The growing worldwide obesity epidemic is frequently linked to an increased risk of developing diseases such as diabetes, cardiovascular disease, and cancer. These diseases are associated with the infiltration of macrophages in white adipose tissue (WAT), the artery wall, and tumors, respectively; and these macrophages likely contribute to disease progression and pathogenesis. Abdominal WAT, adipose tissue surrounding the heart and artery wall, as well as carcinoma cells, secrete many factors that could induce macrophage infiltration. Leptin is an adipocyte-secreted hormone, and deficiency of either leptin or its receptor has been shown to cause morbid obesity in animals and in humans. However, what is more commonly noted in human obesity is the presence of central leptin resistance leading to hyperleptinemia. As leptin receptors are present on macrophages, we hypothesized that leptin could act as a monocyte/macrophage chemoattractant. Our current study demonstrates: 1) leptin is a potent chemoattractant for monocytes and macrophages, inducing maximal chemotactic responses at 1 ng/ml; 2) leptin-mediated chemotaxis requires the presence of full-length leptin receptors on migrating cells; 3) leptin causes increased influx of intracellular calcium in macrophages; and 4) activation of janus kinase/signal transducers and activators of transduction (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) pathways are all necessary for leptin-induced macrophage migration. Taken together, these data demonstrate that leptin is a potent monocyte/macrophage chemoattractant in vitro and that canonical cell motility machinery is activated upon macrophage exposure to leptin. These data have implications for the impact of hyperleptinemia on obesity-related pathophysiological conditions such as diabetes, cardiovascular disease, and cancer.

No abstract

Hypothesis-Toll-like receptor 4 (TLR4) is a receptor for saturated fatty acids (SFAs) and global deficiency of TLR4 has been shown to protect against inflammation, insulin resistance (IR), and atherosclerotic lesion formation. Because macrophages (Mθs) express TLR4 and are important in IR and atherosclerotic lesion formation due to their infiltration of white adipose tissue (WAT) and the artery wall, respectively, we hypothesized that deficiency of Mθ TLR4 could protect against these disorders.Methods-Bone marrow transplantation of agouti, LDL receptor deficient (Ay/a;LDLR-/-) mice with marrow from either C57BL/6 or TLR4-/-mice was performed. Recipient mice with the presence (MθTLR4+/+) or absence (MθTLR4-/-) of Mθ TLR4 were then placed on one of four diets: 1) low fat (LF); 2) high fat (HF); 3) high fat rich in SFAs (HF SFA ); and 4) the HF SFA diet supplemented with fish oil (HF SFA+FO ).Results-There were no differences in body composition or plasma lipids between MθTLR4+/+ and MθTLR4-/-mice on any of the diets. However, there was a decrease in some macrophage and inflammatory markers in WAT of female LF-fed MθTLR4-/-mice compared to MθTLR4+/+ mice. MθTLR4-/-mice fed LF diet also displayed decreased atherosclerotic lesion area. There were no differences in Mθ accrual in WAT or atherosclerosis between MθTLR4+/+ and MθTLR4-/-mice fed any of the high fat diets. Finally, there was no difference in insulin sensitivity between MθTLR4 +/+ and MθTLR4-/-mice fed the HF SFA diet.Conclusions-These data suggest that under certain dietary conditions, Mθ expression of TLR4 can be an important mediator of Mθ accumulation in both WAT and the artery wall.

No 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.