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Caroline ANDRE




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18 publication(s) depuis Novembre 2006:


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13/04/2018 | Mol Metab   IF 6.3
mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptin.
Haissaguerre M, Ferriere A, Simon V, Saucisse N, Dupuy N, Andre C, Clark S, Guzman-Quevedo O, Tabarin A, Cota D

Abstract:
OBJECTIVE: Nutrient availability modulates reactive oxygen species (ROS) production in the hypothalamus. In turn, ROS regulate hypothalamic neuronal activity and feeding behavior. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is an important cellular integrator of the action of nutrients and hormones. Here we tested the hypothesis that modulation of mTORC1 activity, particularly in Proopiomelanocortin (POMC)-expressing neurons, mediates the cellular and behavioral effects of ROS. METHODS: C57BL/6J mice or controls and their knockout (KO) littermates deficient either for the mTORC1 downstream target 70-kDa ribosomal protein S6 kinase 1 (S6K1) or for the mTORC1 component Rptor specifically in POMC neurons (POMC-rptor-KO) were treated with an intracerebroventricular (icv) injection of the ROS hydrogen peroxide (H2O2) or the ROS scavenger honokiol, alone or, respectively, in combination with the mTORC1 inhibitor rapamycin or the mTORC1 activator leptin. Oxidant-related signal in POMC neurons was assessed using dihydroethidium (DHE) fluorescence. RESULTS: Icv administration of H2O2 decreased food intake, while co-administration of rapamycin, whole-body deletion of S6K1, or deletion of rptor in POMC neurons impeded the anorectic action of H2O2. H2O2 also increased oxidant levels in POMC neurons, an effect that hinged on functional mTORC1 in these neurons. Finally, scavenging ROS prevented the hypophagic action of leptin, which in turn required mTORC1 to increase oxidant levels in POMC neurons and to inhibit food intake. CONCLUSIONS: Our results demonstrate that ROS and leptin require mTORC1 pathway activity in POMC neurons to increase oxidant levels in POMC neurons and consequently decrease food intake.




13/03/2018 | Brain Behav Immun   IF 6.3
mTORC1 pathway disruption abrogates the effects of the ciliary neurotrophic factor on energy balance and hypothalamic neuroinflammation.
Andre C, Catania C, Remus-Borel J, Ladeveze E, Leste-Lasserre T, Mazier W, Binder E, Gonzales D, Clark S, Guzman-Quevedo O, Abrous DN, Laye S, Cota D

Abstract:
Ciliary neurotrophic factor (CNTF) potently decreases food intake and body weight in diet-induced obese mice by acting through neuronal circuits and pathways located in the arcuate nucleus (ARC) of the hypothalamus. CNTF also exerts pro-inflammatory actions within the brain. Here we tested whether CNTF modifies energy balance by inducing inflammatory responses in the ARC and whether these effects depend upon the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which regulates both energy metabolism and inflammation. To this purpose, chow- and high fat diet (HFD)- fed mice lacking the S6 kinase 1 (S6K1(-/-)), a downstream target of mTORC1, and their wild-type (WT) littermates received 12 days continuous intracerebroventricular (icv) infusion of the CNTF analogue axokine (CNTFAx15). Behavioral, metabolic and molecular effects were evaluated. Central chronic administration of CNTFAx15 decreased body weight and feed efficiency in WT mice only, when fed HFD, but not chow. These metabolic effects correlated with increased number of iba-1 positive microglia specifically in the ARC and were accompanied by significant increases of IL-1beta and TNF-alpha mRNA expression in the hypothalamus. Hypothalamic iNOS and SOCS3 mRNA, molecular markers of pro-inflammatory response, were also increased by CNTFAx15. All these changes were absent in S6K1(-/-) mice. This study reveals that CNTFAx15 requires a functional S6K1 to modulate energy balance and hypothalamic inflammation in a diet-dependent fashion. Further investigations should determine whether S6K1 is a suitable target for the treatment of pathologies characterized by a high neuroinflammatory state.




27/03/2017 | Neuroscience   IF 3.4
Circulating bacterial lipopolysaccharide-induced inflammation reduces flow in brain-irrigating arteries independently from cerebrovascular prostaglandin production.
Villega F, Delpech JC, Griton M, Andre C, Franconi JM, Miraux S, Konsman JP

