From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes.

Obesity has been suggested to be a low-grade systemic inflammatory state, therefore we studied the interaction between human adipocytes and monocytes via adipose tissue (AT)-derived capillary endothelium. Cells composing the stroma-vascular fraction (SVF) of human ATs were characterized by fluorescence-activated cell sorter (FACS) analysis and two cell subsets (resident macrophages and endothelial cells [ECs]) were isolated using antibody-coupled microbeads. Media conditioned by mature adipocytes maintained in fibrin gels were applied to AT-derived ECs. Thereafter, the expression of endothelial adhesion molecules was analyzed as well as the adhesion and transmigration of human monocytes. FACS analysis showed that 11% of the SVF is composed of CD14(+)/CD31(+) cells, characterized as resident macrophages. A positive correlation was found between the BMI and the percentage of resident macrophages, suggesting that fat tissue growth is associated with a recruitment of blood monocytes. Incubation of AT-derived ECs with adipocyte-conditioned medium resulted in the upregulation of EC adhesion molecules and the increased chemotaxis of blood monocytes, an effect mimicked by recombinant human leptin. These results indicate that adipokines, such as leptin, activate ECs, leading to an enhanced diapedesis of blood monocytes, and suggesting that fat mass growth might be linked to inflammatory processes.

Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects.

Adipose tissue produces inflammation and immunity molecules suspected to be involved in obesity-related complications. The pattern of expression and the nutritional regulation of these molecules in humans are poorly understood. We analyzed the gene expression profiles of subcutaneous white adipose tissue from 29 obese subjects during very low calorie diet (VLCD) using cDNA microarray and reverse transcription quantitative PCR. The patterns of expression were compared with that of 17 non-obese subjects. We determined whether the regulated genes were expressed in adipocytes or stromavascular fraction cells. Gene expression profiling identified 100 inflammation-related transcripts that are regulated in obese individuals when eating a 28 day VLCD but not a 2 day VLCD. Cluster analysis showed that the pattern of gene expression in obese subjects after 28 day VLCD was closer to the profile of lean subjects than to the pattern of obese subjects before VLCD. Weight loss improves the inflammatory profile of obese subjects through a decrease of proinflammatory factors and an increase of anti-inflammatory molecules. The genes are expressed mostly in the stromavascular fraction of adipose tissue, which is shown to contain numerous macrophages. The beneficial effect of weight loss on obesity-related complications may be associated with the modification of the inflammatory profile in adipose tissue.

Discoidin domain receptor 1 controls growth and adhesion of mesangial cells.

Various types of collagen are known as modulators of mesangial cell proliferation. Here the function of the collagen-binding tyrosine kinase receptor discoidin domain receptor 1 (DDR1) in mesangial cells is investigated. The expression of DDR1 in the mouse kidney is confirmed by Northern analysis. In primary mesangial cells isolated from wild-type and DDR1-null mice, tyrosine phosphorylation in response to collagen-stimulation, adhesion to collagen, and cellular proliferation were measured. DDR1 phosphorylation was induced after overnight incubation of cells with type I collagen. Compared with wild-type cells, the adhesion of DDR1-null cells was drastically reduced. In contrast, DDR1-knockout cells showed significantly enhanced proliferation compared with wild-type cells. Both effects were largely independent of the collagen-binding alpha1/beta1 integrin function. This study found that the increased proliferation rate of DDR1-null cells is caused by a constitutive upregulation of p42/p44 and p38 mitogen-activated protein kinases (MAPK) activity. This is the first evidence indicating that DDR1 could be involved in the proliferative stage of renal disorders.