Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments

Abstract

ObjectiveObesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function. Our study aimed to determine whether normalizing the number of AT eosinophils in obese mice, to those of lean healthy mice, would reduce obesity and/or improve metabolic fitness.MethodsC57BL/6J mice fed a high fat diet (HFD) were simultaneously given recombinant interleukin-5 (rIL5) for 8 weeks to increase AT eosinophils. Metabolic fitness was tested by evaluating weight gain, AT inflammation, glucose, lipid, and mixed-meal tolerance, AT insulin signaling, energy substrate utilization, energy expenditure, and white AT beiging capacity.ResultsEosinophils were increased ∼3-fold in AT of obese HFD-fed mice treated with rIL5, and thus were restored to levels observed in lean healthy mice. However, there were no significant differences in rIL5-treated mice among the above listed comprehensive set of metabolic assays, despite the increased AT eosinophils.ConclusionsWe have shown that restoring obese AT eosinophils to lean healthy levels is not sufficient to allow for improvement in any of a range of metabolic features otherwise impaired in obesity. Thus, the mechanisms that identified eosinophils as positive regulators of AT function, and therefore systemic health, are more complex than initially understood and will require further study to fully elucidate.

Contributions of innate type 2 inflammation to adipose function

“…Likewise, our own lab has published data showing that while WAT eosinophils increased with 48 hr cold exposure, fat pads with further increased eosinophils by rIL-5 treatment had no indication of increased beiging capacity [110]. In the same study we found that increased WAT eosinophils from rIL-5 treatment yielded no improvements in lipid & mixed-meal tolerance, insulin sensitivity, weight gain, metabolic rate, food intake & locomotion, or general inflammation ( Table 1).…”

“…It must be acknowledged however, that a parasitic infection most certainly modulates a number of other immune cells, and it is unknown how propolis influences other immune processes; for this reason, it is not possible to by guest, on www.jlr.org Downloaded from say the increased eosinophils are definitively responsible for the improved glucose tolerance in such models as they were non-specific modulations of eosinophils. In our own studies, we found that despite specifically elevating numbers of WAT eosinophils in obese mice with either recombinant IL-5 (rIL-5) treatment or using CCR2 deficient mice, there was no improvement in glucose tolerance [72,110,123]. Several studies have utilized IL-33 to increase ILC2s, eosinophils, and/or M2-like macrophages in WAT, often associated with weight loss and improved glucose control [31,94,106,112,115,117,119].…”

An update on immune dysregulation in obesity‐related insulin resistance

“…Conversely, HFD in hyper‐eosinophilic IL‐5 transgenic mice causes eosinophil recruitment into the AT, M2‐like macrophages accumulation and prevention of IR . However, Bolus et al revealed that increasing the numbers of eosinophils in HFD‐fed mice using recombinant IL‐5 is not sufficient to improve obesity‐related metabolic dysfunctions . These conflicting results reveal that further studies are needed to clearly determine the precise role of eosinophils in the AT of obese animals.…”

Obesity-induced reduction of adipose eosinophils is reversed with low-calorie dietary intervention

“…), restoring AT eosinophils to physiological levels has not recapitulated such beneficial effects (Bolus et al. ). These mixed results demonstrate the need for continued research to determine the exact conditions that allow eosinophils to regulate AT homeostasis (i.e., which circumstances are permissive to eosinophil‐mediated improvements in metabolic health, and which are not).…”

“…Many studies indicate eosinophils and innate lymphoid type 2 cells are key players in maintaining AT homeostasis, but these studies are not without their caveats (Bolus and Hasty 2018;Knights et al 2018). While high levels of systemically elevated eosinophils have been shown to protect against the effects of high-fat diet (HFD)-induced obesity (Wu et al 2011;Molofsky et al 2013;Hussaarts et al 2015), restoring AT eosinophils to physiological levels has not recapitulated such beneficial effects (Bolus et al 2017). These mixed results demonstrate the need for continued research to determine the exact conditions that allow eosinophils to regulate AT homeostasis (i.e., which circumstances are permissive to eosinophil-mediated improvements in metabolic health, and which are not).…”