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）。高营养和遗传因素都有助于疾病的发作和进展。这使得代谢综合征成为一种多器官受累的全身性疾病。脂肪组织（AT）及其三个主要部分，皮下、内脏和棕色AT是代谢综合征的关键参与者，近年来越来越多地被认识到。最近，磷脂酶PNPLA3的多态性已被鉴定为遗传风险因子，存在于大约20%的高加索人群中。PNPLA3的脂肪酶活性降低导致NASH的发作和进展以及其他肝病如酒精性肝病和病毒性肝炎的加重。PNPLA3在其他器官中的作用目前尚不清楚。有趣的是，携带多态性的个体显示出具有有利的AT分布的改变的身体组成。然而，其他报告显示，肥胖症患者发生代谢综合征的风险增加。目前，PNPLA3在代谢综合征中的作用尚不清楚，最近，建立了一种小鼠模型，该模型类似于小鼠中PNPLA3多态性并导致NASH。作为另外的对照，该模型包括具有脂肪酶死亡突变体的小鼠品系。尽管如此，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学。在这个项目中，我们的目标是研究PNPLA3在AT中的作用，以促进NASH和代谢综合征的发展。首先，我们将研究PNPLA3的调节及其对主要AT功能的影响，在瘦和肥胖动物。这包括葡萄糖和脂质代谢，间接热量测定和身体成分分析。在细胞水平上，我们将描述脂质代谢和棕色AT功能，特别是产热。在下一步中，我们计划确定可以作为脂肪因子的因子，并可能介导AT以外的效应，例如在肝脏中。最后，我们将评估我们在已知PNPLA3状态的肥胖患者的组织和血清中的数据。总之，该项目将有助于了解PNPLA3在AT中的作用及其对代谢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，并确定处于疾病发作和进展风险中的患者。

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.