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
View: Text | PDF
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

×

Figure 3

Human s.c. AT-EOS and IL-4 content is decreased in patients with BMI ≥ 30 kg/m2 and is inversely related to BMI and HOMA-IR.

Options: View larger image (or click on image) Download as PowerPoint
Human s.c. AT-EOS and IL-4 content is decreased in patients with BMI ≥ 3...
(A) Representative gating strategy for quantification and isolation of EOS from s.c. AT of healthy lean patients (BMI < 25 kg/m2) and patients with BMI ≥ 30 kg/m2. Samples were gated to remove doublets and dead cells, followed by gating on forward scatter (FSC), side scatter (SSC), and CD45+ for leukocytes. The EOS population was identified as CD45+CD14−CD16−CD66b+EMR1+ and were sorted to ≥ 99% purity. (B) The summary of flow cytometry data for EOS content in s.c. and Om AT of patients is presented in a graph. In patients with BMI ≥ 30 kg/m2, AT-EOS content is significantly reduced when compared with healthy lean patients (BMI < 25 kg/m2) regardless of AT depot. (C) RT-PCR of s.c. and Om AT mRNA expression of EOS-specific gene eosinophil peroxidase (EPX), which is significantly reduced in individuals with BMI ≥ 30 kg/m2. Y-axis = relative fold change (2–ΔΔCt); unpaired 2-tailed t test was used to generate P values. Data were expressed as mean ± SEM. S.c. AT n = 15 per group; Om AT n = 6 per group. (D) In individuals with BMI ≥30 kg/m2 IL4 mRNA levels are reduced in SVF of s.c. AT biopsy (n = 6 per group). The y axis indicates relative fold change (2–ΔΔCt). (E) Circulating levels of IL-4 are evaluated in plasma of all participating patients. Individuals with BMI ≥ 30 kg/m2 display a significant decreased level of IL-4. n = 12 per group. (F) Linear regression analysis was used for F and G. S.c. AT-EOS content expressed as percentage of CD45+ granulocytes is inversely correlated to the individuals BMI. (G) Linear regression analysis demonstrates a worsening in HOMA-IR by –1.030 per every unit percentage s.c. AT-EOS content. n = 30.