Ma Li-Jun, Mao Su-Li, Taylor Kevin L, Kanjanabuch Talerngsak, Guan YouFei, Zhang YaHua, Brown Nancy J, Swift Larry L, McGuinness Owen P, Wasserman David H, Vaughan Douglas E, Fogo Agnes B
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Diabetes. 2004 Feb;53(2):336-46. doi: 10.2337/diabetes.53.2.336.
Increased plasminogen activator inhibitor 1 (PAI-1) has been linked to not only thrombosis and fibrosis but also to obesity and insulin resistance. Increased PAI-1 levels have been presumed to be consequent to obesity. We investigated the interrelationships of PAI-1, obesity, and insulin resistance in a high-fat/high-carbohydrate (HF) diet-induced obesity model in wild-type (WT) and PAI-1-deficient mice (PAI-1(-/-)). Obesity and insulin resistance developing in WT mice on an HF diet were completely prevented in mice lacking PAI-1. PAI-1(-/-) mice on an HF diet had increased resting metabolic rates and total energy expenditure compared with WT mice, along with a marked increase in uncoupling protein 3 mRNA expression in skeletal muscle, likely mechanisms contributing to the prevention of obesity. In addition, insulin sensitivity was enhanced significantly in PAI-1(-/-) mice on an HF diet, as shown by euglycemic-hyperinsulinemic clamp studies. Peroxisome proliferator-activated receptor (PPAR)-gamma and adiponectin mRNA, key control molecules in lipid metabolism and insulin sensitivity, were maintained in response to an HF diet in white adipose tissue in PAI-1(-/-) mice, contrasting with downregulation in WT mice. This maintenance of PPAR-gamma and adiponectin may also contribute to the observed maintenance of body weight and insulin sensitivity in PAI-1(-/-) mice. Treatment in WT mice on an HF diet with the angiotensin type 1 receptor antagonist to downregulate PAI-1 indeed inhibited PAI-1 increases and ameliorated diet-induced obesity, hyperglycemia, and hyperinsulinemia. PAI-1 deficiency also enhanced basal and insulin-stimulated glucose uptake in adipose cells in vitro. Our data suggest that PAI-1 may not merely increase in response to obesity and insulin resistance, but may have a direct causal role in obesity and insulin resistance. Inhibition of PAI-1 might provide a novel anti-obesity and anti-insulin resistance treatment.
纤溶酶原激活物抑制剂1（PAI-1）水平升高不仅与血栓形成和纤维化有关，还与肥胖和胰岛素抵抗相关。PAI-1水平升高被认为是肥胖的结果。我们在野生型（WT）和PAI-1基因缺陷小鼠（PAI-1(-/-)）的高脂/高碳水化合物（HF）饮食诱导的肥胖模型中，研究了PAI-1、肥胖和胰岛素抵抗之间的相互关系。缺乏PAI-1的小鼠完全预防了WT小鼠在HF饮食中出现的肥胖和胰岛素抵抗。与WT小鼠相比，HF饮食喂养的PAI-1(-/-)小鼠静息代谢率和总能量消耗增加，同时骨骼肌中解偶联蛋白3 mRNA表达显著增加，这可能是预防肥胖的机制。此外，如正常血糖-高胰岛素钳夹研究所示，HF饮食喂养的PAI-1(-/-)小鼠胰岛素敏感性显著增强。过氧化物酶体增殖物激活受体（PPAR）-γ和脂联素mRNA是脂质代谢和胰岛素敏感性的关键调控分子，在PAI-1(-/-)小鼠白色脂肪组织中，它们在HF饮食作用下保持稳定，而WT小鼠则下调。PPAR-γ和脂联素的这种稳定也可能有助于观察到的PAI-1(-/-)小鼠体重和胰岛素敏感性的维持。用1型血管紧张素受体拮抗剂治疗HF饮食喂养的WT小鼠以下调PAI-1，确实抑制了PAI-1的升高，并改善了饮食诱导的肥胖、高血糖和高胰岛素血症。PAI-1缺乏还增强了体外脂肪细胞基础和胰岛素刺激的葡萄糖摄取。我们的数据表明，PAI-1可能不仅是对肥胖和胰岛素抵抗的反应性增加，而且可能在肥胖和胰岛素抵抗中起直接因果作用。抑制PAI-1可能提供一种新的抗肥胖和抗胰岛素抵抗治疗方法。
