Marc Lombès

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (159)660.81 Total impact

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    ABSTRACT: Salsalate improves glucose intolerance and dyslipidemia in type 2 diabetes patients, but the mechanism is still unknown. The aim of the present study was to unravel the molecular mechanisms involved in these beneficial metabolic effects of salsalate by treating mice with salsalate during and after development of high fat diet-induced obesity. We found that salsalate attenuated and reversed high fat diet-induced weight gain, in particular fat mass accumulation, improved glucose tolerance and lowered plasma triglyceride (TG) levels. Mechanistically, salsalate selectively promoted the uptake of fatty acids from glycerol tri[(3)H]oleate-labeled lipoprotein-like emulsion particles by brown adipose tissue (BAT), decreased the intracellular lipid content in BAT and increased rectal temperature, all pointing to more active BAT. Treatment of differentiated T37i brown adipocytes with salsalate increased uncoupled respiration in cells. Moreover, salsalate upregulated Ucp1 expression and enhanced glycerol release, a dual effect that was abolished by inhibition of protein kinase A (PKA). In conclusion, salsalate activates BAT, presumably by directly activating brown adipocytes via the PKA pathway, suggesting a novel mechanism that may explain its beneficial metabolic effects in type 2 diabetes patients. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 12/2014; DOI:10.2337/db14-1125 · 7.90 Impact Factor
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    ABSTRACT: Menière's disease, clinically characterized by fluctuating, recurrent, and invalidating vertigo, hearing loss, and tinnitus, is linked to an increase in endolymph volume, the so-called endolymphatic hydrops. Since dysregulation of water transport could account for the generation of this hydrops, we investigated the role of aquaporin 3 (AQP3) in water transport into endolymph, the K-rich, hyperosmotic fluid that bathes the apical ciliated membrane of sensory cells, and we studied the regulatory effect of dexamethasone upon AQP3 expression and water fluxes. The different AQP subtypes were identified in inner ear by RT-PCR. AQP3 was localized in human utricle and mouse inner ear by immunohistochemistry and confocal microscopy. Unidirectional transepithelial water fluxes were studied by means of (3)H2O transport in murine EC5v vestibular cells cultured on filters, treated or not with dexamethasone (10(-7) M). The stimulatory effect of dexamethasone upon AQP3 expression was assessed in EC5v cells and in vivo in mice. AQP3 was unambiguously detected in human utricle and was highly expressed in both endolymph secretory structures of the mouse inner ear, and EC5v cells. We demonstrated that water reabsorption, from the apical (endolymphatic) to the basolateral (perilymphatic) compartments, was stimulated by dexamethasone in EC5v cells. This was accompanied by a glucocorticoid-dependent increase in AQP3 expression at both messenger RNA (mRNA) and protein level, presumably through glucocorticoid receptor-mediated AQP3 transcriptional activation. We show that glucocorticoids enhance AQP3 expression in human inner ear and stimulate endolymphatic water reabsorption. These findings should encourage further clinical trials evaluating glucocorticoids efficacy in Menière's disease.
    Pflügers Archiv - European Journal of Physiology 10/2014; DOI:10.1007/s00424-014-1629-5 · 3.07 Impact Factor
  • Françoise Borson-Chazot, Marc Lombès
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    ABSTRACT: Background: Tubular immaturity, responsible for sodium wasting, is critical during the neonatal period, particularly in preterm neonates. This relates to partial renal aldosterone resistance (Martinerie, Ped Res 2009), coincident with low tubular expression of the mineralocorticoid receptor in newborns (Martinerie, Endocrinology 2009). Objective and methods: Our clinical trial (NCT01176162) aimed to assess aldosterone resistance in neonates according to gestational age and during a 1-year postnatal follow-up period, by measuring urinary aldosterone concentration (UAC) and its correlation to the urinary Na/K ratio as an index of renal aldosterone sensitivity. Results: We enrolled 170 newborns prospectively, classified into three groups: <33 GW (gestational weeks) (52 patients), 33–36 GW (69 patients), >37 GW (49 patients). Plasma aldosterone levels measured from umbilical cord blood samples were very high in the >37 GW group (1001±98 pg/ml) and decreased significantly with gestational age (583±48 and 380±55 pg/ml in the 33–36 and <33 GW groups, respectively, P<0.0001). This was associated with an increase in renin levels (from 81±10 pg/ml in the >37 GW group to 135±22 pg/ml in the <33 GW group), suggesting an aldosterone biosynthesis/secretion defect in preterms. UAC followed a similar pattern (from 20.2±3.2 g/mmol urinary creatinine in term neonates to 8.8±1.2 in preterms, P<0.0001) significantly correlated with plasma aldosterone levels in all groups (P<0.0001), demonstrating its accuracy as a non-invasive index of aldosterone secretion. Renal aldosterone resistance was demonstrated in all groups given the lack of correlation between UAC and the urinary Na/K ratio, and high sodium wasting at birth in very preterm infants. Renal aldosterone responsiveness appears in term infants at 1 month of age (P=0.02) while renal aldosterone insensitivity persists in the preterm groups beyond 3 months. Conclusion: These results uncover the mechanism of sodium wasting in preterm neonates and underscore new potential therapeutic management based on UAC measurement.
