Immune cells in adipose tissue: key players in metabolic disorders.

Obesity, defined as the excess development of adipose tissue, is an important risk factor for metabolic and cardiovascular diseases such as type 2 diabetes, hypertension and atherosclerosis. Over the past few years, metabolic inflammation has emerged as a major process underlying the link between obesity and its associated pathologies. Adipose tissue appears to play a primary and crucial role as a source and site of inflammation. Accumulation of immune cells within adipose tissue occurs in obese conditions. The present review focuses on the relationship between adipose tissue and immune cells, including macrophages, dendritic cells, T and B lymphocytes, and natural killer cells, in both the physiological state and under obese conditions. The factors involved in the accumulation of both myeloid and lymphoid cells in adipose tissue are also described. In addition, the role of adipose-tissue immune cells on adipocyte metabolism and cells of the adipose tissue stromal-vascular fraction are discussed, with particular emphasis on the cross-talk between macrophages and adipocytes, together with recent reports of T lymphocytes in adipose tissue.

Desmoplastic infantile astrocytoma with benign histological phenotype and multiple intracranial localizations at presentation.

Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are rare intracranial tumors that mostly occur in the first 2 years of life and involve superficial cerebral cortex. Despite the large size of these lesions and some worrisome histological and radiological features, prognosis is generally favorable after gross total resection. We report an original observation of a desmoplastic infantile astrocytoma in a 5-year-old boy with multiple localizations on initial presentation, including the unusual subtentorial region. Magnetic resonance imaging showed a temporal tumor with prepontine and interpeduncular extension, and two other distinct localizations in cisterna magna and left cerebellar hemisphere. Leptomeningeal enhancements were present around the basal cistern. The surgical samples, corresponding exclusively to subtentorial lesions, were devoid of anaplastic features; the temporal lesion was untouched because of the interpeduncular extension. Adjuvant chemotherapy was applied, with shrinkage of lesions. DIA and DIG are more generally unifocal at initial presentation. When the tumor is large, multilobular involvement is common, but multiple location of DIG is, on the contrary, very rare. Previously, only five cases of DIG/DIA located in two or more separate locations have been published. We report the sixth, and first noninfantile, case of DIA/DIG with multifocal initial presentation.

The role of endothelial cells in inflamed adipose tissue.

In recent years, the general concept has emerged that chronic low-grade inflammation can be the condition linking excessive development of adipose tissue (AT) and obesity-associated pathologies such as type II diabetes and atherosclerosis. Moreover, the evidence that the growth of the fat mass was associated with an accumulation of adipose tissue macrophages (ATM) has raised the hypothesis that the development of an inflammatory process within the growing fat mass is a primary event involved in the genesis of systemic metabolic and vascular alterations. As ATM originate from the bone marrow/blood compartment, enhanced macrophage recruitment to growing AT is suspected. However, the mechanisms responsible for attracting the blood cells and their entry into the fat mass remain to be clearly defined. The present review highlights the key role of endothelial cells in the control of the inflammatory process and describes the potential involvement of AT-endothelial cells as well as the factors involved in the regulation of their phenotype in the 'inflamed fat tissue'.

Atrial natriuretic peptide inhibits the production of adipokines and cytokines linked to inflammation and insulin resistance in human subcutaneous adipose tissue.

