Division of Metabolic and Vascular Medicine, Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA.
Metabolism. 2024 Dec;161:156053. doi: 10.1016/j.metabol.2024.156053. Epub 2024 Oct 28.
Leptin has been established as the prototype adipose tissue secreted hormone and as a major regulator of several human physiology functions. Here, we are primarily reviewing the findings from studies in humans involving leptin administration. We are describing the metabolic, endocrine and immunologic effects of leptin replacement in conditions of leptin deficiency, such as short-term fasting in healthy individuals, relative energy deficiency in sports (REDS), congenital leptin deficiency (CLD), generalized (GL) and partial lipodystrophy (PL), HIV-associated lipodystrophy (HIV-L) and of leptin treatment in conditions of leptin excess (common obesity, type 2 diabetes, steatotic liver disease). We are comparing the results with the findings from preclinical models and present the main conclusions regarding the role of leptin in human physiology, pathophysiology and therapeutics. We conclude that, in conditions of energy deficiency, leptin substitution effectively reduces body weight and fat mass through reduction of appetite, it improves hypertriglyceridemia, insulin resistance and hepatic steatosis (especially in GL and PL), it restores neuroendocrine function (especially the gonadotropic axis), it regulates adaptive immune system cell populations and it improves bone health. On the contrary, leptin treatment in conditions of leptin excess, such as common obesity and type 2 diabetes, does not improve any metabolic abnormalities. Strategies to overcome leptin tolerance/resistance in obesity and type 2 diabetes have provided promising results in animal studies, which should though be tested in humans in randomized clinical trials.
瘦素已被确立为脂肪组织分泌的典型激素，也是多种人体生理功能的主要调节剂。在这里，我们主要回顾了涉及瘦素给药的人类研究结果。我们描述了瘦素替代治疗在瘦素缺乏症（如健康个体的短期禁食、运动相关的相对能量不足（REDS）、先天性瘦素缺乏症（CLD）、全身性（GL）和部分脂肪营养不良（PL）、HIV 相关脂肪营养不良（HIV-L））中的代谢、内分泌和免疫作用，以及在瘦素过多症（常见肥胖、2 型糖尿病、脂肪性肝病）中的治疗作用。我们将这些结果与临床前模型的研究结果进行了比较，并提出了关于瘦素在人体生理学、病理生理学和治疗学中的主要作用的结论。我们的结论是，在能量缺乏的情况下，瘦素替代通过降低食欲有效地减轻体重和体脂肪量，改善高甘油三酯血症、胰岛素抵抗和肝脂肪变性（特别是在 GL 和 PL 中），恢复神经内分泌功能（特别是促性腺激素轴），调节适应性免疫系统细胞群，并改善骨骼健康。相反，在瘦素过多症（如常见肥胖和 2 型糖尿病）的情况下，瘦素治疗并不能改善任何代谢异常。在肥胖和 2 型糖尿病中克服瘦素耐受/抵抗的策略在动物研究中提供了有希望的结果，这些结果应在随机临床试验中在人类中进行测试。
