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.

Eosinophil biology from the standpoint of metabolism: implications for metabolic disorders and asthma

“…A recent human study highlights the significant reduction in adipose tissue eosinophil content among obese patients. 24 This finding underscores the obesity-resistant effect of eosinophils within this microenvironment. Notably, the protective effect of eosinophils against high-fat diet-induced obesity in mice was first reported in 2011 by Wu et al 9 Their study demonstrated that C57BL/6 mice lacking eosinophils (ΔdblGATA mice) and fed a high-fat diet exhibited increased body fat, impaired glucose tolerance, and decreased insulin sensitivity compared to their wild-type littermate control mice.…”

“…This omission is significant, considering recent human studies have shown that specifically adipose tissue eosinophils have more influence on weight gain and metabolic dysfunction in obesity. 24 , 77 Kuruvilla et al 78 observed a mild but significant decrease in BMI of severe asthma patients over 6 mo on anti–IL-5 therapy. Again, eosinophils were only measured in blood, not in body fat.…”

“…Furthermore, as shown in both animal and human studies, eosinophils are proficient in secreting various cytokines and chemokines, such as IL-4 and IL-13, which may directly influence behavior of adipocytes and other immune cells resident in adipose tissue, ultimately influencing systemic metabolism. 24 , 27 , 28 …”