Abstract:
Brain dysfunction is a frequent complication of the systemic inflammatory response to bacterial infection or sepsis. In the present work, the effects of intravenous bacterial lipopolysaccharide (LPS) administration on cerebral arterial blood flow were assessed with time-of-flight (TOF)-based magnetic resonance angiography (MRA) in mice. Cerebral expression of the transcription factors nuclear factor-kappaB (NF-kappaB) and c-Fos and that of enzymes synthesizing vasoactive mediators, such as prostaglandins and nitric oxide, known to be increased under inflammatory conditions, were studied in the same animals. Time-resolved TOF MRA revealed no differences in blood flow in the internal carotids upstream of the circle of Willis, but indicated lower flow in its lateral parts as well as in the middle and anterior cerebral arteries after intravenous LPS injection as compared to saline administration. Although LPS did not increase c-Fos expression in ventral forebrain structures of these animals, it did induce NF-kappaB in meningeal blood vessels. LPS also increased cerebral expression of cyclooxygenase-2 and prostaglandin E synthase mRNAs, but de novo expression occurred in veins rather than in arteries. In conclusion, our work indicates that LPS-induced systemic inflammation does not necessarily affect filling of the circle of the Willis from the periphery, but that circulating LPS alters outflow from the circle of Willis to the middle and anterior cerebral arteries. These modifications in arterial flow were not related to increased cerebral synthesis of prostaglandins, but may instead be the consequence of the action of circulating prostaglandins and other vasoactive mediators on brain-irrigating arteries during systemic inflammation.




30/11/2016 | Diabetes   IF 7.3
Inhibiting Microglia Expansion Prevents Diet-induced Hypothalamic and Peripheral Inflammation.
Andre C, Guzman-Quevedo O, Rey C, Remus-Borel J, Clark S, Castellanos-Jankiewicz A, Ladeveze E, Leste-Lasserre T, Nadjar A, Abrous DN, Laye S, Cota D

Abstract:
Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. Here we tested whether the intertwining of these two processes has a role in the metabolic changes caused by three weeks of saturated high-fat diet (HFD) consumption.As compared to chow, HFD-fed mice rapidly increased body weight and fat mass, and specifically showed increased microglia number in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet, since feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain and adiposity. AraC treatment completely prevented the increase in the number of activated microglia in the ARC, the expression of the pro-inflammatory cytokine TNFalpha in microglia and the recruitment of the NF-kappaB pathway, while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and IL-1beta and decreased peritoneal pro-inflammatory CD86-IR macrophages number.These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload.




02/12/2014 | Endocrinology   IF 4
Cannabinoid type 1 (CB) receptors on Sim1-expressing neurons regulate energy expenditure in male mice.
Cardinal P, Bellocchio L, Guzman-Quevedo O, Andre C, Clark S, Elie M, Leste-Lasserre T, Gonzales D, Cannich A, Marsicano G, Cota D

Abstract:
The paraventricular nucleus of the hypothalamus (PVN) regulates energy balance by modulating not only food intake, but also energy expenditure and brown adipose tissue (BAT) thermogenesis. To test the hypothesis that cannabinoid type 1 (CB1) receptor in PVN neurons might control these processes, we used the Cre/loxP system to delete CB1 from Single minded 1 (Sim1) neurons, which account for the majority of PVN neurons. On standard chow, mice lacking CB1 receptor in Sim1 neurons (Sim1-CB1-KO) had food intake, body weight, adiposity, glucose metabolism and energy expenditure comparable to wild-type (Sim1-CB1-WT) littermates. However, maintenance on a high-fat diet (HFD) revealed a gene-by-diet interaction whereby Sim1-CB1-KO mice had decreased adiposity, improved insulin sensitivity and increased energy expenditure, while feeding behavior was similar to Sim1-CB1-WT mice. Additionally, HFD-fed Sim1-CB1-KO mice had increased mRNA expression of the beta3-adrenergic receptor, as well as of UCP-1, Cox-IV and Tfam in the BAT, all molecular changes suggestive of increased thermogenesis. Pharmacological studies using beta-blockers suggested that modulation of beta-adrenergic transmission play an important role in determining energy expenditure changes observed in Sim1-CB1-KO. Finally, chemical sympathectomy abolished the obesity-resistant phenotype of Sim1-CB1-KO mice. Altogether, these findings reveal a diet-dependent dissociation in the CB1 receptor control of food intake and energy expenditure, likely mediated by the PVN, where CB1 receptors on Sim1-positive neurons do not impact food intake, but hinder energy expenditure during dietary environmental challenges that promote body weight gain.




Abstract:
Obesity is associated with a high prevalence of mood symptoms and cognitive dysfunctions that emerges as significant risk factors for important health complications such as cardiovascular diseases and type 2 diabetes. It is therefore important to identify the dynamic of development and the pathophysiological mechanisms underlying these neuropsychiatric symptoms. Obesity is also associated with peripheral low-grade inflammation and increased susceptibility to immune-mediated diseases. Excessive production of proinflammatory cytokines and the resulting activation of the brain tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) have been shown to promote neurobehavioral complications, particularly depression. In that context, questions arise about the impact of diet-induced obesity on the onset of neuropsychiatric alterations and the increased susceptibility to immune-mediated diseases displayed by obese patients, particularly through brain IDO activation. To answer these questions, we used C57Bl/6 mice exposed to standard diet or western diet (WD; consisting of palatable energy-dense food) since weaning and for 20 weeks. We then measured inflammatory and behavioral responses to a systemic immune challenge with lipopolysaccharide (LPS) in experimental conditions known to alter cognitive and emotional behaviors independently of any motor impairment. We first showed that in absence of LPS, 9 weeks of WD is sufficient to impair spatial recognition memory (in the Y-maze). On the other hand, 18 weeks of WD increased anxiety-like behavior (in the elevated plus-maze), but did not affect depressive-like behavior (in the tail-suspension and forced-swim tests). However, 20 weeks of WD altered LPS-induced depressive-like behavior compared to LPS-treated lean mice and exacerbated hippocampal and hypothalamic proinflammatory cytokine expression and brain IDO activation. Taken together, these results show that WD exposure alters cognition and anxiety in unstimulated conditions and enhances activation of neurobiological mechanisms underlying depression after immune stimulation. They suggest therefore that obesity, and possibly obesity-associated inflammatory priming, may represent a vulnerability state to immune-mediated depressive symptoms.




