PARP inhibition attenuates histopathological lesion in ischemia/reperfusion renal mouse model after cold prolonged ischemia.

We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN) and other renal lesions related to prolonged cold ischemia/reperfusion (IR) in kidneys preserved at 4°C in University of Wisconsin (UW) solution. Material and Methods. We used 30 male Parp1(+/+) wild-type and 15 male Parp1(0/0) knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ). We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp1(0/0) knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

The role of nonhematopoietic MHC class II expression in immune responses and tolerance

Si les rôles fonctionnels de diverses cellules immunitaires infiltrant des tissus enflammés sont assez bien compris, par contre, étonnamment, on connaît bien moins la capacité des cellules non hématopoïétiques résidant dans des tissus, à moduler l'activité biologique des cellules immunitaires immigrantes, et donc le résultat de la réponse immunitaire. La présentation des antigènes, dans le contexte des molécules du CMH de classe II (CMHII) à la surface des cellules présentatrices d'antigènes (CPA) professionnelles à une sous- population de lymphocytes T, est cruciale pour le développement des réponses immunitaires protectives spécifiques de l'antigène. En général, l'expression de CMHII est réservée aux CPAs. Toutefois, au cours des pathologies inflammatoires spécifiques d'organe, telles que l'auto-immunité ou la maladie inflammatoire de l'intestin, l'expression de CMHII est également induite par la cytokine interféron (IFN)-y sur des cellules non hématopoïétiques qui résident dans des tissus enflammés. Les conséquences de ce phénomène sont encore peu comprises. Dans cette étude, nous avons utilisé une souche de souris génétiquement modifiées, qui n'a pas la capacité d'induire l'expression de CMHII sur les cellules non hématopoïétiques, mais a maintenu la régulation normale d'expression de CMHII sur les cellules hématopoïétiques. Nous avons appliqué ces souris à différents modèles d'inflammation intestinale et à un modèle de maladie qui imite la maladie auto-immune de l'inflammation du muscle cardiaque (myocardite) chez l'homme. Nous avons pu montrer que, au cours de l'inflammation intestinale, l'expression du CMHII nonhématopoïétique, ou encore l'expression du CMHII par les cellules épithéliales de l'intestin, confère une protection contre la maladie, en réduisant les cellules immunitaires inflammatoires et en augmentant les cellules Τ régulatrices anti-inflammatoires. Ces résultats pourraient expliquer l'échec des traitements d'anti-IFN-γ dans les maladies intestinales inflammatoires chez l'homme. En revanche, dans la myocardite auto-immune, nos résultats indiquent que la présentation d'antigènes par les cellules non hématopoïétiques du coeur est nécessaire pour l'apparition de la pathologie cardiaque, comme nos souris sont résistantes à la maladie. Toutefois, cela n'est pas dû à un défaut d'activation des lymphocytes T, car les lymphocytes Τ des souris mutantes sont parfaitement capables de promouvoir la maladie après le transfert adoptif dans des animaux de type naturel. Nos résultats suggèrent que, durant les maladies inflammatoires spécifiques d'organe, la présentation d'antigène par des cellules non hématopoïétiques module et contribue au résultat de la réponse immunitaire d'une manière opposée, conférant soit la protection contre la maladie ou sa promotion. Nos résultats pourraient ouvrir la voie à des thérapies qui prennent en compte la contribution de la présentation d'antigènes par les cellules non hématopoïétiques, au cours des maladies inflammatoires spécifiques d'organe. - Les molécules du CMH de classe II (CMHII) sont fondamentales pour la présentation des antigènes aux lymphocytes Τ CD4+, car elles permettent le développement des réponses immunitaires spécifiques de l'antigène. Il est largement admis que l'expression de CMHII est réservée aux cellules présentatrices d'antigènes (CPA). Cependant, dans des conditions inflammatoires, l'expression de CMHII est en principe également induite par l'interféron (IFN)-y sur les cellules non hématopoïétiques, telles que les cellules épithéliales et les cardiomyocytes. Une controverse existe jusqu'à présent au sujet de la fonction de cette présentation d'antigènes non professionnelle, pour savoir si elle favorise la tolérance ou l'immunité dépendante des lymphocytes Τ in vivo. Pour répondre à cette question, nous avons testé des souris qui ne sont pas capables d'induire l'expression du CMHII sur les cellules non hématopoïétiques (souris PIV-/- K14 CIITA Tg) parmi différents modèles murins de pathologies inflammatoires, à savoir les modèles de vaccination pour induire des réponses spécifiques d'antigènes des lymphocytes B, plusieurs modèles de colite et un modèle de myocardite auto-immune expérimental (EAM). Pour cela, nous avons administré à ces souris un modèle de colite atténuée, induite par une infection chronique à Helicobacter hepaticus et par l'administration d'anticorps monoclonaux bloquant le récepteur de l'interleukine (IL)-10 (anti-IL-10R). Dans ce système, nous avons pu observer que l'expression abrogée de CMHII a aggravé la colite bactérienne, soit