AIMS/HYPOTHESIS: Increased adipose tissue secretion of adipokines and cytokines has been implicated in the chronic low-grade inflammation state and insulin resistance associated with obesity. We tested here whether the cardiovascular and metabolic hormone atrial natriuretic peptide (ANP) was able to modulate adipose tissue secretion of several adipokines (derived from adipocytes) and cytokines (derived from adipose tissue macrophages). SUBJECTS AND METHODS: We used protein array to measure the secretion of adipokines and cytokines after a 24-h culture of human subcutaneous adipose tissue pieces treated or not with a physiological concentration of ANP. The effect of ANP on protein secretion was also directly studied on isolated adipocytes and macrophages. Gene expression was measured by real-time RT-quantitative PCR. RESULTS: ANP decreased the secretion of the pro-inflammatory cytokines IL-6 and TNF-alpha, of several chemokines, and of the adipokines leptin and retinol-binding protein-4 (RBP-4). The secretion of the anti-inflammatory molecules IL-10 and adiponectin remained unaffected. The cytokines were mainly expressed in macrophages that expressed all components of the ANP-dependent signalling pathway. The adipokines, leptin, adiponectin and RBP-4 were specifically expressed in mature adipocytes. ANP directly inhibited the secretion of IL-6 and monocyte chemoattractant protein-1 by macrophages. The inhibitory effects of ANP on leptin and growth-related oncogene-alpha secretions were not seen under selective hormone-sensitive lipase inhibition. CONCLUSIONS/INTERPRETATION: We suggest that ANP, either by direct action on adipocytes and macrophages or through activation of adipocyte hormone-sensitive lipase, inhibits the secretion of factors involved in inflammation and insulin resistance.

Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes.

OBJECTIVE: Adipocyte hypertrophy combined with hyperplasia, observed during the growth of adipose tissue in obesity, might promote the occurrence of hypoxic areas within the tissue. The aim of the present study is to assess the influence of hypoxia on the expression and secretion of adipocyte-derived proangiogenic factors. DESIGN AND METHODS: Differentiated 3T3-F442A adipocytes were submitted either to ambient hypoxia (5% O(2)) or to chemically induced hypoxia by treatments with cobalt chloride or desferrioxamine. The activities of the matrix metalloproteinases 2 and 9 (MMP-2 and -9) were determined by gelatin zymography. The expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor 1 alpha (HIF-1alpha), leptin, MMP-2 and -9 were studied by the use of Western blotting and RT-PCR analyses. RESULTS: Low oxygen pressure exposure and hypoxia mimics treatments were associated with increased glucose consumption and release of lactate in differentiated 3T3-F442A adipocytes. They also led to an upregulation of the expression of leptin, VEGF and MMPs. An enhanced accumulation of HIF-1alpha protein was observed in the hypoxic adipocyte nuclei. CONCLUSION: Hypoxia, in adipocytes, markedly enhances the expression of leptin, VEGF and MMPs and stimulates the HIF-1 pathway. The present data demonstrate that hypoxic adipocytes express more proangiogenic factors and suggest that hypoxia, if occurring in adipose tissue, might be a modulator of the angiogenic process.

Culture of human adipose tissue explants leads to profound alteration of adipocyte gene expression.

Primary culture of adipose tissue has often been used to investigate pharmacological and nutritional regulation of adipocyte gene expression. Possible alteration of adipocyte gene expression by primary culture on its own has not been explored in detail. In order to address this issue, explants were prepared from human subcutaneous adipose tissue recovered from plastic surgery and maintained for 0 to 48 h in DMEM supplemented with 10 % serum. At different time points, adipocytes were isolated from the explants by collagenase digestion, and mRNA expression and lipolysis were studied. Culture was associated with an accumulation of tumor necrosis factor-alpha (TNFalpha) in the culture medium, an increase in anaerobic glycolysis, and an increase in the basal lipolysis. In parallel, a rapid and dramatic decrease in the level of mRNA encoding for several adipocyte-specific proteins such as adipocyte lipid-binding protein, hormone-sensitive lipase, lipoprotein lipase, and peroxisome proliferation activating receptor-gamma2 was observed in isolated adipocytes. These downregulations were reminiscent of a dedifferentiation process. In parallel, primary culture was associated with an increase in adipocyte beta-actin, TNFalpha, glucose transporter-1 and hypoxia-induced factor-1alpha mRNAs. Treatment of explants with agents that increase cAMP (isobutylmethylxanthine and forskolin) prevented TNFalpha production and expression and culture-induced alterations of adipocyte gene expression. These data show that primary culture of human adipose tissue explants dramatically alters adipocyte gene expression.