    ESPE, Dublin; 09/2014
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    ABSTRACT: The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.-Boon, M. R., Kooijman, S., van Dam, A. D., Pelgrom, L. R., Berbée, J. F. P., Visseren, C. A. R., van Aggele, R. C., van den Hoek, A. M., Sips, H. C. M., Lombès, M., Havekes, L. M., Tamsma, J. T., Guigas, B., Meijer, O. C., Jukema, J. W., Rensen, P. C. N. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity.
    The FASEB Journal 08/2014; DOI:10.1096/fj.13-247643 · 5.48 Impact Factor
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    ABSTRACT: Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23°C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.-Van den Beukel, J. C., Grefhorst, A., Quarta, C., Steenbergen, J., Mastroberardino, P. G., Lombès, M., Delhanty, P. J., Mazza, R., Pagotto, U., van der Lely, A. J., Themmen, A. P. N. Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone.
    The FASEB Journal 08/2014; 28(11). DOI:10.1096/fj.14-254839 · 5.48 Impact Factor
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    ABSTRACT: Glucocorticoid Receptor (GR), a ubiquitous transcriptional factor, regulates target gene expression upon activation by glucocorticoids, notably cortisol, a corticosteroid hormone synthesized in the adrenal cortex. We thus hypothesized that both GR and cortisol might be involved in the regulation of adrenal physiology and steroidogenesis in an autocrine manner. In a cortisol-secreting human adrenocortical cell line (H295R), GR-dependent signaling pathway was pharmacologically modulated either by dexamethasone (DEX), a GR agonist or by RU486, a GR antagonist or was knocked-down by small interfering RNA strategy (SiRNA). We showed that GR activation, elicited by 48 h exposure to DEX, exerts a global positive regulatory effect on adrenal steroidogenesis as revealed by a 1.5- to 2-fold increase in cortisol, 11-deoxycortisol and 17-hydroxyprogesterone secretion associated with a significant enhanced expression of steroidogenesis factors such as StAR, CYP11A1, CYP21A2 and CYP11B1. In sharp contrast, RU486 treatment exerted opposite effects by decreasing both steroid production and expression of these steroidogenic factors. Likewise, GR repression by SiRNA also significantly reduced StAR, CYP11A1, and CYP11B1 mRNA levels. Interestingly, RU486 resulted in a significant CYP21A2 enzymatic blockade as demonstrated by a massive increase in 17-hydroxyprogesterone concentrations in RU486-treated H295R cell supernatants while cortisol and 11-deoxycortisol secretions were reduced by more than 60%. Consistently, we also demonstrated that metabolic conversion of 17-hydroxyprogesterone into 11-deoxycortisol onto H295R cells was drastically blunted in the presence of RU 486. Finally, steady state levels of MC2R transcripts encoding for ACTH receptor were significantly induced by DEX, unlikely through a direct GR-mediated transcriptional activation as opposed to CYP11A1 and FKBP5 target genes. These results could account for a higher glucocorticoid-elicited ACTH sensitivity of adrenocortical cells. Our study identifies a positive ultra-short regulatory loop exerted by GR on steroidogenesis in H295R cells, thus supporting a complex intra-adrenal GR-mediated feedback, likely relevant for human adrenocortical pathologies.