par les cellules non hématopoïétiques, soit exclusivement par les cellules épithéliales intestinales (CEI) dans un autre modèle murin (souris plV_fl/fl vil-Cre Tg). Ce phénotype du côlon a été associé à une augmentation des fréquences de cellules immunitaires innées, de lymphocytes Th1 CD4+, et d'expression des cytokines et de chimiokines pro-inflammatoires, y compris l'IFN-γ. Notamment, l'expression défectueuse de CMHII non hématopoïétique a également réduit les cellules Τ régulatrices (Treg) Forkhead box P3 (FoxP3)+, sans influencer les fréquences des cellules innées lymphoïdes et des cellules Th17. Ces résultats suggèrent un rôle tolérogène de CEIs CMHII+ qui contribue à l'homéostasie immunitaire intestinale. En revanche, dans le modèle d'EAM, les souris ayant subi une ablation de CMHII non hématopoïétique étaient résistantes à l'induction de la maladie, alors que la progression de la pathologie cardiaque, dans les souris de type naturel ou hétérozygotes, a été accompagnée par une régulation positive de l'expression de CMHII du myocarde. Cependant, l'inflammation cardiaque pourrait être transférée de manière adoptive depuis des souris amorcées PIV-/- K14 CIITA Tg vers des souris de type naturel, indiquant l'absence de défaut intrinsèque d'amorçage des cellules T CD4+ dans notre modèle de souris. Ces observations impliquent un rôle à jouer pour des cellules CMHII+ non hématopoïétiques résidentes du coeur, dans la promotion active de ΙΈΑΜ. En conclusion, nos résultats, provenant de diverses pathologies inflammatoires spécifiques d'organes, suggèrent un rôle complexe et divergent, soit tolérogène, soit immunogène/ pathologique, pour l'expression de CMHII non hématopoïétique au cours des pathologies inflammatoires. L'expression non professionnelle de CMHII semble influencer le résultat des réponses immunitaires en fonction de différents facteurs, tels que le tissu cible, le(s) type(s) de cellule(s) non hématopoïétique(s) participante(s) et l'origine de l'inflammation. Nos résultats pourraient potentiellement ouvrir la voie à des applications thérapeutiques, qui tiennent compte de la contribution de la présentation d'antigènes par des CPAs non professionnelles, au cours de l'inflammation spécifique d'organe. - MHC class II (MHCII) molecules are fundamental for the presentation of antigens to CD4+ Τ cells, allowing the development of antigen-specific immune responses. It is widely accepted that MHCII expression is restricted to antigen-presenting cells (APC). However, under inflammatory conditions, MHCII expression is typically also induced by interferon (IFN)-y on nonhematopoietic cells such as epithelial cells and cardiomyocytes. So far, it remains controversial whether this nonprofessional antigen-presentation function promotes CD4+ Τ cell-dependent tolerance or immunity in vivo. To address this issue, we utilised mice which lack inducible MHCII expression on nonhematopoietic cells (pIV-/- K14 CIITA Tg mice) in different mouse models of inflammatory pathologies, namely immunisation models to induce antigen-specific Β cell responses, various colitis models and a model of experimental autoimmune myocarditis (EAM). In an attenuated model of colitis induced by chronic Helicobacter hepaticus infection and treatment with anti-interleukin (IL)-10 receptor (anti-IL-10R) monoclonal blocking antibody, we observed that abrogated MHCII expression by nonhematopoietic cells or, in an alternative tamoxifen-inducible mouse model (plV_fl/fl vil-Cre Tg mice), exclusively by intestinal epithelial cells (IEC), exacerbated bacterial-driven colitis, which was associated with increased colonic frequencies of innate immune cells, CD4+ Th1 cells and expression of proinflammatory cytokines and chemokines, including IFN-γ. Notably, defective nonhematopoietic MHCII expression also resulted in reduced Forkhead box P3 (FoxP3)+ regulatory Τ (Treg) cells without influencing innate lymphoid cell (ILC) and Th17 cell frequencies. These findings suggest a tolerogenic role of MHClT lECs to contribute to intestinal immune homeostasis. In contrast, in the EAM model, mice ablated of nonhematopoietic MHCII were resistant to disease induction, whereas progression of cardiac pathology in WT and heterozygous control mice was accompanied by upregulation of myocardial MHCII expression. However, cardiac inflammation could be adoptively transferred from primed pIV-/- K14 CIITA Tg mice into WT mice, indicating no intrinsic defect of CD4+ Τ activation in our mouse model. These observations imply a role for MHCIT heart-resident nonhematopoietic cells in actively promoting EAM. In conclusion, our findings from different organ-specific inflammatory pathologies suggest a complex and diverging role - either tolerogenic or immunogenic/ pathologic - for nonhematopoietic MHCII expression during inflammatory pathologies: Nonprofessional MHCII expression appears to influence the outcome of immune responses depending on 7 factors such as the target tissue, participating non hematopoietic cell type(s) and the origin of inflammation. Our findings may potentially open the way to therapeutic applications taking into account the contribution of antigen presentation by nonprofessional, tissue-resident APCs during organ-specific inflammation.

