Activité physique et ses déterminants chez des personnes diabétiques de type 2 vivant en France

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Involvement of adipokines, AMPK, PI3K and the PPAR signaling pathways in ovarian follicle development and cancer

The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together, these mechanisms optimize reproductive success under fluctuating metabolic conditions. Adipose tissue plays an important role in this regulation. Indeed, it releases a variety of factors, termed adipokines that regulate energy metabolism, but also reproductive functions. This article summarizes the function and regulation of some better-characterized adipokines (leptin, adiponectin, resistin, visfatin, chemerin and apelin) involved in ovarian follicle development. The follicle appears to use various nutrient sensing mechanisms that may form the link between nutrient status and folliculogenesis. This review examines evidence for the presence of pathways that may sense nutrient flux from within the follicle including the PI3K/Akt pathway, adenosine monophosphate-activated kinase (AMPK), and peroxisome proliferator-activated receptors (PPARs). It also reviews current information on the role of these adipokines and signalling pathways in ovarian cancers

La vistafine est exprimée par les cellules de la granulosa humaine : Régulation par la metformine via la voie AMPK/SIRT1 et rôle dans la stéroïdogenèse ?

National audienc

Expression et rôle de l'omentine dans les cellules de la granulosa humaine

National audienc

Caractérisation et rôle de l'omentine dans les cellules de la granulosa humaine ?

National audienc

Visfatin is expressed in human granulosa cells: regulation by metformin through AMPK/SIRT1 pathways and its role in steroidogenesis

Visfatin is a cytokine hormone and an enzyme involved in metabolic (obesity, type II diabetes) and immune disorders. Some data suggest a role of visfatin in ovarian function. Here, we identified visfatin in human follicles and investigated the molecular mechanisms involved in the regulation of its expression in response to insulin sensitizers, metformin (MetF) and rosiglitazone, in primary human granulosa cells (hGCs) and in a human ovarian granulosa-like tumour cell line (KGN). We also studied the effects of human recombinant visfatin (RhVisf) on steroid production and on the activation of various signalling pathways. By RT-PCR, immunoblotting and immunohistochemistry, we showed that visfatin is expressed not only in hGCs and KGN cells, but also in human cumulus cells and oocytes. In hGCs and KGN cells, MetF increased visfatin mRNA in a dose-dependent manner (0.1, 1 and 10 mM), and rosiglitazone increased visfatin mRNA expression (only at 10 μM) after treatments for 24 h, whereas both reduced it after 48 h of incubation. This regulation was confirmed at the protein level for the MetF treatment only. Using the compound C and Aicar, inhibitor and activator of AMP-activated protein kinase (AMPK), respectively, and Sirtinol, an inhibitor of sirtuin-1 (SIRT1), we observed that these MetF effects on visfatin expression were mediated through the AMPK/SIRT1 signalling pathways. RhVisf (10 ng/ml) significantly increased insulin-like growth factor-1 (IGF-1) (10 nM)- but not FSH (10 nM)-induced secretion of progesterone and estradiol as determined by radioimmunoassay and IGF-1-induced thymidine incorporation in hGCs and KGN cells. Finally, rhVisf rapidly activates the mitogen-activated protein kinase pathway via ERK1/2, P38 and Akt phosphorylation under basal conditions in primary hGC cells. In conclusion, visfatin is present in ovarian human follicles, and in hGCs and KGN cells, visfatin increases IGF-1-induced steroidogenesis and cell proliferation and MetF regulates visfatin expression through the AMPK/SIRT1 signalling pathway

Expression and regulation of INTELECTIN1 in human granulosa-lutein cells: role in IGF-1-induced steroidogenesis through NAMPT

INTELECTIN (ITLN) is an adipokine involved in the regulation of insulin sensitivity and inflammatory and immunity responses. Serum ITLN levels are lower in obese, diabetic, and polycystic ovary syndrome (PCOS) women than in control subjects. ITLN has never been studied in ovarian cells. Here, we identified ITLN1 in human ovarian follicles and investigated the molecular mechanisms involved in the regulation of its expression in response to the insulin sensitizers metformin and rosiglitazone, in human granulosa-lutein cells (hGLCs) and in a human ovarian granulosa-like tumor cell line (KGN). We also studied the effects of human recombinant ITLN1 (hRom1) on steroid production and on the activation of various signaling pathways. Using RT-PCR, immunoblotting, and immunohistochemistry, we found that INTL1 is present in human follicular cells. Using ELISA, we showed that INTL levels are similar in plasma and follicular fluid (FF) in control patients, whereas they are higher in FF than in plasma in PCOS patients. In KGN cells and hGLCs, insulin (10(-8) M), insulin-like growth factor-1 (IGF-1; 10(-8) M), and metformin (10(-2) M or 10(-3) M) increased INTL1 expression (mRNA and protein) after 12 and 24 h of stimulation. For metformin, this effect was mediated by adenosine monophosphate-activated kinase (PRKA). Furthermore, hRom1 increased nicotinamide phosphoribosyltransferase (NAMPT) expression in KGN and hGLCs. We also showed that hRom1 increased IGF-1-induced progesterone and estradiol secretion and this was associated with an increase in the STAR and CYP19A1 protein levels and an increase in IGF-1R signaling. Furthermore, all these data were abolished when NAMPT was knocked down in KGN cells, suggesting that INTL1 improves IGF-1-induced steroidogenesis through induction of NAMPT in hGLCs

Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas

International audienceObjectives: Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival. Design: Multicenter retrospective study by members of the French Society of Endocrinology. Methods: Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment. Results: The median treatment duration was 6.5 cycles (range 2-24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0-72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0-57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success. Discussion: Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols

Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study

Background: GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions. The bilateral nature of this disease suggests germline genetic predisposition. We aimed to identify the genetic driver event responsible for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Methods: We conducted a multicentre, retrospective, cohort study at endocrine hospitals and university hospitals in France, Canada, Italy, Greece, Belgium, and the Netherlands. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production and those with GIP-dependent unilateral adrenocortical adenomas were used as control groups. We performed whole genome, whole exome, and targeted next generation sequencing, and copy number analyses of blood and adrenal DNA from patients with familial or sporadic disease. We performed RNA sequencing on adrenal samples and functional analyses of the identified genetic defect in the human adrenocortical cell line H295R. Findings: 17 patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome were studied. The median age of patients was 43·3 (95% CI 38·8–47·8) years and most patients (15 [88%]) were women. We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients. None of the 29 patients in the control groups had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions. Global gene expression analysis showed GIP receptor upregulation with a log2 fold change of 7·99 (95% CI 7·34–8·66; p=4·4 × 10−125), and differential regulation of several other G protein-coupled receptors in GIP-dependent primary bilateral macronodular hyperplasia samples compared with control samples. In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells. Interpretation: We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis. Genetic testing and counselling should be offered to these patients and their relatives. Funding: Agence Nationale de la Recherche, Fondation du Grand défi Pierre Lavoie, and the French National Cancer Institute