    Molecular and Cellular Endocrinology 07/2014; DOI:10.1016/j.mce.2014.07.012 · 4.24 Impact Factor
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    ABSTRACT: Mitotane (o,p'DDD) is the most effective treatment of advanced adrenocortical carcinoma (ACC) but its mechanism of action remains unknown. Previous studies suggested that o,p'DDA may represent the active metabolite of mitotane. We aimed at reevaluating the potential role and pharmacological effects of o,p'DDA. Functional consequences of o,p'DDA exposure were studied on proliferation, steroidogenesis, and mitochondrial respiratory chain in human H295R and SW13 adrenocortical cells. Mitotane and its metabolites were quantified using high-performance liquid chromatography combined to an ultraviolet detection in these cells treated with o,p'DDD or o,p'DDA and in human adrenal tissues. Dose-response curves up to 300 μM showed that, as opposed to o,p'DDD, o,p'DDA did not inhibit cell proliferation nor alter respiratory chain complex IV activity, gene expression nor induce mitochondrial biogenesis, oxidative stress, or apoptosis. However, whereas mitotane drastically decreased expression of genes involved in steroidogenesis, o,p'DDA slightly reduced expression of some steroidogenic enzymes and exerts weak anti-secretory effects only at high doses. While o,p'DDD concentration was significantly reduced by 40 % in H295R cell supernatants after 48 h incubation, o,p'DDA levels remained unchanged suggesting that o,p'DDA was not efficiently transported into the cells. o,p'DDA was not detected in cell homogenates or supernatants after 48 h exposure to o,p'DDD, consistent with the absence of o,p'DDA production in these models. Finally, unlike o'p'DDD, we found that o,p'DDA content was undetectable in two ACC and one normal adrenal gland of mitotane-treated patients, suggesting a lack of cellular uptake and in situ production. Our results demonstrate that o,p'DDD, but not o,p'DDA, induces functional alterations in adrenal cells.
    07/2014; 5(5). DOI:10.1007/s12672-014-0189-7
  • Damien Le Menuet, Marc Lombès
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    ABSTRACT: Mineralocorticoid receptor (MR), a hormone-activated transcription factor belonging to the nuclear receptor superfamily, exerts widespread actions in many tissues such as tight epithelia, the cardiovascular system, adipose tissues and macrophages. In the mammalian brain, MR is present in the limbic areas where it is highly expressed in neurons of the hippocampus and mostly absent in other regions while the glucocorticoid receptor (GR) expression is ubiquitous. MR binds both aldosterone and glucocorticoids, the latter having a ten-fold higher affinity for MR than for the closely related GR. However, owing to the minimal aldosterone transfer across the blood brain barrier and the absence of neuronal 11β hydroxysteroid dehydrogenase type 2 as an intracellular gate-keeper, neuronal MR appears to be fully occupied even at low physiological glucocorticoid levels while GR activation only occurs at high glucocorticoid concentrations, i.e. at the peak of the circadian rhythm or under stress. This defined a one hormone/two receptors system that works in balance, modulating a large spectrum of actions in the central nervous system. MR and GR are involved in the stress responses, the regulation of neuron excitability, long term potentiation, neuroprotection and neurogenesis in the dentate gyrus. MR thus constitutes a key factor in the arising of higher cognitive functions such as memorization, learning and mood. This review presents an overview of various roles of MR in the central nervous system which are somewhat less studied than that of GR, in the light of recent data obtained using cellular models, animal models and clinical investigations.
