Background-Adipose tissue macrophages (ATMs) have become a focus of attention recently because they have been shown to accumulate with an increase in fat mass and to be involved in the genesis of insulin resistance in obese mice. However, the phenotype and functions of human ATMs are still to be defined. Methods and Results-The present study, performed on human subcutaneous AT, showed that ATMs from lean to overweight individuals are composed of distinct macrophage subsets based on the expression of several cell surface markers: CD45, CD14, CD31, CD44, HLA-DR, CD206, and CD16, as assessed by flow cytometry. ATMs isolated by an immunoselection protocol showed a mixed expression of proinflammatory (tumor necrosis factor-␣, interleukin-6 [IL-6], IL-23, monocyte chemoattractant protein-1, IL-8, cyclooxygenase-2) and antiinflammatory (IL-10, transforming growth factor-␤, alternative macrophage activation-associated cc chemokine-1, cyclooxygenase-1) factors. Fat mass enlargement is associated with accumulation of the CD206 ϩ /CD16 Ϫ macrophage subset that exhibits an M2 remodeling phenotype characterized by decreased expression of proinflammatory IL-8 and cyclooxygenase-2 and increased expression of lymphatic vessel endothelial hyaluronan receptor-1. ATMs specifically produced and released matrix metalloproteinase-9 compared with adipocytes and capillary endothelial cells, and secretion of matrix metalloproteinase-9 from human AT in vivo, assessed by arteriovenous difference measurement, was correlated with body mass index. Finally, ATMs exerted a marked proangiogenic effect on AT-derived endothelial and progenitor cells. Conclusions-The present results showed that the ATMs that accumulate with fat mass development exhibit a particular M2 remodeling phenotype. ATMs may be active players in the process of AT development through the extension of the capillary network and in the genesis of obesity-associated cardiovascular pathologies.

Adipose stroma/stem cells (ASC) represent an ideal source of autologous cells for cell-based therapy. Their transplantation enhances neovascularization after experimental ischemic injury. Aging is associated with a progressive decrease in the regenerative potential of mesenchymal stem cells (MSCs) from bone marrow. This work aims to determine the aging effect on human ASC capacities. First, we show that aging impairs angiogenic capacities of human ASC (hASC) in a mouse ischemic hindlimb model. Although no change in hASC number, phenotype, and proliferation was observed with aging, several mechanisms involved in the adverse effects of aging have been identified in vitro combining a concomitant decrease in (i) ASC ability to differentiate towards endothelial cells, (ii) secretion of proangiogenic and pro-survival factors, and (iii) oxidative stress. These effects were counteracted by a hypoxic preconditioning that improved in vivo angiogenic capacities of hASC from older donors, while hASC from young donors that have a strong ability to manage hypoxic stress were not. Finally, we identified reactive oxygen species (ROS) generation as a key signal of hypoxia on hASC angiogenic capacities. This study demonstrates for the first time that age of donor impaired angiogenic capacities of hASC in ischemic muscle and change in ROS generation by hypoxic preconditioning reverse the adverse effect of aging.

ABSTRACT

We previously showed that human and murine 3T3-F442A preadipocytes produced and released matrix metalloproteinases (MMPs) 2 and 9 and that a treatment by MMP inhibitors resulted in the blockade of murine fat cell adipose conversion. In parallel, investigators reported that other protease inhibitors, the human immunodeficiency virus (HIV) protease inhibitors (PIs) involved in lipodystrophy in humans, also reduced the adipocyte differentiation process of several murine cell lines. The present work was performed to define the effects of MMP inhibitors and HIV-PIs on the human adipocyte differentiation process, to clarify the involvement of MMPs in the control of human adipogenesis, and to determine whether HIV-PIs interact with MMPs in the control of this process. The effect of two MMP inhibitor and four HIV-PI treatments on the differentiation of primary culture human preadipocytes, as well as the putative relationships between HIV-PIs and MMP-2 and -9 expression, release, or activity were investigated. We showed that MMP inhibitors and HIV-PIs reduced the human adipocyte differentiation process as assessed by the decrease of cell protein and/or triglyceride contents and expression of fatty acid binding protein and hormone-sensitive lipase, two adipocyte markers. Unlike MMP inhibitors, HIV-PIs were devoid of any effect per se on recombinant MMP-2 and 9 activities but reduced the expression and release of MMP-9 by human preadipocytes. Thus, the present study indicates that the modulation of the extracellular matrix components through the production and/or activity of MMPs, and, more precisely, MMP-9 might be a key factor in the regulation of human adipose tissue development.The mechanisms responsible for the growth of adipose tissue (AT) are still not well defined. Adipocyte hypertrophy and hyperplasia, due to the recruitment and differentiation of adipocyte precursor cells, or preadipocytes, into adipocytes are major cellular events in the development of the fat mass. Together with the hypertrophy and the hyperplasia events, recent investigations have clearly demonstrated that angiogenesis and extracellular matrix (ECM) remodeling are required for coordinated growth of the fat depot (Lijnen et al., 2002;Rupnick et al., 2002). Among the enzymes involved in the degradation of the ECM components, the matrix metalloproteinase (MMP) family is considered to play a major role (Sternlicht and Werb, 2001). In a previous report, we demonstrated that mature human adipocytes and preadipocytes produce and release two members of the MMP family, MMP-2 and -9, the expression and activity of which were shown to be dependent on the adipocyte differentiation process (Bouloumié et al., 2001). Interestingly, we also reported that treatment of the murine 3T3-F442A preadipocytes, which also produced MMP-2 and -9 during adipose conversion, with MMP inhibitors decreased the rate of adipocyte differentiation, suggesting that MMP activities are required for adipogenesis in rodents. However, no data are available concerning the poten...

