Camille ALLARD





Phone : 33(0)5 57 57 37 93 / 33(0)5 57 57 37 06
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Cursus:
Master Physiopathologie (Univ. Toulouse Paul Sabatier)
Doctorat Sciences de la Vie (Univ. de Bourgogne)
Post-doc (Tulane University, NO, Louisiana)

Expertise: Hypothalamic glia in energy homeostasis, Islet biology, Sex hormones , Biochemistry/biomol tests, Brain surgery





14 publication(s) since Août 2012:


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* equal contribution
The indicated IF have been collected by the Web of Sciences in


19/04/2021 | Cell Metab   IF 21.6
Hypothalamic bile acid-TGR5 signaling protects from obesity.
Castellanos-Jankiewicz A, Guzman-Quevedo O, Fenelon VS, Zizzari P, Quarta C, Bellocchio L, Tailleux A, Charton J, Fernandois D, Henricsson M, Piveteau C, Simon V, Allard C, Quemener S, Guinot V, Hennuyer N, Perino A, Duveau A, Maitre M, Leste-Lasserre T, Clark S, Dupuy N, Cannich A, Gonzales D, Deprez B, Mithieux G, Dombrowicz D, Backhed F, Prevot V, Marsicano G, Staels B, Schoonjans K, Cota D

Abstract:
Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.




03/11/2020 | Diabetes   IF 7.7
CB1 and GLP-1 Receptors Cross-Talk Provides New Therapies for Obesity.
Zizzari P, He R, Falk S, Bellocchio L, Allard C, Clark S, Lest, Quarta C

Abstract:
GLP-1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity, but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally-restricted cannabinoid-1 receptor (CB1R) inhibitors, which are devoid of the neuropsychiatric side-effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the co-administration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies, by promoting negative energy balance. This co-treatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the anti-obesity and anti-diabetic effects of currently available GLP-1R agonists.




14/02/2019 | Mol Metab   IF 6.2
Activation of hepatic estrogen receptor-alpha increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice.
Allard C, Bonnet F, Xu B, Coons L, Albarado D, Hill C, Fagherazzi G, Korach KS, Levin ER, Lefante J, Morrison C, Mauvais-Jarvis F

Abstract:
OBJECTIVE: The endogenous estrogen 17beta-estradiol (E2) promotes metabolic homeostasis in premenopausal women. In a mouse model of post-menopausal metabolic syndrome, we reported that estrogens increased energy expenditure, thus preventing estrogen deficiency-induced adiposity. Estrogens' prevention of fat accumulation was associated with increased serum concentrations of fibroblast growth factor 21 (FGF21), suggesting that FGF21 participates in estrogens' promotion of energy expenditure. METHODS: We studied the effect of E2 on FGF21 production and the role of FGF21 in E2 stimulation of energy expenditure and prevention of adiposity, using female estrogen receptor (ER)- and FGF21-deficient mice fed a normal chow and a cohort of ovariectomized women from the French E3N prospective cohort study. RESULTS: E2 acting on the hepatocyte ERalpha increases hepatic expression and production of FGF21 in female mice. In vivo activation of ERalpha increases the transcription of Fgf21 via an estrogen response element outside the promoter of Fgf21. Treatment with E2 increases oxygen consumption and energy expenditure and prevents whole body fat accumulation in ovariectomized female WT mice. The effect of E2 on energy expenditure is not observed in FGF21-deficient mice. While E2 treatment still prevents fat accumulation in FGF21-deficient mice, this effect is decreased compared to WT mice. In an observational cohort of ovariectomized women, E2 treatment was associated with lower serum FGF21 concentrations, which may reflect a healthier metabolic profile. CONCLUSIONS: In female mice, E2 action on the hepatocyte ERalpha increases Fgf21 transcription and FGF21 production, thus promoting energy expenditure and partially decreasing fat accumulation.