    Steroids 06/2014; 91. DOI:10.1016/j.steroids.2014.05.018 · 2.72 Impact Factor
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    ABSTRACT: The neonatal period is characterized in humans by a tubular immaturity responsible for sodium wasting, notably in preterm neonates. We have previously demonstrated a partial renal aldosterone resistance coincident with low tubular expression of the mineralocorticoid receptor in term newborns (1, 2). The objective of our clinical trial (NCT01176162) was to assess aldosterone resistance in neonates according to gestational age and during a one-year postnatal follow-up period, by measuring urinary aldosterone concentration (UAC) and its correlation to the urinary Na/K ratio as an index of renal aldosterone sensitivity. One hundred and seventy newborns were enrolled prospectively, classified into 3 gestational age groups: <33 GW (gestational weeks) (52 patients), 33-36 GW (69 patients), >37 GW (49 patients). Plasma aldosterone levels measured from umbilical cord blood samples were very high in the >37 GW group (1001±98 pg/ml). However, these levels significantly decreased with gestational age (583±48 and 380±55 pg/ml in the 33-36 and <33 GW groups, respectively, p<0.0001). This was associated with an increase in renin levels (from 81±10 pg/ml in the >37 GW group to 135±22 pg/ml in the <33 GW group) suggesting an aldosterone biosynthesis/secretion defect in preterms. UAC followed a similar pattern (from 20.2±3.2 mg/mmol urinary creatinine in term neonates to 8.8±1.2 in preterms, p<0.0001), significantly correlated with plasma aldosterone levels in all groups (p<0.0001), demonstrating its reliability as an accurate and non-invasive index of aldosterone secretion. Renal aldosterone resistance was demonstrated in newborns given the lack of correlation between UAC and the urinary Na/K ratio in all groups, and high sodium wasting at birth in very preterm infants (Na/creatinine urinary ratio: 75.7, 46.0 and 10.7 in the <33 GW, 33-36 GW and >37 GW group, respectively). During follow-up, UAC progressively decreased to reach adult levels at one year of age in term infants, while in the <33 GW group, UAC increased till one month reaching values of term newborns at birth, with a delayed diminution afterwards. Renal aldosterone responsiveness appears in term infants at one month of age (p=0.02) while renal aldosterone insensitivity persists in the preterm groups beyond 3 months of follow-up. These results uncover the mechanism of sodium wasting in preterm neonates and underscore new potential therapeutic management of sodium homeostasis based on UAC measurement. 1- Martinerie et al., Ped Research 2009; 66: 323-328 2- Martinerie et al., Endocrinology 2009; 150: 4414-4424
    ICE/ENDO, Chicago; 06/2014
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    ABSTRACT: Testicular morphology and immunohistochemical studies have never been reported in genetically documented adult patients with 5 alpha-reductase type 2 deficiency (5alpha-R2 deficiency).
    BMC Endocrine Disorders 05/2014; 14(1):43. DOI:10.1186/1472-6823-14-43 · 1.67 Impact Factor
  • Archives de Pédiatrie 05/2014; 21(5):640. DOI:10.1016/S0929-693X(14)71900-1 · 0.41 Impact Factor
  • 04/2014; DOI:10.1530/endoabs.35.P308
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    ABSTRACT: The mineralocorticoid receptor (MR) mediates the Na(+)-retaining action of aldosterone. MR is highly expressed in the distal nephron, which is submitted to intense variations in extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that post-transcriptional events control renal MR abundance. Here, we report that hypertonicity increases expression of the mRNA-destabilizing protein Tis11b, a member of the tristetraprolin/ZFP36 family, and thereby, decreases MR expression in renal KC3AC1 cells. The 3'-untranslated regions (3'-UTRs) of human and mouse MR mRNA, containing several highly conserved adenylate/uridylate-rich elements (AREs), were cloned downstream of a reporter gene. Luciferase activities of full-length or truncated MR Luc-3'-UTR mutants decreased drastically when cotransfected with Tis11b plasmid, correlating with an approximately 50% shorter half-life of ARE-containing transcripts. Using site-directed mutagenesis and RNA immunoprecipitation, we identified a crucial ARE motif within the MR 3'-UTR, to which Tis11b must bind for destabilizing activity. Coimmunoprecipitation experiments suggested that endogenous Tis11b physically interacts with MR mRNA in KC3AC1 cells, and Tis11b knockdown prevented hypertonicity-elicited repression of MR. Moreover, hypertonicity blunted aldosterone-stimulated expression of glucocorticoid-induced leucine-zipper protein and the α-subunit of the epithelial Na(+) channel, supporting impaired MR signaling. Challenging the renal osmotic gradient by submitting mice to water deprivation, diuretic administration, or high-Na(+) diet increased renal Tis11b and decreased MR expression, particularly in the cortex, thus establishing a mechanistic pathway for osmotic regulation of MR expression in vivo. Altogether, we uncovered a mechanism by which renal MR expression is regulated through mRNA turnover, a post-transcriptional control that seems physiologically relevant.
