A reduced lipase- activity of PNPLA3 leads to the onset and progression of NASH and aggravation of other liver diseases such as alcoholic liver disease and viral hepatitis. The role of PNPLA3 in other organs is currently unclear. Interestingly, individuals bearing the polymorphism show an altered body composition with a favorable AT distribution. However, other reports have revealed an increased risk for the development of metabolic syndrome in the presence of obesity. So far, the role of PNPLA3 in metabolic syndrome remains elusive.Recently, a mouse model has been established, resembling the PNPLA3 polymorphism in mice and leading to NASH. As additional control, the model comprises a mouse strain with a lipase-dead mutant. Though, we have an excellent model to study the function and physiology of this important human risk factor.In this project, we aim to investigate the role of PNPLA3 in AT for the development of NASH and metabolic syndrome. First, we will examine the regulation of PNPLA3 and its impact on major AT functions, in lean and obese animals. This comprises the glucose- and lipid- metabolism, indirect calorimetry and body composition analysis. On cellular level, we will characterize the lipid metabolism and brown AT function, in particular thermogenesis. In a next step, we plan to identify factors that can serve as adipokines and potentially mediate effects outside the AT, such as in liver. Finally, we will evaluate our data in tissue and serum of a human cohort of obese patients with known PNPLA3 status.In summary, this project will help to understand the role of PNPLA3 in AT and its impact on metabolic disease and liver disease. This will help to develop new therapeutic strategies for patients with metabolic syndrome and to identify patients at risk for disease onset and progression.