27/11/2018 | Mol Metab   IF 6.3
Mitochondrial Dynamin-Related Protein 1 (DRP1) translocation in response to cerebral glucose is impaired in a rat model of early alteration in hypothalamic glucose sensing.
Desmoulins L, Chretien C, Paccoud R, Collins S, Cruciani-Guglielmacci C, Galinier A, Lienard F, Quinault A, Grall S, Allard C, Fenech C, Carneiro L, Mouillot T, Fournel A, Knauf C, Magnan C, Fioramonti X, Penicaud L, Leloup C

Abstract:
OBJECTIVE: Hypothalamic glucose sensing (HGS) initiates insulin secretion (IS) via a vagal control, participating in energy homeostasis. This requires mitochondrial reactive oxygen species (mROS) signaling, dependent on mitochondrial fission, as shown by invalidation of the hypothalamic DRP1 protein. Here, our objectives were to determine whether a model with a HGS defect induced by a short, high fat-high sucrose (HFHS) diet in rats affected the fission machinery and mROS signaling within the mediobasal hypothalamus (MBH). METHODS: Rats fed a HFHS diet for 3 weeks were compared with animals fed a normal chow. Both in vitro (calcium imaging) and in vivo (vagal nerve activity recordings) experiments to measure the electrical activity of isolated MBH gluco-sensitive neurons in response to increased glucose level were performed. In parallel, insulin secretion to a direct glucose stimulus in isolated islets vs. insulin secretion resulting from brain glucose stimulation was evaluated. Intra-carotid glucose load-induced hypothalamic DRP1 translocation to mitochondria and mROS (H2O2) production were assessed in both groups. Finally, compound C was intracerebroventricularly injected to block the proposed AMPK-inhibited DRP1 translocation in the MBH to reverse the phenotype of HFHS fed animals. RESULTS: Rats fed a HFHS diet displayed a decreased HGS-induced IS. Responses of MBH neurons to glucose exhibited an alteration of their electrical activity, whereas glucose-induced insulin secretion in isolated islets was not affected. These MBH defects correlated with a decreased ROS signaling and glucose-induced translocation of the fission protein DRP1, as the vagal activity was altered. AMPK-induced inhibition of DRP1 translocation increased in this model, but its reversal through the injection of the compound C, an AMPK inhibitor, failed to restore HGS-induced IS. CONCLUSIONS: A hypothalamic alteration of DRP1-induced fission and mROS signaling in response to glucose was observed in HGS-induced IS of rats exposed to a 3 week HFHS diet. Early hypothalamic modifications of the neuronal activity could participate in a primary defect of the control of IS and ultimately, the development of diabetes.




10/10/2018 | Diabetes   IF 7.3
Loss of Nuclear and Membrane Estrogen Receptor-alpha Differentially Impairs Insulin Secretion and Action in Male and Female Mice.
Allard C, Morford JJ, Xu B, Salwen B, Xu W, Desmoulins L, Zsombok A, Kim JK, Levin ER, Mauvais-Jarvis F

Abstract:
Estrogens favor glucose homeostasis primarily through the estrogen receptor alpha (ERalpha), but the respective importance of nuclear and membrane ERalpha pools to glucose homeostasis are unknown. We studied glucose homeostasis, insulin secretion and insulin sensitivity in male and female mice expressing either the nuclear ERalpha (NOER) or the membrane ERalpha (MOER). Male and female MOER mice exhibited fasting and fed hyperglycemia and glucose intolerance. Female MOER mice displayed impaired central insulin signaling associated with hyperinsulinemia and insulin resistance due to unrestrained hepatic gluconeogenesis, without alterations in glucose stimulated-insulin secretion (GSIS). In contrast, male MOER mice did not exhibit detectable insulin resistance, but showed impaired GSIS associated with reduced brain glucose sensing. Female NOER mice exhibited milder hepatic insulin resistance and glucose intolerance. In conclusion, nuclear ERalpha signaling is predominant in maintaining glucose homeostasis in mice of both sexes. Lack of nuclear ERalpha alters the central control of insulin sensitivity in females, and predominantly impairs the central regulation of insulin secretion in males.




