The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.

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-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 hours to relevant leptin concentrations in vitro and measured cytokine production. In addition, after removing leptin, we incubated monocytes for 5 days 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 LPS- and R848-induced tumor necrosis factor (TNF-α) production after 1 week. In a separate in vivo study in a cohort of 302 obese subjects (BMI>27, 55-81 years), 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.

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© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology.