Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, the Netherlands.
Center for Molecular Medicine, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria.
J Leukoc Biol. 2024 Jan 19;115(2):374-384. doi: 10.1093/jleuko/qiad118.
Leptin is associated with cardiometabolic complications of obesity, such as metabolic syndrome and atherosclerosis. In obese men, the presence of metabolic syndrome is associated with higher circulating leptin and interleukin (IL)-6 concentrations and increased monocyte cytokine production capacity. Here, we investigated the effects of leptin on monocyte function and systemic inflammatory markers in obese individuals. We specifically explored whether leptin can induce long-term changes in innate immune function by inducing innate immune memory (also called trained immunity). We exposed human primary monocytes for 24 h to relevant leptin concentrations in vitro and measured cytokine production. In addition, after removing leptin, we incubated monocytes for 5 d in culture medium, and we restimulated them on day 6 to assess cytokine production capacity, phagocytosis, and foam cell formation. Direct stimulation with leptin did not induce cytokine production, but exposure to 50 ng/mL leptin augmented lipopolysaccharide- and R848-induced tumor necrosis factor α (TNF-α) production after 1 wk. In a separate in vivo study in a cohort of 302 obese subjects (body mass index [BMI] >27 kg/m2, 55 to 81 yr), we measured circulating leptin, inflammatory markers, and cytokine production upon ex vivo stimulation of isolated peripheral blood mononuclear cells. Circulating leptin concentrations positively correlated with circulating IL-1β and IL-6, which was more pronounced in men than in women. Four single nucleotide polymorphisms in the leptin gene influenced circulating IL-6 concentrations in men, suggesting a direct effect of leptin on IL-6. In conclusion, in vitro, leptin does not directly stimulate monocytes to produce cytokines, yet induces long-term monocyte hyperresponsiveness, i.e. trained immunity. In obese subjects, leptin is associated with circulating IL-6 in a sex-dependent manner. The underlying mechanisms of the sex-specific effect of leptin on innate immune cells remain to be further investigated.
瘦素与肥胖的代谢和心血管并发症有关，如代谢综合征和动脉粥样硬化。在肥胖男性中，代谢综合征的存在与循环瘦素和白细胞介素 (IL)-6 浓度升高以及单核细胞细胞因子产生能力增加有关。在这里，我们研究了瘦素对肥胖个体单核细胞功能和全身炎症标志物的影响。我们特别探讨了瘦素是否可以通过诱导先天免疫记忆（也称为训练免疫）来诱导先天免疫功能的长期变化。我们在体外将人类原代单核细胞暴露于相关浓度的瘦素 24 小时，并测量细胞因子的产生。此外，在去除瘦素后，我们在培养物中孵育单核细胞 5 天，并在第 6 天重新刺激它们以评估细胞因子产生能力、吞噬作用和泡沫细胞形成。直接刺激瘦素不会诱导细胞因子产生，但暴露于 50ng/mL 瘦素可在 1 周后增强脂多糖和 R848 诱导的肿瘤坏死因子 α（TNF-α）的产生。在一项由 302 名肥胖受试者（BMI＞27kg/m2，55 至 81 岁）组成的队列的独立体内研究中，我们测量了分离的外周血单核细胞经体外刺激后循环中的瘦素、炎症标志物和细胞因子的产生。循环瘦素浓度与循环中的 IL-1β 和 IL-6 呈正相关，在男性中比女性中更为明显。瘦素基因中的四个单核苷酸多态性影响男性循环中 IL-6 的浓度，这表明瘦素对 IL-6 有直接影响。总之，在体外，瘦素不会直接刺激单核细胞产生细胞因子，但会诱导单核细胞长期的高反应性，即训练免疫。在肥胖人群中，瘦素与循环中的 IL-6 呈性别依赖性相关。瘦素对先天免疫细胞的性别特异性影响的潜在机制仍有待进一步研究。
