Linking adipose tissue eosinophils, IL-4, and leptin in human obesity and insulin resistance
James D. Hernandez, Ting Li, Hamza Ghannam, Cassandra M. Rau, Mia Y. Masuda, James A. Madura II, Elizabeth A. Jacobsen, Eleanna De Filippis
James D. Hernandez, Ting Li, Hamza Ghannam, Cassandra M. Rau, Mia Y. Masuda, James A. Madura II, Elizabeth A. Jacobsen, Eleanna De Filippis
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Clinical Research and Public Health Inflammation Metabolism

Linking adipose tissue eosinophils, IL-4, and leptin in human obesity and insulin resistance

Abstract

BACKGROUND Obesity is a multifactorial disease with adverse health implications including insulin resistance (IR). In patients with obesity, the presence of high circulating levels of leptin, deemed hyperleptinemia, is associated with IR. Recent data in mice with diet-induced obesity (DIO) show that a partial reduction in leptin levels improves IR. Additional animal studies demonstrate that IL-4 decreases leptin levels. In rodents, resident adipose tissue eosinophils (AT-EOS) are the main source of IL-4 and are instrumental in maintaining metabolic homeostasis. A marked reduction in AT-EOS content is observed in animal models of DIO. These observations have not been explored in humans.METHODS We analyzed AT from individuals with obesity and age-matched lean counterparts for AT-EOS content, IL-4, circulating leptin levels, and measures of IR.RESULTS Our results show that individuals with obesity (n = 15) had a significant reduction in AT-EOS content (P < 0.01), decreased AT–IL-4 gene expression (P = 0.02), and decreased IL-4 plasma levels (P < 0.05) in addition to expected IR (P < 0.001) and hyperleptinemia (P < 0.01) compared with lean subjects (n = 15). AT-EOS content inversely correlated with BMI (P = 0.002) and IR (P = 0.005). Ex vivo AT explants and in vitro cell culture of primary human mature adipocytes exposed to either IL-4 or EOS conditioned media produced less leptin (P < 0.05).CONCLUSION Our results suggest that IL-4 acts as a link between EOS, AT, and leptin production. Future studies exploring this interaction may identify an avenue for the treatment of obesity and its complications through amelioration of hyperleptinemia.TRIAL REGISTRATION Clinicaltrials.gov NCT02378077 & NCT04234295.

Authors

James D. Hernandez, Ting Li, Hamza Ghannam, Cassandra M. Rau, Mia Y. Masuda, James A. Madura II, Elizabeth A. Jacobsen, Eleanna De Filippis

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Figure 4

IL-4 decrease LEP mRNA expression and secretion in primary adipocytes in vitro, and EOS conditioned media reduce LEP mRNA expression and secretion in s.c. AT ex vivo and in primary adipocytes in vitro.

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IL-4 decrease LEP mRNA expression and secretion in primary adipocytes in...
(A) LEP mRNA levels in human s.c. primary mature adipocytes collected from individuals with BMI ≥ 30 kg/m2 is significantly reduced after 24 hours of IL-4 (20 ng/mL) treatment. The response is blunted by coincubation of IL-4R α antibody (anti–IL-4RA 2.5 ng/mL for 24 hours) (1-way ANOVA, Bonferroni corrected, n = 6). (B) Leptin levels in the supernatant of human s.c. primary adipocytes collected from individuals with BMI ≥ 30 kg/m2 is significantly reduced after 24 hours of IL-4 (20 ng/mL) treatment. The response is blunted by coincubation of anti–IL-4RA (2.5ng/mL for 24 hours) (1-way ANOVA, Bonferroni corrected, n = 6). (C) EOS isolated from whole blood of healthy volunteers were cultured and treated with a cytokine cocktail mimicking tissue activation (1 ng/mL IL-5, 5 ng/mL GM-CSF, and 50 ng/mL IL-33 for 16 hours) resulting in increased secretion of IL-4 into the conditioned media (CM) (unpaired 2-tailed t test, n = 4). (D) LEP mRNA expression is decreased in s.c. AT (100 mg minced) after incubation with 1 mL conditioned media for 24 hours (unpaired 2-tailed t test, n = 4). (E) LEP mRNA levels in human s.c. primary mature adipocytes collected from individuals with BMI ≥ 30 kg/m2 is significantly reduced after incubation with 1 mL CM for 24 hours. The response is blunted by coincubation of anti–IL-4RA (2.5 ng/mL for 24 hours) (1-way ANOVA, Bonferroni corrected, n = 4). (A, D, and E) The y axes indicate relative fold change (2–ΔΔCt). Data are expressed as mean ± SEM.