Department of Cellular and Physiological Sciences (A.M.D., A.A., J.D.J., T.J.K.), Department of Biochemistry and Molecular Biology (S.D.C.), and Department of Surgery (J.D.J., T.J.K.), University of British Columbia, Vancouver British Columbia, Canada V5Z 4E3.
Endocrinology. 2014 Apr;155(4):1268-79. doi: 10.1210/en.2013-1523. Epub 2014 Jan 27.
Leptin, an adipocyte-derived hormone, has well-established anorexigenic effects but is also able to regulate glucose homeostasis independent of body weight. Until recently, the ob/ob mouse was the only animal model of global leptin deficiency. Here we report the effects of leptin deficiency on glucose homeostasis in male and female leptin knockout (KO) rats. Leptin KO rats developed obesity by 6 to 7 weeks of age, and lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age. Hyperinsulinemia and insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting hyperglycemia between 14 and 25 weeks of age, but thereafter fasting glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of β-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more insulin when stimulated than islets from WT littermates. Leptin replacement via miniosmotic pump (100 μg/d) reduced food intake, attenuated weight gain, normalized glucose tolerance, and improved glucose-stimulated insulin secretion and insulin sensitivity. Together, these data demonstrate that the absence of leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of hyperinsulinemia, obesity, and insulin resistance.
瘦素是一种脂肪细胞衍生的激素，具有明确的厌食作用，但也能够独立于体重调节葡萄糖稳态。直到最近，ob/ob 小鼠仍是唯一的全身性瘦素缺乏动物模型。在这里，我们报告了瘦素缺乏对雄性和雌性瘦素敲除（KO）大鼠葡萄糖稳态的影响。瘦素 KO 大鼠在 6 至 7 周龄时就发展为肥胖，并且在 18 周龄时与野生型（WT）同窝仔相比，脂肪量增加了两倍多。雄性和雌性 KO 大鼠均表现出高胰岛素血症和胰岛素抵抗，并且随着年龄的增长而持续存在。雄性 KO 大鼠在 14 至 25 周龄之间经历了短暂的轻度空腹高血糖，但此后至 36 周龄时，空腹血糖水平与 WT 同窝仔相当。雌性 KO 大鼠的空腹血糖水平与 WT 同窝仔相似。雄性 KO 大鼠在 36 周龄时，β细胞面积占胰腺总面积的比例增加了 3 倍。与 WT 同窝仔相比，12 周龄 KO 大鼠的胰岛在受到刺激时分泌的胰岛素更多。通过迷你渗透泵（100μg/d）进行的瘦素替代治疗减少了食物摄入，减轻了体重增加，使葡萄糖耐量正常化，并改善了葡萄糖刺激的胰岛素分泌和胰岛素敏感性。综上所述，这些数据表明，大鼠中瘦素的缺失重现了以前在 ob/ob 小鼠中观察到的一些表型，包括高胰岛素血症、肥胖和胰岛素抵抗的发展。
