Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children

Abstract

BackgroundChildhood obesity prevalence has increased worldwide and is an important risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). The production of inflammatory adipokines by obese adipose tissue contributes to the development of T2D and CVD. While levels of circulating adipokines such as adiponectin and leptin have been established in obese children and adults, the expression of adiponectin and leptin receptors on circulating immune cells can modulate adipokine signalling, but has not been studied so far. Here, we aim to establish the expression of adiponectin and leptin receptors on circulating immune cells in obese children pre and post-lifestyle intervention compared to normal weight control children.Methods13 obese children before and after a 1-year lifestyle intervention were compared with an age and sex-matched normal weight control group of 15 children. Next to routine clinical and biochemical parameters, circulating adipokines were measured, and flow cytometric analysis of adiponectin receptor 1 and 2 (AdipoR1, AdipoR2) and leptin receptor expression on peripheral blood mononuclear cell subsets was performed.ResultsObese children exhibited typical clinical and biochemical characteristics compared to controls, including a higher BMI-SD, blood pressure and circulating leptin levels, combined with a lower insulin sensitivity index (QUICKI). The 1-year lifestyle intervention resulted in stabilization of their BMI-SD. Overall, circulating leukocyte subsets showed distinct adipokine receptor expression profiles. While monocytes expressed high levels of all adipokine receptors, NK and iNKT cells predominantly expressed AdipoR2, and B-lymphocytes and CD4+ and CD8+ T-lymphocyte subsets expressed AdipoR2 as well as leptin receptor. Strikingly though, leukocyte subset numbers and adipokine receptor expression profiles were largely similar in obese children and controls. Obese children showed higher naïve B-cell numbers, and pre-intervention also higher numbers of immature transition B-cells and intermediate CD14++CD16+ monocytes combined with lower total monocyte numbers, compared to controls. Furthermore, adiponectin receptor 1 expression on nonclassical CD14+CD16++ monocytes was consistently upregulated in obese children pre-intervention, compared to controls. However, none of the differences in leukocyte subset numbers and adipokine receptor expression profiles between obese children and controls remained significant after multiple testing correction.ConclusionsFirst, the distinct adipokine receptor profiles of circulating leukocyte subsets may partly explain the differential impact of adipokines on leukocyte subsets. Second, the similarities in adipokine receptor expression profiles between obese children and normal weight controls suggest that adipokine signaling in childhood obesity is primarily modulated by circulating adipokine levels, instead of adipokine receptor expression.

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

“…In line with the findings on leptin, adiponectin failed to enhance NK cell activity in obese humans (99). Moreover, studies on obese individuals showed that the expression of the adiponectin receptor 2 is reduced and that low plasma adiponectin concentrations correlated with a diminished cytolytic activity of NK cells from obese individuals (70,81). Taken together, data on adiponectin effects on NK cells are conflicting.…”

“…Investigations demonstrated that the leptin receptor (obesity receptor, ObR) is expressed on splenic and peripheral blood NK cells of rats as well as on human hepatic and peripheral blood NK cells (67-76) ( Table 1). Although leptin receptor expression levels on NK cells are rather dim, functional data upon leptin treatment performed by different laboratories demonstrate a functional role for this receptor on NK cells (69)(70)(71)(72)(73)77).…”

Natürliche Killerzellen, Adipositas & Tumorgenese

“…Eine Adipokin-vermittelte direkte Regulation von Immunzellen wird durch das Exprimieren der Adipokinrezeptoren vermutet und bietet eine Erklärung für die veränderte Anzahl und Funktion verschiedener Immunzellen durch erhöhte Adipokin-Konzentrationen im Falle einer Adipositas [9,16,[31][32][33]. Monozyten zeigen extrem hohe Oberflächenexpressionsmuster für die Rezeptoren diverser Adipokine [34]. Zudem weisen T-Zellen und NK-Zellen Subpopulations-assoziiert unterschiedliche Adipokin-Rezeptorprofile auf [16,31].…”

Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis

“…The two cytokines that play this role in professional APC, IL‐12 and IL‐18, do not seem to be secreted by adipocytes in significant amounts, suggesting that other factors like adipokines may fulfil this role. Interesting candidates for this are for example leptin and adiponectin, as iNKT cells express the receptors for both adipokines . As leptin levels increase and adiponectin levels decrease in obesity, these adipokines may present an apoptotic/toxic and a pro‐survival signal for iNKT cells, respectively, thereby contributing to the decrease in AT‐resident iNKT cell numbers in obesity.…”

“…Interesting candidates for this are for example leptin and adiponectin, as iNKT cells express the receptors for both adipokines. 87,88 As leptin levels increase and adiponectin levels decrease in obesity, these adipokines may present an apoptotic/toxic and a pro-survival signal for iNKT cells, respectively, thereby contributing to the decrease in AT-resident iNKT cell numbers in obesity. The finding that Ob/Ob micewhich lack the leptin genedisplay reduced iNKT cell numbers 35 supports this view.…”