    Journal of the American Society of Nephrology 04/2014; 25(10). DOI:10.1681/ASN.2013091023 · 9.47 Impact Factor
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    ABSTRACT: Context: Sotos syndrome is a rare genetic disorder with a distinct phenotypic spectrum including overgrowth and learning difficulties. Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. Objective: We strived to elucidate the evanescent nature of the observed hypercalcemia by studying the ontogenesis of FGFR3 and FGFR4 - which are both associated with FGF23-mediated mineral homeostasis - in the developing human kidney. Design: RT-qPCR and immunohistochemical analyses were used on archival human kidney samples to investigate expression of the FGFR signaling pathway during renal development. Results: We demonstrated that renal gene and protein expression of both FGFRs increased during fetal development between the gestational ages (GA) of 14-40 weeks. Yet, FGFR4 expression increased more rapidly as compared to FGFR3 (slope: 0.047 vs. 0.0075, p = 0.0018). Moreover, gene and protein expression of the essential FGFR co-receptor, Klotho, also increased with a significant positive correlation between FGFR and Klotho mRNA expression during renal development. Interestingly, we found that perinatal FGFR4 expression (GA 38-40 weeks) was 7-fold higher as compared to FGFR3 (p=0.0035), while in adult kidney tissues, FGFR4 gene expression level was more than 2-fold lower compared to FGFR3 (p=0.0029), thus identifying a molecular developmental switch of FGFR isoforms. Conclusion: We propose that the heterozygous FGFR4 deletion, as observed in the Sotos syndrome patient, leads to a compromised FGF23 signaling during infancy accounting for transient hypercalcemia. These findings represent a novel and intriguing view on FGF23-mediated calcium homeostasis.
    The Journal of Clinical Endocrinology and Metabolism 03/2014; 99(7):jc20141123. DOI:10.1210/jc.2014-1123 · 6.31 Impact Factor
  • Diabetes & Metabolism 03/2014; 40:A24. DOI:10.1016/S1262-3636(14)72273-6 · 2.85 Impact Factor
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    ABSTRACT: Mature Sertoli cells (SC) are critical mediators of androgen regulation of spermatogenesis, via the androgen receptor (AR) signaling. Available immortalized SC lines loose AR expression or androgen responsiveness, hampering the study of endogenous AR regulation in SC. We have established and characterized a novel clonal mouse immortalized SC line, ST38c. These cells express some SC specific genes (sox9, wt1, tjp1, clu, abp, inhbb), but not fshr, yet more importantly, maintain substantial expression of endogenous AR as determined by PCR, immunocytochemistry, testosterone binding assays and Western blots. Microarrays allowed identification of some (146) but not all (rhox5, spinlw1), androgen-dependent, SC expressed target genes. Quantitative Real-Time PCR validated regulation of five up-regulated and two down-regulated genes. We show that AR undergoes androgen-dependent transcriptional activation as well as agonist-dependent posttranslational stabilization in ST38c cells. This cell line constitutes a useful experimental tool for future investigations on the molecular and cellular mechanisms of androgen receptor signaling in SC function.
    Molecular and Cellular Endocrinology 01/2014; DOI:10.1016/j.mce.2014.01.008 · 4.24 Impact Factor
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    ABSTRACT: Metformin is the first-line drug for the treatment of type 2 diabetes. Besides its well-characterized anti-hyperglycemic properties, metformin also lowers plasma very low-density lipoprotein (VLDL)-triglycerides (TG). In this study, we investigated the underlying mechanisms in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism. We found that metformin markedly lowered plasma total cholesterol and TG levels, an effect mostly due a decrease in VLDL-TG whereas high-density lipoprotein was slightly increased. Strikingly, metformin did not affect hepatic VLDL-TG production, VLDL particle composition and hepatic lipid composition but selectively enhanced clearance of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles into brown adipose tissue (BAT). BAT mass and lipid droplet content were reduced in metformin-treated mice, pointing to increased BAT activation. In addition, both AMPKα1 expression and activity, and HSL and mitochondrial content were increased in BAT. Furthermore, therapeutic concentrations of metformin increased AMPK and HSL activities and promoted lipolysis in T37i differentiated brown adipocytes. Collectively, our results identify BAT as an important player in the TG-lowering effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be considered as a future therapeutic strategy for the treatment of dyslipidemia.