Comparative analysis of human and mouse expression data illuminates tissue-specific evolutionary patterns of miRNAs.

MicroRNAs (miRNAs) constitute an important class of gene regulators. While models have been proposed to explain their appearance and expansion, the validation of these models has been difficult due to the lack of comparative studies. Here, we analyze miRNA evolutionary patterns in two mammals, human and mouse, in relation to the age of miRNA families. In this comparative framework, we confirm some predictions of previously advanced models of miRNA evolution, e.g. that miRNAs arise more frequently de novo than by duplication, or that the number of protein-coding gene targeted by miRNAs decreases with evolutionary time. We also corroborate that miRNAs display an increase in expression level with evolutionary time, however we show that this relation is largely tissue-dependent, and especially low in embryonic or nervous tissues. We identify a bias of tag-sequencing techniques regarding the assessment of breadth of expression, leading us, contrary to predictions, to find more tissue-specific expression of older miRNAs. Together, our results refine the models used so far to depict the evolution of miRNA genes. They underline the role of tissue-specific selective forces on the evolution of miRNAs, as well as the potential co-evolution patterns between miRNAs and the protein-coding genes they target.

BAFF mediates survival of peripheral immature B lymphocytes.

B cell maturation is a very selective process that requires finely tuned differentiation and survival signals. B cell activation factor from the TNF family (BAFF) is a TNF family member that binds to B cells and potentiates B cell receptor (BCR)-mediated proliferation. A role for BAFF in B cell survival was suggested by the observation of reduced peripheral B cell numbers in mice treated with reagents blocking BAFF, and high Bcl-2 levels detected in B cells from BAFF transgenic (Tg) mice. We tested in vitro the survival effect of BAFF on lymphocytes derived from primary and secondary lymphoid organs. BAFF induced survival of a subset of splenic immature B cells, referred to as transitional type 2 (T2) B cells. BAFF treatment allowed T2 B cells to survive and differentiate into mature B cells in response to signals through the BCR. The T2 and the marginal zone (MZ) B cell compartments were particularly enlarged in BAFF Tg mice. Immature transitional B cells are targets for negative selection, a feature thought to promote self-tolerance. These findings support a model in which excessive BAFF-mediated survival of peripheral immature B cells contributes to the emergence and maturation of autoreactive B cells, skewed towards the MZ compartment. This work provides new clues on mechanisms regulating B cell maturation and tolerance.

Adipose tissue concentrations of persistent organic pollutants and total cancer risk in an adult cohort from Southern Spain: preliminary data from year 9 of the follow-up.

There is an increasing trend in the incidence of cancer worldwide, and it has been accepted that environmental factors account for an important proportion of the global burden. The present paper reports preliminary findings on the influence of the historical exposure to a group of persistent organic pollutants on total cancer risk, at year 9 in the follow-up of a cohort from Southern Spain. A cohort of 368 participants (median age 51 years) was recruited in 2003. Their historical exposure was estimated by analyzing residues of persistent organic pollutants in adipose tissue. Estimation of cancer incidence was based on data from a population-based cancer registry. Statistical analyses were performed using multivariable Cox-regression models. In males, PCB 153 concentrations were positively associated with total cancer risk, with an adjusted hazard ratio (95% confidence interval) of 1.20 (1.01-1.41) for an increment of 100 ng/g lipid. Our preliminary findings suggest a potential relationship between the historical exposure to persistent organic pollutants and the risk of cancer in men. However, these results should be interpreted with caution and require verification during the future follow-up of this cohort.

