84 research outputs found

    Implication de "Liver X Receptors" dans la physiopathologie des gonades

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    Sterility affects 15 % of French population and its prevalence is propagating since four or five decades. Many human physiological and epidemiological arguments support the impact of lipid homeostasis on the gonads; indeed, cholesterol is a key regulator of steroidogenesis and gametogenesis. Nevertheless, the molecular mechanisms remain hidden. Liver X receptors alpha and beta (LXRα and ÎČ) belong to the superfamily of nuclear receptors and are activated upon binding to oxysterols. LXRs are mainly implicated in cholesterol homeostasis. Increasing bulk of literature identified these non-steroid nuclear receptors as major regulators of the gonad physiology. This work uncovers previously unidentified putative roles of LXRs and ability of cholecterol excess to alter male and female germ cell maturation. Herein, we analyse a new mouse strain (Lxrαϐ-/-:AMHLxrϐ) re-expressing LXRÎČ under control of AMH promoter (specific to Sertoli in testis and granulosa cells in ovary) in a background of Lxrαϐ-/- mouse. Our results identify LXRs as primordial to maintain male and female fertility. They have pleotropic « non-classical » roles ranging from lipid homeostasis to the regulation of germ cell maturation and bi-directional control of steroid synthesis.If the cellular defects in the absence of LXRs within the testis are significant, they are generally compensated and consequently, single cell compartment is tolerated.Unlike the testis, LXRÎČ in the granulosa cells is « the regulator » of multiple mechanisms essential for follicle maturation, ovocyte survival and for controlled ovulation. LXRÎČ is therefore a potnetial target to regulate female fertility and to prevent ovarian hyperstimulation syndrome.Our results open the perspectives for the identification of new diagnostic and/or prognostic markers in both male and female fertility.La stĂ©rilitĂ© affecte Ă  l’heure actuelle prĂšs de 15-20 % des couples et sa prĂ©valence est en progression depuis quatre Ă  cinq dĂ©cennies. Cette progression Ă©volue parallĂšlement Ă  la prĂ©valence de l’épidĂ©mie d’obĂ©sitĂ© et de syndrome mĂ©tabolique dans le monde. De multiples arguments physiologiques et Ă©pidĂ©miologiques chez l’Homme soutiennent l’hypothĂšse de l’influence de l’homĂ©ostasie des lipides sur la fonction gonadique. En particulier, le cholestĂ©rol est un facteur clef dans la rĂ©gulation de la stĂ©roĂŻdogenĂšse et de la gamĂ©togenĂšse. Bien que les atteintes gonadiques semblent multifactorielles, les mĂ©canismes molĂ©culaires restent mĂ©connus dans la majoritĂ© des cas. Les Liver X receptors (LXRα et ÎČ) sont des rĂ©cepteurs nuclĂ©aires activĂ©s par les oxystĂ©rols. Ce sont classiquement des rĂ©gulateurs du mĂ©tabolisme lipidique. Plusieurs Ă©tudes ont dĂ©montrĂ© l’importance de ces rĂ©cepteurs dans la physiologie des gonades.Ce travail identifie les rĂŽles multiples des LXRs dans le maintien de la fertilitĂ© masculine et fĂ©minine, et dĂ©crit l’effet de l’homĂ©ostasie du cholestĂ©rol sur la maturation des cellules germinales dans le testicule et l’ovaire. Ce travail se concentre sur l’analyse comparative d’une lignĂ©e de souris rĂ©-exprimant LXRÎČ (Lxrαϐ-/-:AMHLxrϐ) sous contrĂŽle de promoteur d’AMH humain (expression spĂ©cifique dans les cellules de Sertoli dans le testicule et les cellules de granulosa dans l’ovaire) sur un fond gĂ©nĂ©tique de souris Lxrαϐ-/-.L’absence d’un isoforme d LXR aboutit Ă  des dĂ©fauts spĂ©cifiques dans un type cellulaire du testicule. NĂ©anmoins, le dysfonctionnement d’un type cellulaire est compensĂ©. En effet, de multiples dĂ©fauts sont nĂ©cessaires pour aboutir Ă  la stĂ©rilitĂ©.LXR dans les cellules de granulosa est critique pour la maturation et la survie des ovocytes, l’ovulation, et par consĂ©quence pour la fertilitĂ©. Ainsi, LXRÎČ est une cible potentielle pour rĂ©guler la fertilitĂ© fĂ©minine et la prĂ©vention de syndrome d’hyperstimulation ovarienne.Nos rĂ©sultats ouvrent des perspectives pour des nouvelles cibles diagnostiques et pronostiques dans la fertilitĂ©

