Abstract:
:Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor, playing key roles in maintenance of adipose tissue and in regulation of glucose and lipid homeostasis. This receptor is the target of thiazolidinediones, a class of antidiabetic drugs, which improve insulin sensitization and regulate glycemia in type 2 diabetes. Despite the beneficial effects of drugs, such as rosiglitazone and pioglitazone, their use is associated with several side effects, including weight gain, heart failure, and liver disease, since these drugs induce full activation of the receptor. By contrast, a promising activation-independent mechanism that involves the inhibition of cyclin-dependent kinase 5 (CDK5)-mediated PPARγ phosphorylation has been related to the insulin-sensitizing effects induced by these drugs. Thus, we aimed to identify novel PPARγ ligands that do not possess agonist properties by conducting a mini-trial with 80 compounds using the sequential steps of thermal shift assay, 8-anilino-1-naphthalenesulfonic acid fluorescence quenching, and a cell-based transactivation assay. We identified two non-agonist PPARγ ligands, AM-879 and P11, and one partial-agonist, R32. Using fluorescence anisotropy, we show that AM-879 does not dissociate the NCOR corepressor in vitro, and it has only a small effect on TRAP coactivator recruitment. In cells, AM-879 could not induce adipocyte differentiation or positively regulate the expression of genes associated with adipogenesis. In addition, AM-879 inhibited CDK5-mediated phosphorylation of PPARγ in vitro. Taken together, these findings supported an interaction between AM-879 and PPARγ; this interaction was identified by the analysis of the crystal structure of the PPARγ:AM-879 complex and evidenced by AM-879's mechanism of action as a putative PPARγ non-agonist with antidiabetic properties. Moreover, we present an optimized assay pipeline capable of detecting ligands that physically bind to PPARγ but do not cause its activation as a new strategy to identify ligands for this nuclear receptor.
journal_name
Front Endocrinol (Lausanne)journal_title
Frontiers in endocrinologyauthors
Ribeiro Filho HV,Bernardi Videira N,Bridi AV,Tittanegro TH,Helena Batista FA,de Carvalho Pereira JG,de Oliveira PSL,Bajgelman MC,Le Maire A,Figueira ACMdoi
10.3389/fendo.2018.00011subject
Has Abstractpub_date
2018-02-01 00:00:00pages
11issn
1664-2392journal_volume
9pub_type
杂志文章abstract::Gonadotropin-releasing hormone (GnRH) is the ultimate output signal of an intricate network of neuroendocrine factors that, acting on the pituitary, trigger gonadotropin release. In turn, gonadotropins exert their trophic action on the gonads to stimulate the synthesis of sex steroids thus completing the gonadotropic ...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2012.00048
更新日期:2012-04-02 00:00:00
abstract::Hashimoto's thyroiditis (HT) is the most common cause of thyroid disease in children and adolescents. Along with significant modifications of thyroid function, HT in pediatric age can be accompanied by relevant thyroid structural alterations. Over time, benign thyroid nodules, carcinoma and, rarely, primary non-Hodgki...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2018.00565
更新日期:2018-10-09 00:00:00
abstract::Radiotherapy continues to be one of the most accepted medical treatments for cancer. Localized irradiation is the most common treatment for prostate, pancreatic, rectal, cervical and endometrial malignancies. Conventional localized fractions are total doses of 30-62Gy at 1.8-2Gy per fraction, with administration of ~6...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2019.00587
更新日期:2019-08-29 00:00:00
abstract::Prostate cancer (PCa) is the major cause of cancer-related death among the male population of Western society, and androgen-deprivation therapy (ADT) represents the first line in PCa treatment. However, although androgen receptor (AR) expression is maintained throughout the various stages of PCa, ADT frequently fails....
