Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity

Abstract

The adipokine leptin is primarily produced by white adipose tissue (AT) and is a potent monocyte/macrophage chemoattractant in vitro. The long form of the leptin receptor (LepR) is required for monocyte/macrophage chemotaxis towards leptin. In this study, we examined the effects of haematopoietic LepR as well as LepR with C-C Chemokine Receptor 2 (CCR2) deficiency (double knockout; DKO) on macrophage recruitment to AT after two different periods of high fat diet (HFD) feeding. Briefly, 8 week old C57BL/6 mice were transplanted with bone marrow from LepR+/+, LepR-/- or DKO donors (groups named BM-LepR+/+, BMLepR-/- and BM-DKO, respectively), and were placed on a HFD for 6 or 12 weeks. At the end of the study, macrophage infiltration and the inflammatory state of AT were evaluated by real-time RT-PCR, histology, and flow cytometry. In addition, glucose and insulin tolerance were assessed at both time points. Our results showed no differences in macrophage accumulation or AT inflammatory state between the BM-LepR+/+ and BM-LepR-/- mice after 6 or 12 weeks of HFD feeding; any effects observed in the BM-DKO were attributed to the haematopoietic deficiency of CCR2. In addition, no changes in glucose or insulin tolerance were observed between groups after either period of HFD feeding. Our findings suggest that although leptin is a potent chemoattractant in vitro, haematopoietic LepR deficiency does not affect macrophage accumulation in AT in early to moderate stages of diet induced obesity.

Macrophage recruitment in obese adipose tissue

“…Leptin may affect macrophage infiltration to AT through the up‐regulation of adhesion molecules in the endothelial cells of the stromal vascular compartment . However, despite the convincing nature of these findings from the different groups, there are equally convincing data showing that leptin does not influence weight gain and macrophage infiltration in AT . The contrasting results generated from these studies may be caused by different background strain, potential effects of gut microbiota, different baseline of body weight, and different percentage of fat in the diet .…”

A decade of progress in adipose tissue macrophage biology

“…We hypothesized that an inability of macrophages to respond to obesity‐related changes in leptin gradients would prevent macrophage accrual in AT during HFD feeding. To test this hypothesis, we reconstituted wildtype mice with leptin receptor deficient (LepR −/− ) marrow and placed them on a HFD . However, we detected no differences in the number or phenotype of their ATMs.…”

Nuevas proyecciones fisiológicas, patológicas y terapéuticas de la leptina

“…Contrariamente a lo esperado, la ausencia de LepR en células inmunes no determinó menor reclutamiento de macrófagos en el tejido adiposo, ni mayor resistencia insulínica en ratones alimentados con una dieta rica en grasa 50 , por lo que la relevancia de la leptina en la inflamación del tejido adiposo aún permanece incierta.…”