    Implication of « Liver X Receptors » in the physiopathology of gonads

    No full text
    La stĂ©rilitĂ© affecte Ă  l’heure actuelle prĂšs de 15-20 % des couples et sa prĂ©valence est en progression depuis quatre Ă  cinq dĂ©cennies. Cette progression Ă©volue parallĂšlement Ă  la prĂ©valence de l’épidĂ©mie d’obĂ©sitĂ© et de syndrome mĂ©tabolique dans le monde. De multiples arguments physiologiques et Ă©pidĂ©miologiques chez l’Homme soutiennent l’hypothĂšse de l’influence de l’homĂ©ostasie des lipides sur la fonction gonadique. En particulier, le cholestĂ©rol est un facteur clef dans la rĂ©gulation de la stĂ©roĂŻdogenĂšse et de la gamĂ©togenĂšse. Bien que les atteintes gonadiques semblent multifactorielles, les mĂ©canismes molĂ©culaires restent mĂ©connus dans la majoritĂ© des cas. Les Liver X receptors (LXRα et ÎČ) sont des rĂ©cepteurs nuclĂ©aires activĂ©s par les oxystĂ©rols. Ce sont classiquement des rĂ©gulateurs du mĂ©tabolisme lipidique. Plusieurs Ă©tudes ont dĂ©montrĂ© l’importance de ces rĂ©cepteurs dans la physiologie des gonades. Ce travail identifie les rĂŽles multiples des LXRs dans le maintien de la fertilitĂ© masculine et fĂ©minine, et dĂ©crit l’effet de l’homĂ©ostasie du cholestĂ©rol sur la maturation des cellules germinales dans le testicule et l’ovaire. Ce travail se concentre sur l’analyse comparative d’une lignĂ©e de souris rĂ©-exprimant LXRÎČ (Lxrαϐ-/-:AMHLxrϐ) sous contrĂŽle de promoteur d’AMH humain (expression spĂ©cifique dans les cellules de Sertoli dans le testicule et les cellules de granulosa dans l’ovaire) sur un fond gĂ©nĂ©tique de souris Lxrαϐ-/-. L’absence d’un isoforme d LXR aboutit Ă  des dĂ©fauts spĂ©cifiques dans un type cellulaire du testicule. NĂ©anmoins, le dysfonctionnement d’un type cellulaire est compensĂ©. En effet, de multiples dĂ©fauts sont nĂ©cessaires pour aboutir Ă  la stĂ©rilitĂ©. LXR dans les cellules de granulosa est critique pour la maturation et la survie des ovocytes, l’ovulation, et par consĂ©quence pour la fertilitĂ©. Ainsi, LXRÎČ est une cible potentielle pour rĂ©guler la fertilitĂ© fĂ©minine et la prĂ©vention de syndrome d’hyperstimulation ovarienne. Nos rĂ©sultats ouvrent des perspectives pour des nouvelles cibles diagnostiques et pronostiques dans la fertilitĂ©.Sterility affects 15 % of French population and its prevalence is propagating since four or five decades. Many human physiological and epidemiological arguments support the impact of lipid homeostasis on the gonads; indeed, cholesterol is a key regulator of steroidogenesis and gametogenesis. Nevertheless, the molecular mechanisms remain hidden. Liver X receptors alpha and beta (LXRα and ÎČ) belong to the superfamily of nuclear receptors and are activated upon binding to oxysterols. LXRs are mainly implicated in cholesterol homeostasis. Increasing bulk of literature identified these non-steroid nuclear receptors as major regulators of the gonad physiology. This work uncovers previously unidentified putative roles of LXRs and ability of cholecterol excess to alter male and female germ cell maturation. Herein, we analyse a new mouse strain (Lxrαϐ-/-:AMHLxrϐ) re-expressing LXRÎČ under control of AMH promoter (specific to Sertoli in testis and granulosa cells in ovary) in a background of Lxrαϐ-/- mouse. Our results identify LXRs as primordial to maintain male and female fertility. They have pleotropic « non-classical » roles ranging from lipid homeostasis to the regulation of germ cell maturation and bi-directional control of steroid synthesis. If the cellular defects in the absence of LXRs within the testis are significant, they are generally compensated and consequently, single cell compartment is tolerated. Unlike the testis, LXRÎČ in the granulosa cells is « the regulator » of multiple mechanisms essential for follicle maturation, ovocyte survival and for controlled ovulation. LXRÎČ is therefore a potnetial target to regulate female fertility and to prevent ovarian hyperstimulation syndrome. Our results open the perspectives for the identification of new diagnostic and/or prognostic markers in both male and female fertility

    Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility

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    A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms. In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women

    Once and for all, LXRalpha and LXRbeta are gatekeepers of the endocrine system.