No abstract

In a previous publication, we reported that human immunodeficiency virus (HIV) protease inhibitors (PIs) inhibited the differentiation of human preadipocytes in primary culture, reducing the expression and secretion of matrix metalloproteinase 9 (MMP-9). The present work was performed to clarify this mechanism. Interestingly, HIV-PIs have been reported to be inhibitors of the proteasome complex, which is known to regulate nuclear factor (NF)-B activation and transcription of its target genes, among them MMP-9. We thus investigated the potential involvement of the proteasome in the antiadipogenic effects of HIV-PIs. The effect of four HIV-PIs was tested on preadipocyte proteasomal activity, and chronic treatment with the specific proteasome inhibitor lactacystin was performed to evaluate alterations of adipogenesis and MMP-9 expression/secretion. Finally, modifications of the NF-B pathway induced by either HIV-PIs or lactacystin were studied. We demonstrated that preadipocyte proteasomal activity was decreased by several HIV-PIs and that chronic treatment with lactacystin mimicked the effects of HIV-PIs by reducing adipogenesis and MMP-9 expression/secretion. Furthermore, we observed an intracellular accumulation of the NF-B inhibitor, IB␤, with chronic treatment with HIV-PIs or lactacystin as well as a decrease in MMP-9 expression induced by acute tumor necrosis factor-␣ stimulation. These results indicate that inhibition of the proteasome by specific (lactacystin) or nonspecific (HIV-PIs) inhibitors leads to a reduction of human adipogenesis, and they therefore implicate deregulation of the NF-B pathway and the related decrease of the key adipogenic factor, MMP-9. This study adds significantly to recent reports that have linked HIV-PI-related lipodystrophic syndrome with altered proteasome function, endoplasmic reticulum stress, and metabolic disorders.Proteasomes are highly conserved multimeric peptidases present in all eukaryotic cells. Whereas various forms of proteasomes exist, the 20S proteasome (multicatalytic core of all proteasomes) and the 26S proteasome (20S core capped with two 19S regulatory units) are major proteasomes. Proteasomes were initially thought to be just recyclers of damaged or misfolded proteins, but over the last decade the activity of this enzymatic complex has been found to be of critical importance for many cellular functions. Cell-cycle progression, oncogenesis, apoptosis, regulation of gene expression, and inflammation or immune surveillance are all physiological functions regulated by the proteasome pathway (Kisselev and Goldberg, 2001). Among the substrates of the proteasome, cyclins (e.g., cyclin B1), cyclin-dependent kinase inhibitors (e.g., p21 and p27), tumor suppressors (e.g., p53), and inhibitors (IB) or precursors (e.g., p105) of the transcription factor NF-B are well established (Kisselev and Goldberg, 2001;Adams, 2004). Accordingly, the proteasome complex has emerged as an attractive target for cancer therapy, and numerous proteasome inhibitors have been devel-

No abstract

Psychotropic drugs (PD) are often used close to a cancer diagnosis and may be considered as a way of coping. We aimed to determine the incidence of anxiolytics, hypnotics, antidepressants, and antipsychotics initiation around a diagnosis of chronic myelogenous leukemia (CML). Population‐based cohort: Data were extracted from Systeme National des données de Santé (SNDS, the French health insurance database) at the regional level (Midi‐Pyrenees area, 2.9 million inhabitants). All newly diagnosed patients treated by a CML tyrosine kinase inhibitor (TKI) between 10/01/2011 and 04/01/2014 were included. Pre‐CML (9 months before to 3 months before first TKI prescription—F‐TKI) and CML (3 months before to 9 months after F‐TKI) phases were defined. The main evaluation criterion was the initiation of PD during CML phase. Determinants associated with this incident PD use were studied through a logistic regression model. We compared pre‐CML and CML healthcare consumption. The cohort included 103 patients (mean age of 60.8 years). PD initiation rate was 35.9%, anxiolytics being the most initiated PD (59.5%). Advanced age was associated with PD initiation (adjusted OR = 1.029, 95% CI = 1.001–1.056). The number of consultations during the pre‐CML phase and female gender tended to be associated with increased risk of PD initiation in univariate analysis. For PD initiators, healthcare consumption was greater in CML but not in pre‐CML phase. PD initiation is a frequent finding around a CML diagnosis. Its risk increases with age. It could be a way to identify a subgroup with higher healthcare consumption.