Omentin, A Novel Adipocytokine From Omental Fat Tissue

脂肪组织在肥胖及其相关疾病如2型糖尿病、心血管疾病和血脂异常的发病机制中起着重要作用。脂肪组织分泌多种生物活性因子，调节能量代谢。这些因子统称为脂肪细胞因子，包括瘦素、肿瘤坏死因子α、纤溶酶原激活物抑制物-1、脂联素/ACRP30/ADIPOQ和抵抗素。脂肪细胞因子的失调可能导致或促进肥胖及其合并症的发展。然而，目前已知的脂肪细胞因子不能完全解释这些疾病的表型。例如，为什么内脏肥胖比皮下肥胖更具病理性？为了发现新的内脏脂肪基因和更好地了解脂肪细胞生物学，我们从人类大网膜脂肪文库中测序了10,411个表达序列标签(EST)。生物信息学分析表明，一个频繁测序的EST是一个潜在的分泌因子，Northern分析表明该EST只在大网膜表达，而在皮下脂肪组织中不表达。因此，我们将这一新的脂肪细胞因子命名为omentin。进一步的实验证明，omentin确实是一种分泌性蛋白质，在人类血液中可以检测到。重要的和出乎意料的是，omentin显著增强胰岛素介导的3T3-L1脂肪细胞的葡萄糖运输，并激活Akt，无论有无胰岛素。我们假设omentin是一种新的脂肪细胞因子，调节能量代谢和胰岛素信号转导。为了验证这一假设，我们提出：(1)通过在体外解剖3T3 LL脂肪细胞的omentin信号通路来确定omentin增加胰岛素敏感性的机制：(2)通过给正常和肥胖/胰岛素抵抗小鼠注射重组蛋白或给正常小鼠注射中和抗体来确定omentin对肥胖、胰岛素抵抗和葡萄糖代谢的体内影响；以及(3)通过测量参加Amish Family糖尿病研究的900名受试者的血清omentin水平，并确定血清omentin水平与各种代谢参数之间的关系，包括肥胖、体脂分布、葡萄糖耐量、胰岛素水平和糖尿病，来确定omentin在人类中的作用。这些研究将确定这种新型脂肪细胞因子的作用机制，以及它在脂肪细胞生物学、能量调节和葡萄糖代谢中的作用。这些新的见解可能导致预防和治疗肥胖症、胰岛素抵抗和糖尿病的新策略。

Adipose tissue plays an important role in the pathogenesis of obesity and its associated diseases such as type 2 diabetes, cardiovascular disease and dyslipidemia. Adipose tissue secretes a variety of bioactive factors to regulate energy metabolism. Collectively known as adipocytokines, these factors include leptin, tumor necrosis factor alpha, plaminogen activator inhibitor-1, adiponectin/ACRP30/adipoQ and resistin. Dysregulation of adipocytokines may cause or contribute to the development of obesity and its comorbidities. However, the currently known adipocytokines cannot fully explain the phenotypes of these diseases. For example, why is visceral obesity more pathological than subcutaneous obesity? In an attempt to discover novel visceral adipose genes and to better understand fat cell biology, we sequenced 10,411 expressed sequence tags (ESTs) from a human omental fat library. Bioinformatics analysis revealed that one frequently sequenced EST was a potential secretory factor and Northern analyses revealed that this EST was expressed only in omental, not in subcutaneous adipose tissue. We therefore have named this novel adipocytokine, omentin. Further experiments demonstrated that omentin is indeed a secretory protein and is detectable in human blood. Importantly and unexpectedly, omentin markedly enhances insulin-mediated glucose transport in 3T3-L1 adipocytes and activates Akt, both in the presence and absence of insulin. We hypothesize that omentin is a novel adipocytokine that regulates energy metabolism and insulin signaling. To test this hypothesis, we propose: (1) to determine the mechanism by which omentin increases insulin sensitivity by dissecting the omentin signaling pathway in vitro in 3T3 Ll adipocytes; (2) to determine the in vivo effect of omentin on obesity, insulin resistance and glucose metabolism by administering the recombinant protein to normal and obese/insulin-resistant mice or by administering neutralizing antibodies to normal mice; and (3) to define the role of omentin in humans by measuring serum levels of omentin in 900 subjects enrolled in the Amish Family Diabetes Study, and determining the relationship between serum omentin levels and a variety of metabolic parameters, including obesity, body fat distribution, glucose tolerance, insulin levels, and diabetes. These studies will define the mechanism of action of this novel adipocytokine, as well as its role in fat cell biology, energy regulation, and glucose metabolism. These new insights may lead to new strategies to prevent and treat obesity, insulin resistance and diabetes.