    Diabetes 11/2013; DOI:10.2337/db13-0194 · 7.90 Impact Factor
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    ABSTRACT: The mineralocorticoid receptor (MR) exerts pro-adipogenic and anti-thermogenic effects in vitro, yet its in vivo metabolic impact remains elusive. Wild type (WT) and transgenic (Tg) mice overexpressing human MR were subjected to standard chow (SC) or high fat diet (HFD) for 16 wks. Tg mice had a lower body weight gain than WT animals, and exhibited a relative resistance to HFD-induced obesity. This was associated with a decrease of fat mass, an increased population of smaller adipocytes, and an improved glucose tolerance compared to WT animals. Quantitative RT-PCR studies revealed decreased expression of PPARγ2, a master adipogenic gene, and of glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1, consistent with an impaired local glucocorticoid signaling in adipose tissues (AT). This paradoxical resistance to HFD-induced obesity was not related to an adipogenesis defect since differentiation capacity of Tg preadipocytes isolated from stroma-vascular fractions was unaltered, suggesting that other non-adipocyte factors might compromise AT development. While AT macrophage infiltration was not different between genotypes, Tg mice exhibited a distinct macrophage polarization as revealed by FACS analysis and CD11c/CD206 expression studies. We further demonstrated that Tg macrophage-conditioned medium partially impaired preadipocyte differentiation. Therefore we propose that modification of M1/M2 polarization of hMR-overexpressing macrophages could account in part for the metabolic phenotype of Tg mice. Collectively, our results provide evidence that MR exerts a pivotal immunometabolic role by directly controlling adipocyte differentiation processes but also indirectly through macrophage polarization regulation. Our findings should be taken into account for the pharmacological treatment of metabolic disorders.
    AJP Endocrinology and Metabolism 11/2013; 306(1). DOI:10.1152/ajpendo.00323.2013 · 4.51 Impact Factor
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    ABSTRACT: Several autoimmune diseases (AID), including primary Sjögren's syndrome (pSS), are associated with an increased risk of lymphoma. Polymorphisms of TNFAIP3, which encodes the A20 protein that plays a key role in controlling NF-kB activation, have been associated with several AID. Somatic mutations of TNFAIP3 have been observed in the MALT lymphoma subtype frequently associated with pSS. We studied germline and somatic abnormalities of TNFAIP3 in 574 pSS patients, including 25 with lymphoma. Nineteen additional patients with pSS and lymphoma were available for exome sequence analysis. Functional abnormalities of A20 were assessed by gene reporter assays. The rs2230926 exonic variant was associated with an increased risk of pSS complicated by lymphoma (OR= 3.36 [95%CI 1.34-8.42] and OR=3.26 [95%CI 1.31-8.12], p=0.011, versus controls and pSS patients without lymphoma, respectively). Twelve of the 20 (60%) patients with paired germline and lymphoma TNFAIP3 sequence data had functional abnormalities of A20, 6 in germline DNA, 5 in lymphoma DNA and 1 in both. The frequency was even higher (77%) among pSS patients with MALT lymphoma. Some of these variants showed impaired control of NF-kB activation. These results support a key role for germline and somatic variations of A20 in the transformation between autoimmunity and lymphoma.
    Blood 10/2013; 122(25). DOI:10.1182/blood-2013-05-503383 · 9.78 Impact Factor

Publication Stats

3k Citations
660.81 Total Impact Points


  • 1995–2014
    • Université Paris-Sud 11
      • Faculty of Medicine
      Orsay, Île-de-France, France
  • 1984–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2010–2013
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Armand-Trousseau (Hôpitaux Universitaires Est Parisien)
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • The PremUp Foundation
      Lutetia Parisorum, Île-de-France, France
  • 2006–2010
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Baylor College of Medicine
      • Department of Molecular & Cellular Biology
      Houston, Texas, United States
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2003
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 1989–1990
    • Columbia University
      • • Department of Microbiology and Immunology
      • • College of Physicians and Surgeons
      New York City, NY, United States