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    International audienceLiver X receptors (LXRs) alpha and beta are nuclear receptors whose transcriptional activity is regulated by oxysterols, the oxidized forms of cholesterol. Described in the late 1990s as lipid sensors, both LXRs regulate cholesterol and fatty acid homeostasis. Over the years, deep phenotypic analyses of mouse models deficient for LXRalpha and/or LXRbeta have pointed out various other physiological functions including glucose homeostasis, immunology, and neuroprotection. This review enlightens the "endocrine" functions of LXRs; they deeply impact plasma glucose directly and by modulating insulin signaling, renin-angiotensin-aldosterone axis, thyroid and pituitary hormone levels, and bone homeostasis. Besides, LXR signaling is also involved in adrenal physiology, steroid synthesis, and male and female reproduction. Hence, LXRs are definitely involved in the endocrine system and could thus be considered as endocrine receptors, even though oxysterols do not fully correspond to the definition of hormones. Finally, because they are ligand-regulated transcription factors, LXRs are potential pharmacological targets with promising beneficial metabolic effects

    Common sense model of self-regulation for understanding adherence and quality of life in type 2 diabetes with structural equation modeling

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    International audienceObjectives The objective of the present study was to test the Common Sense Model of self-regulation (CSM) for its relevance for improving adherence and quality of life in type 2 diabetes. Methods A sample of 253 patients with type 2 diabetes was recruited. They completed questionnaires about their perceptions regarding diabetes, coping strategies, therapeutic adherence and quality of life. Their HbA1c levels were also collected. Structural equation modeling (SEM) was used to check the adequacy of our theoretical model (CSM) with the patient data. Results The final model indicated that perceptions were directly and indirectly related to health outcomes through coping strategies and adequately matched the data (χ2 / df = 561/ 220 = 2.55; RMSEA = 0.08; PCFI = 0.66; PGFI = 0.70). Moreover, the model appeared to be identical for both types of treatment (oral and injectable). Conclusions Illness perceptions and coping strategies, or, more specifically, how patients accept disease and think they are able to manage it, significantly affect therapeutic adherence and quality of life in type 2 diabetes. Practice implications These results pave the way for developing psychological treatments aimed at improving patient acceptance and internal resources (e.g. use of autobiographical memory, Acceptance and Commitment Therapy)

    Heart rate variability in type 2 diabetes mellitus : A systematic review and meta-analysis

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    Background Cardiac autonomic neuropathy in type 2 dibetes mellitus (T2DM) patients is frequent and associated with high cardiovascular mortality. Heart rate variability (HRV) is the gold standard to measure cardiac autonomic neuropathy. We aimed to conduct a systematic review and meta–analysis to evaluate the impact of T2DM on HRV parameters. Methods The PubMed, Cochrane Library, Embase and Science Direct databases were searched on 1st October 2017 using the keywords “diabetes” AND (“heart rate variability” OR “HRV”). Included articles had to report HRV parameters in T2DM patients and healthy controls measured during 24 hours with a Holter–electrocardiogram. Measurements of HRV retieved were: RR–intervals (or Normal to Normal intervals—NN), standard deviation of RR intervals (SDNN), percetange of adjacent NN intervals differing by more than 50 milliseconds (pNN50), square root of the mean squared difference of successive RR intervals (RMSSD), total power, Low Frequency (LF), High Frequency (HF) and LF/HF ratio, as per Task Force recommendations. Results We included twenty-five case-control studies with 2,932 patients: 1,356 with T2DM and 1,576 healthy controls. T2DM patients had significantly (P<0.01) lower RR–intervals (effect size = –0.61; 95%CI –1.21 to –0.01), lower SDNN (–0.65; –0.83 to –0.47), lower RMSSD (–0.92; –1.37 to –0.47), lower pNN50 (–0.46; –0.84 to –0.09), lower total power (–1.52; –2.13 to –0.91), lower LF (–1.08; –1.46 to –0.69]), and lower HF (–0.79; –1.09 to –0.50). LF/HF did not differ between groups. Levels of blood glucose and HbA1c were associated with several HRV parameters, as well as Time from diagnosis of T2DM Conclusions T2DM was associated with an overall decrease in the HRV of T2DM patients. Both sympathetic and parasympathetic activity were decreased, which can be explained by the deleterious effects of altered glucose metabolism on HRV, leading to cardiac autonomic neuropathy

    Importance of the Microenvironment and Mechanosensing in Adipose Tissue Biology

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    International audienceThe expansion of adipose tissue is an adaptive mechanism that increases nutrient buffering capacity in response to an overall positive energy balance. Over the course of expansion, the adipose microenvironment undergoes continual remodeling to maintain its structural and functional integrity. However, in the long run, adipose tissue remodeling, typically characterized by adipocyte hypertrophy, immune cells infiltration, fibrosis and changes in vascular architecture, generates mechanical stress on adipose cells. This mechanical stimulus is then transduced into a biochemical signal that alters adipose function through mechanotransduction. In this review, we describe the physical changes occurring during adipose tissue remodeling, and how they regulate adipose cell physiology and promote obesity-associated dysfunction in adipose tissue
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