Optimisation of the formation and distribution of protoporphyrin IX in the urothelium: an in vitro approach.

PURPOSE: To optimize conditions for photodynamic detection (PDD) and photodynamic therapy (PDT) of bladder carcinoma, urothelial accumulation of protoporphyrin IX (PpIX) and conditions leading to cell photodestruction were studied. MATERIALS AND METHODS: Porcine and human bladder mucosae were superfused with derivatives of 5-aminolevulinic acid (ALA). PpIX accumulation and distribution across the mucosa was studied by microspectrofluorometry. Cell viability and structural integrity were assessed by using vital dyes and microscopy. RESULTS: ALA esters, especially hexyl-ALA, accelerated and regularized urothelial PpIX accumulation and allowed for necrosis upon illumination. CONCLUSIONS: hexyl-ALA used at micromolar concentrations is the most efficient PpIX precursor for PDD and PDT.

CB1 blockade potentiates down-regulation of lipogenic gene expression in perirenal adipose tissue in high carbohydrate diet-induced obesity.

De novo lipogenesis and hypercaloric diets are thought to contribute to increased fat mass, particularly in abdominal fat depots. CB1 is highly expressed in adipose tissue, and CB1-mediated signalling is associated with stimulation of lipogenesis and diet-induced obesity, though its contribution to increasing fat deposition in adipose tissue is controversial. Lipogenesis is regulated by transcription factors such as liver X receptor (LXR), sterol-response element binding protein (SREBP) and carbohydrate-responsive-element-binding protein (ChREBP). We evaluated the role of CB1 in the gene expression of these factors and their target genes in relation to lipogenesis in the perirenal adipose tissue (PrAT) of rats fed a high-carbohydrate diet (HCHD) or a high-fat diet (HFD). Both obesity models showed an up-regulated gene expression of CB1 and Lxrα in this adipose pad. The Srebf-1 and ChREBP gene expressions were down-regulated in HFD but not in HCHD. The expression of their target genes encoding for lipogenic enzymes showed a decrease in diet-induced obesity and was particularly dramatic in HFD. In HCHD, CB1 blockade by AM251 reduced the Srebf-1 and ChREBP expression and totally abrogated the remnant gene expression of their target lipogenic enzymes. The phosphorylated form of the extracellular signal-regulated kinase (ERK-p), which participates in the CB1-mediated signalling pathway, was markedly present in the PrAT of obese rats. ERK-p was drastically repressed by AM251 indicating that CB1 is actually functional in PrAT of obese animals, though its activation loses the ability to stimulate lipogenesis in PrAT of obese rats. Even so, the remnant expression levels of lipogenic transcription factors found in HCHD-fed rats are still dependent on CB1 activity. Hence, in HCHD-induced obesity, CB1 blockade may help to further potentiate the reduction of lipogenesis in PrAT by means of inducing down-regulation of the ChREBP and Srebf-1 gene expression, and consequently in the expression of lipogenic enzymes.

Osteoarticular Expression of Musashi-1 in an Experimental Model of Arthritis.

Background. Collagen-induced arthritis (CIA), a murine experimental disease model induced by immunization with type II collagen (CII), is used to evaluate novel therapeutic strategies for rheumatoid arthritis. Adult stem cell marker Musashi-1 (Msi1) plays an important role in regulating the maintenance and differentiation of stem/precursor cells. The objectives of this investigation were to perform a morphological study of the experimental CIA model, evaluate the effect of TNFα-blocker (etanercept) treatment, and determine the immunohistochemical expression of Msi1 protein. Methods. CIA was induced in 50 male DBA1/J mice for analyses of tissue and serum cytokine; clinical and morphological lesions in limbs; and immunohistochemical expression of Msi1. Results. Clinically, TNFα-blocker treatment attenuated CIA on day 32 after immunization (P < 0.001). Msi1 protein expression was significantly higher in joints damaged by CIA than in those with no lesions (P < 0.0001) and was related to the severity of the lesions (Spearman's rho = 0.775, P = 0.0001). Conclusions. Treatment with etanercept attenuates osteoarticular lesions in the murine CIA model. Osteoarticular expression of Msi1 protein is increased in joints with CIA-induced lesion and absent in nonlesioned joints, suggesting that this protein is expressed when the lesion is produced in order to favor tissue repair.