03/07/2018 | Cell Rep   IF 8
Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes.
Xu B, Allard C, Alvarez-Mercado AI, Fuselier T, Kim JH, Coons LA, Hewitt SC, Urano F, Korach KS, Levin ER, Arvan P, Floyd ZE, Mauvais-Jarvis F

Abstract:
Conjugated estrogens (CE) delay the onset of type 2 diabetes (T2D) in postmenopausal women, but the mechanism is unclear. In T2D, the endoplasmic reticulum (ER) fails to promote proinsulin folding and, in failing to do so, promotes ER stress and beta cell dysfunction. We show that CE prevent insulin-deficient diabetes in male and in female Akita mice using a model of misfolded proinsulin. CE stabilize the ER-associated protein degradation (ERAD) system and promote misfolded proinsulin proteasomal degradation. This involves activation of nuclear and membrane estrogen receptor-alpha (ERalpha), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERalpha modulator bazedoxifene mimics CE protection of beta cells in females but not in males.




21/06/2018 | JCI Insight
Androgen excess in pancreatic beta cells and neurons predisposes female mice to type 2 diabetes.
Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino-Rosano M, Sure VN, Yu S, Zhang R, M, Mauvais-Jarvis F

Abstract:
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic ? cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in ? cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in ? cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic ? cells, promoting insulin hypersecretion, oxidative injury, and secondary ? cell failure.




26/05/2016 | Neuroscience   IF 3.2
Glucose and hypothalamic astrocytes: More than a fueling role?
Leloup C, Allard C, Carneiro L, Fioramonti X, Collins S, Penicaud L

Abstract:
Brain plays a central role in energy homeostasis continuously integrating numerous peripheral signals such as circulating nutrients, and in particular blood glucose level, a variable that must be highly regulated. Then, the brain orchestrates adaptive responses to modulate food intake and peripheral organs activity in order to achieve the fine tuning of glycemia. More than fifty years ago, the presence of glucose-sensitive neurons was discovered in the hypothalamus, but what makes them specific and identifiable still remains disconnected from their electrophysiological signature. On the other hand, astrocytes represent the major class of macroglial cells and are now recognized to support an increasing number of neuronal functions. One of these functions consists in the regulation of energy homeostasis through neuronal fueling and nutrient sensing. Twenty years ago, we discovered that the glucose transporter GLUT2, the canonical 'glucosensor' of the pancreatic beta-cell together with the glucokinase, was also present in astrocytes and participated in hypothalamic glucose sensing. Since then, many studies have identified other actors and emphasized the astroglial participation in this mechanism. Growing evidence suggest that astrocytes form a complex network and have to be considered as spatially coordinated and regulated metabolic units. In this review we aim to provide an updated view of the molecular and respective cellular pathways involved in hypothalamic glucose sensing, and their relevance in physiological and pathological states.




10/05/2016 | Cell Metab   IF 17.3
Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.
Navarro G, Xu W, Jacobson DA, Wicksteed B, Allard C, Zhang G, De Gendt K, Kim SH, Wu H, Zhang H, Verhoeven G, Katzenellenbogen JA, Mauvais-Jarvis F

Abstract:
Although men with testosterone deficiency are at increased risk for type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic ? cells. We show that male mice lacking AR in ? cells (?ARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS), leading to glucose intolerance. The AR agonist dihydrotestosterone (DHT) enhances GSIS in cultured male islets, an effect that is abolished in ?ARKO(-/y) islets and human islets treated with an AR antagonist. In ? cells, DHT-activated AR




04/2015 | Obesity (Silver Spring)   IF 3.7
The role of androgens in metabolism, obesity, and diabetes in males and females.
Navarro G, Allard C, Xu W, Mauvais-Jarvis F

Abstract:
OBJECTIVE: In men, androgen deprivation contributes to the development of metabolic syndrome and type 2 diabetes (T2D). In women, androgen excess predisposes to insulin resistance and T2D. There is a bidirectional modulation of glucose homeostasis by androgens in males and females that is analyzed in this review. METHODS: We reviewed the literature in both rodents and humans on the role of androgens and the androgen receptor (AR) in the control of glucose and energy metabolism in health, obesity, and T2D. RESULTS: Sex-specific activation of AR in the hypothalamus, skeletal muscle, liver, adipose tissue, and pancreatic islet beta-cells accounts for maintenance or disruption in energy metabolism and glucose homeostasis. CONCLUSIONS: We argue that AR is a target to prevent androgen-related metabolic disorders.