Genetic and Metabolic Basis of Familial Lipodystrophies

描述（由申请人提供）：肥胖在美国仍然是一个主要的健康问题，并导致代谢并发症，如糖尿病，血脂异常和胰岛素抵抗。家族性脂肪营养不良、以部分（家族性部分脂肪营养不良，FPL）或几乎完全（先天性全身性脂肪营养不良，CGL）体脂缺乏为特征的单基因疾病患者也会出现类似的并发症。在过去的几年里，一些基因，即1-酰基甘油-3-磷酸o -酰基转移酶2 （AGPAT2）和Berardinelli-Seip先天性脂肪营养不良2 (BSCL2)，常染色体隐性遗传，CGL；常染色体显性FPL的纤层蛋白A/C （LMNA）、过氧化物酶体增殖物激活受体- d （ppar）和v-AKT小鼠胸腺瘤癌基因同源物2 (AKT2)；以及LMNA和锌金属蛋白酶（ZMPSTE24）与下颌骨发育不良相关的脂肪营养不良的关系已被确定。然而，来自许多家系的受影响受试者缺乏这些基因的突变，这表明存在额外的位点。此外，与SHORT和新生儿类早衰综合征相关的许多极其罕见的脂肪营养不良的遗传基础仍然未知。因此，本提案的第一个目的是确定额外的基因(s)参与脂肪细胞的生物学，发育和分化，导致脂肪营养不良。我们的实验室也一直在体外或通过开发敲除小鼠模型研究AGPAT的各种亚型（主要是AGPAT1和2）的功能作用。Agpat2-/-小鼠再现了人类CGL的许多特征，如体脂极度缺乏、早发性高血糖、高胰岛素血症、高甘油三酯血症和肝脂肪变性。有趣的是，我们的研究表明，在这些小鼠中，饮食甘油三酯是肝脏脂肪变性的主要原因。Agpatl-/-小鼠也具有严重的体脂缺乏，但详细的表型仍有待表征。此外，BSCL2编码蛋白seipin的生物学功能仍然未知，因此BSCL2突变如何导致脂肪营养不良仍然是一个谜。因此，本研究的第二个目标是进一步表征Agpat2- /-和Agpatl-/-小鼠，并建立Bscl2敲除小鼠模型，以深入了解与广泛性脂肪营养不良有关的各种基因的生物学作用，并了解胰岛素抵抗及其相关疾病的分子机制。

DESCRIPTION (provided by applicant): Obesity remains a major health problem in US and causes metabolic complications such as diabetes, dyslipidemia and insulin resistance. Similar complications also occur in patients with familial lipodystrophies, monogenic disorders characterized by partial (familial partial lipodystrophy, FPL) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last few years, several genes, namely, 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2), for the autosomal recessive, CGL; lamin A/C (LMNA), peroxisome proliferator-activated receptor-D (PPARG), and v-AKT murine thymoma oncogene homolog 2 (AKT2) for the autosomal dominant FPL; and LMNA and zinc metalloproteinase (ZMPSTE24) for mandibuloacral dysplasia associated lipodystrophies have been identified. However, affected subjects from many pedigrees lack mutations in these genes suggesting additional loci. Furthermore, the genetic basis of many extremely rare varieties of lipodystrophies associated with SHORT and neonatal progeroid syndromes remains unknown. Thus, the first aim of this proposal is to identify additional gene(s) involved in adipocyte biology, development and differentiation that cause lipodystrophies. Our laboratory has also been studying the functional role of various isoforms of AGPAT (mainly AGPAT1 and 2) either in vitro or by developing knockout mouse models. The Agpat2-/- mice reproduce many features of human CGL such as extreme lack of body fat, early onset hyperglycemia, hyperinsulinemia, hypertriglyceridemia and hepatic steatosis. Interestingly, our studies reveal that in these null mice, dietary triglycerides are major contributors to hepatic steatosis. The Agpatl-/- mice also have profound lack of body fat but the detailed phenotype remains to be characterized. Furthermore, the biological function of BSCL2-encoded protein, seipin, still remains unknown and thus how BSCL2 mutations cause lipodystrophy remains puzzling. Therefore, the second aim of this proposal is to further characterize Agpat2- /- and Agpatl-/- mice and to develop Bscl2 knockout mouse model to gain insights into biological role of various genes implicated in generalized lipodystrophies and to understand molecular mechanisms involved in causation of insulin resistance and its associated morbidities.