TRAF1/C5 but not PTPRC variants are potential predictors of rheumatoid arthritis response to anti-tumor necrosis factor therapy.

BACKGROUND The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF) treatment in rheumatoid arthritis (RA). We also looked at associations between five RA risk alleles and treatment response. METHODS We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. RESULTS No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. CONCLUSION This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response.

T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes.

Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. The inflammatory response must be actively terminated, however, because failure to do so can result in 'bystander' damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4(+) T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1beta release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4(+) T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.

Can near infrared spectroscopy of the liver monitor tissue oxygenation?

Measurement of the hepatic oxygenation index by near infrared spectroscopy is a suitable method to estimate the oxygenation and can be a non-invasive means to continuously monitor tissue perfusion and to detect early haemodynamic disturbances in critically ill children.

Biological treatments in Behçet's disease: beyond anti-TNF therapy.

Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, and IL-6. However, although biological treatment with anti-TNF-α agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium.

Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance.

CONTEXT Glucose-dependent insulinotropic peptide (GIP) has a central role in glucose homeostasis through its amplification of insulin secretion; however, its physiological role in adipose tissue is unclear. OBJECTIVE Our objective was to define the function of GIP in human adipose tissue in relation to obesity and insulin resistance. DESIGN GIP receptor (GIPR) expression was analyzed in human sc adipose tissue (SAT) and visceral adipose (VAT) from lean and obese subjects in 3 independent cohorts. GIPR expression was associated with anthropometric and biochemical variables. GIP responsiveness on insulin sensitivity was analyzed in human adipocyte cell lines in normoxic and hypoxic environments as well as in adipose-derived stem cells obtained from lean and obese patients. RESULTS GIPR expression was downregulated in SAT from obese patients and correlated negatively with body mass index, waist circumference, systolic blood pressure, and glucose and triglyceride levels. Furthermore, homeostasis model assessment of insulin resistance, glucose, and G protein-coupled receptor kinase 2 (GRK2) emerged as variables strongly associated with GIPR expression in SAT. Glucose uptake studies and insulin signaling in human adipocytes revealed GIP as an insulin-sensitizer incretin. Immunoprecipitation experiments suggested that GIP promotes the interaction of GRK2 with GIPR and decreases the association of GRK2 to insulin receptor substrate 1. These effects of GIP observed under normoxia were lost in human fat cells cultured in hypoxia. In support of this, GIP increased insulin sensitivity in human adipose-derived stem cells from lean patients. GIP also induced GIPR expression, which was concomitant with a downregulation of the incretin-degrading enzyme dipeptidyl peptidase 4. None of the physiological effects of GIP were detected in human fat cells obtained from an obese environment with reduced levels of GIPR. CONCLUSIONS GIP/GIPR signaling is disrupted in insulin-resistant states, such as obesity, and normalizing this function might represent a potential therapy in the treatment of obesity-associated metabolic disorders.

Impaired adipose tissue expandability and lipogenic capacities as ones of the main causes of metabolic disorders.

Obesity is considered a major health problem. However, mechanisms involved and its comorbidities are not elucidated. Recent theories concerning the causes of obesity have focused on a limit to the functional capacity of adipose tissue, comparing it with other vital organs. This assumption has been the central point of interest in our laboratory. We proposed that the failure of adipose tissue is initiated by the difficulty of this tissue to increase its cellularity due to excess in fat contribution, owing to genetic or environmental factors. Nevertheless, why the adipose tissue reduces its capacity to make new adipocytes via mesenchymal cells of the stroma has not yet been elucidated. Thus, we suggest that this tissue ceases fulfilling its main function, the storage of excess fat, thereby affecting some of the key factors involved in lipogenesis, some of which are reviewed in this paper (PPARγ, ROR1, FASN, SCD1, Rab18, BrCa1, ZAG, and FABP4). On the other hand, mechanisms involved in adipose tissue expandability are also impaired, predominating hypertrophy via an increase in apoptosis and a decrease in adipogenesis and angiogenesis. However, adipose tissue failure is only part of this great orchestra, only a chapter of this nightmare.

Peroxisome proliferator-activated receptor-alpha-null mice have increased white adipose tissue glucose utilization, GLUT4, and fat mass: Role in liver and brain.

Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.