Regulation of metabolic responses by adipocyte/macrophage fatty acid-binding proteins in leptin-deficient mice
Regulation of metabolic responses by adipocyte/macrophage fatty acid-binding proteins in leptin-deficient mice
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DOI：
10.2337/db05-1496
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发表时间：
2006-07-01
期刊：
影响因子：
7.7
通讯作者：
Hotamisligil, Gokhan S.
中科院分区：
文献类型：
--
作者：
Cao, Haiming;Maeda, Kazuhisa;Hotamisligil, Gokhan S.
脂肪酸结合蛋白（FABPs）是细胞溶质脂肪酸伴侣蛋白，在脂质和葡萄糖代谢的系统性调节中起关键作用。在缺乏脂肪细胞/巨噬细胞FABP异构体aP2和mall的动物中，对饮食诱导的肥胖、胰岛素抵抗、2型糖尿病、脂肪肝疾病和高胆固醇血症性动脉粥样硬化有很强的保护作用。在高脂肪饮食下，FABP缺陷小鼠还表现出肌肉AMP活化激酶（AMPK）增强和肝脏硬脂酰 - CoA去饱和酶 - 1（SCD - 1）活性降低。在此，我们将aP2（ - / - ）、mall（ - / - ）和瘦素缺陷（ob/ob）小鼠进行杂交，以阐明瘦素作用对aP2 - mall缺陷代谢表型的影响。ob/ob - aP2 - mall（ - / - ）小鼠的肥胖程度与ob/ob小鼠相当。然而，尽管严重肥胖，ob/ob - aP2 - mall（ - / - ）小鼠仍保持血糖正常，并表现出外周胰岛素敏感性改善。ob/ob - aP2 - mall（ - / - ）小鼠的肝脏脂肪浸润也受到显著保护，SCD - 1活性受到强烈抑制。另一方面，aP2 - mall（ - / - ）小鼠中增强的肌肉AMPK活性在ob/ob背景下丧失。这些结果表明，aP2 - mall（ - / - ）小鼠体重减轻和肌肉AMPK活性增强可能依赖于瘦素，但系统性胰岛素敏感性改善和肝脏脂肪浸润保护在很大程度上与瘦素作用无关，并且FABP缺陷的胰岛素增敏作用至少部分独立于其对全身肥胖的影响。
Fatty acid-binding proteins (FABPs) are cytosolic fatty acid chaperones that play a critical role in systemic regulation of lipid and glucose metabolism. In animals lacking the adipocyte/macrophage FABP isoforms aP2 and mall, there is strong protection against diet-induced obesity, insulin resistance, type 2 diabetes, fatty liver disease, and hypercholesterolemic atherosclerosis. On high-fat diet, FABP-deficient mice also exhibit enhanced muscle AMP-activated kinase (AMFK) and reduced liver stearoyl-CoA desaturase-1 (SCD-1) activities. Here, we performed a cross between aP2(-/-), mall(-/-), and leptin-deficient (ob/ob) mice to elucidate the role of leptin action on the metabolic phenotype of aP2-mall deficiency. The extent of obesity in the ob/ob-aP2-mall(-/-) mice was comparable with ob/ob mice. However, despite severe obesity, ob/ob-aP2mall(-/-) mice remained euglycemic and demonstrated improved peripheral insulin sensitivity. There was also a striking protection from liver fatty infiltration in the ob/ob-aP2-mall(-/-) mice with strong suppression of SCD-1 activity. On the other hand, the enhanced muscle AMPK activity in aP2-mall(-/-) mice was lost in the ob/ob background. These results indicated that both decreased body weight and enhanced muscle AMPK activity in aP2-mall(-/-) mice are potentially leptin dependent but improved systemic insulin sensitivity and protection from liver fatty infiltration are largely unrelated to leptin action and that insulin-sensitizing effects of FABP deficiency are, at least in part, independent of its effects on total-body adiposity.