Licinio Julio, Caglayan Sinan, Ozata Metin, Yildiz Bulent O, de Miranda Patricia B, O'Kirwan Fiona, Whitby Robert, Liang Liyin, Cohen Pinchas, Bhasin Shalender, Krauss Ronald M, Veldhuis Johannes D, Wagner Anthony J, DePaoli Alex M, McCann Samuel M, Wong Ma-Li
Center for Pharmacogenomics, Neuropsychiatric Institute, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1761, USA.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4531-6. doi: 10.1073/pnas.0308767101. Epub 2004 Mar 9.
Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.
瘦素通路中的基因突变可能是人类肥胖的一个原因。目前尚不清楚瘦素是否能有效治疗成人已完全形成的病态肥胖及其内分泌和代谢后果。为了验证瘦素在成人代谢和内分泌调节中起关键作用这一假设，我们对迄今为止仅有的三名经基因检测证实存在瘦素缺乏的成年人进行了人瘦素替代治疗效果的研究。我们用重组人瘦素以0.01 - 0.04 mg/kg的低生理替代剂量治疗这三名病态肥胖的纯合子瘦素缺乏成年患者，为期18个月。患者存在性腺功能减退，其中一人还患有2型糖尿病。我们选择能使瘦素浓度达到正常水平的重组甲硫氨酰人瘦素剂量，并在晚上每日给药，以模拟内源性瘦素正常的昼夜变化。治疗18个月后，平均体重指数从基线时的51.2±2.5（均值±标准误）降至26.9±2.1 kg/m²，主要是因为脂肪量减少。我们在此记录到，对已患有病态肥胖的瘦素缺乏成年人进行瘦素替代治疗可导致显著体重减轻、身体活动增加、内分泌功能和代谢发生变化，包括2型糖尿病和性腺功能减退的缓解，以及对摄食和非摄食行为产生有益影响。这些结果突出了瘦素通路在成年人中对体重调节、性腺功能和行为具有关键作用。