10/2014 | Mol Metab   IF 6.3
CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin.
Cardinal P, Andre C, Quarta C, Bellocchio L, Clark S, Elie M, Leste-Lasserre T, Maitre M, Gonzales D, Cannich A, Pagotto U, Marsicano G, Cota D

Abstract:
Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.




Abstract:
Although peripheral low-grade inflammation has been associated with a high incidence of mood symptoms in patients with metabolic syndrome (MetS), much less is known about the potential involvement of brain activation of cytokines in that context. Recently we showed in a mouse model of MetS, namely the db/db mice, an enhanced hippocampal inflammation associated with increased anxiety-like behavior (Dinel et al., 2011). However, depressive-like behavior was not affected in db/db mice. Based on the strong association between depressive-like behavior and cytokine-induced brain activation of indoleamine 2,3-dioxygenase (IDO), the enzyme that metabolizes tryptophan along the kynurenine pathway, these results may suggest an impairment of brain IDO activation in db/db mice. To test this hypothesis, we measured the ability of db/db mice and their healthy db/+ littermates to enhance brain IDO activity and depressive-like behavior after a systemic immune challenge with lipopolysaccharide (LPS). Here we show that LPS (5 mug/mouse) significantly increased depressive-like behavior (increased immobility time in a forced-swim test, FST) 24h after treatment in db/+ mice, but not in db/db mice. Interestingly, db/db mice also displayed after LPS treatment blunted increase of brain kynurenine/tryptophan ratio compared to their db/+ counterparts, despite enhanced induction of hippocampal cytokine expression (interleukin-1beta, tumor necrosis factor-alpha). Moreover, this was associated with an impaired effect of LPS on hippocampal expression of the brain-derived neurotrophic factor (BDNF) that contributes to mood regulation, including under inflammatory conditions. Collectively, these data indicate that the rise in brain tryptophan catabolism and depressive-like behavior induced by innate immune system activation is impaired in db/db mice. These findings could have relevance in improving the management and treatment of inflammation-related complications in MetS.




27/09/2013 | J Biol Chem   IF 4
Agonist-dependent endocytosis of gamma-aminobutyric acid type A (GABAA) receptors revealed by a gamma2(R43Q) epilepsy mutation.
Chaumont S, Andre C, Perrais D, Boue-Grabot E, Taly A, Garret M

Abstract:
GABA-gated chloride channels (GABAARs) trafficking is involved in the regulation of fast inhibitory transmission. Here, we took advantage of a gamma2(R43Q) subunit mutation linked to epilepsy in humans that considerably reduces the number of GABAARs on the cell surface to better understand the trafficking of GABAARs. Using recombinant expression in cultured rat hippocampal neurons and COS-7 cells, we showed that receptors containing gamma2(R43Q) were addressed to the cell membrane but underwent clathrin-mediated dynamin-dependent endocytosis. The gamma2(R43Q)-dependent endocytosis was reduced by GABAAR antagonists. These data, in addition to a new homology model, suggested that a conformational change in the extracellular domain of gamma2(R43Q)-containing GABAARs increased their internalization. This led us to show that endogenous and recombinant wild-type GABAAR endocytosis in both cultured neurons and COS-7 cells can be amplified by their agonists. These findings revealed not only a direct relationship between endocytosis of GABAARs and a genetic neurological disorder but also that trafficking of these receptors can be modulated by their agonist.




07/2013 | planta med   IF 2.5
Inhibitory activity of plant stilbenoids against nitric oxide production by lipopolysaccharide-activated microglia.
Nassra M, Krisa S, Papastamoulis Y, Kapche GD, Bisson J, Andre C, Konsman JP, Schmitter JM, Merillon JM, Waffo-Teguo P

Abstract:
Microglia-driven inflammatory processes are thought to play an important role in ageing and several neurological disorders. Since consumption of a diet rich in polyphenols has been associated with anti-inflammatory and neuroprotective effects, we studied the effects of twenty-five stilbenoids isolated from Milicia excelsa, Morus alba, Gnetum africanum, and Vitis vinifera. These compounds were tested at 5 and 10 microM on BV-2 microglial cells stimulated with bacterial lipopolysaccharide. Ten stilbenoids reduced lipopolysaccharide-induced nitric oxide production at 5 and/or 10 microM. Two tetramers, E-vitisin A and E-vitisin B, were the most effective molecules. Moreover, they attenuated the expression of the inducible NO synthase protein and gene.