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2014.00225
更新日期:2015-01-19 00:00:00
abstract::Background: Chronic inflammatory disorders and dyslipidemia in type 2 diabetes mellitus (T2DM) are essential contributors to the development of atherosclerotic cardiovascular disease. Monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) is a novel and simple measure associated positively with the body ...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2019.00191
更新日期:2019-04-04 00:00:00
abstract::Pituitary adenomas are common neoplasms. Their classification is based upon size, invasion of adjacent structures, sporadic or familial cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment and recurrence. Although they are considered benign tumors, some of them are...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2015.00097
更新日期:2015-06-12 00:00:00
abstract::Osteoporosis is metabolic bone disease caused by an altered balance between bone anabolism and catabolism. This dysregulated balance is responsible for fragile bones that fracture easily after minor falls. With an aging population, the incidence is rising and as yet pharmaceutical options to restore this imbalance is ...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2019.00006
更新日期:2019-01-29 00:00:00
abstract::RET gene rearrangements (RET/PTCs) represent together with BRAF point mutations the two major groups of mutations involved in papillary thyroid carcinoma (PTC) initiation and progression. In this review, we will examine the mechanisms involved in RET/PTC-induced thyroid cell transformation. In detail, we will summariz...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2012.00067
更新日期:2012-05-22 00:00:00
abstract::O-linked N-acetylglucosaminylation (O-GlcNAcylation) is a reversible post-translational modification consisting in the addition of a sugar moiety to serine/threonine residues of cytosolic or nuclear proteins. Catalyzed by O-GlcNAc-transferase (OGT) and removed by O-GlcNAcase, this dynamic modification is dependent on ...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2013.00099
更新日期:2013-08-12 00:00:00
abstract::Introduction: An increase of serum dehydroepiandrosterone (DHEA) sulfate (DHEAS) is observed in premature adrenarche and congenital adrenal hyperplasia. Very high DHEAS levels are typical for adrenal tumors. Approximately 74% of DHEAS is hydrolyzed to DHEA by the steroid sulfatase (STS). The reverse reaction is DHEA s...
journal_title:Frontiers in endocrinology
pub_type:
doi:10.3389/fendo.2020.00240
更新日期:2020-05-06 00:00:00
abstract::Giant pandas represent one of the most endangered species worldwide, and their reproductive capacity is extremely low. They have a relatively long gestational period, mainly because embryo implantation is delayed. Giant panda cubs comprise only a small proportion of the mother's body weight, making it difficult to det...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2020.00215
更新日期:2020-04-16 00:00:00
abstract::Background: The management of children and adolescents with chronic kidney disease (CKD) and growth failure candidate for recombinant human growth hormone therapy (rhGH) is based on an appraisal of the literature established on a 2006 consensus statement and 2019 Clinical practice recommendations. The performance of t...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2020.00587
更新日期:2020-09-02 00:00:00
abstract::Aim: Type 2 Diabetes Mellitus (T2DM) is associated with both microvascular complications such as diabetic retinopathy (DR), and macrovascular complications like coronary artery disease (CAD). Genetic risk factors have a role in the development of these complications. In the present case-control study, we investigated ...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2019.00283
更新日期:2019-05-03 00:00:00
abstract::Growth hormone (GH) has been used as an adjunct in the field of female infertility treatment for more than 25 years, although, apart from treating women with GH deficiency its role has not yet been clarified. Contributing to this lack of clarity is that several underpowered studies have been performed on women undergo...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2019.00500
更新日期:2019-07-24 00:00:00
abstract::Aims: This study aimed to investigate the clinical courses and outcomes of diabetes mellitus patients with coronavirus disease 2019 (COVID-19) in Wuhan. Methods: This study enrolled 1,880 consecutive patients with confirmed COVID-19 in Leishenshan Hospital. We collected and analyzed their data, including demographic d...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2020.00478
更新日期:2020-07-14 00:00:00
abstract::Obesity has emerged as one of the most burdensome conditions in modern society. In this context, understanding the mechanisms controlling food intake is critical. At present, the adipocyte-derived hormone leptin and the pancreatic β-cell-derived hormone insulin are considered the principal anorexigenic hormones. Altho...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2016.00138
更新日期:2016-10-20 00:00:00
abstract::Background: Insulin plays a pivotal role in the regulation of both carbohydrate and lipid intermediate turnover and metabolism. In the transition from a fasted to fed state, insulin action inhibits lipolysis in adipocytes, and acylcarnitine synthesis in the muscles and heart. The aim of this study was to measure free ...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2019.00870
更新日期:2019-12-17 00:00:00
abstract:Background:Vandetanib is the most largely used tyrosine kinase inhibitor (TKI) in patients with locally advanced and/or metastatic medullary thyroid cancer (MTC). Here, we conducted a systematic review on its efficacy and attempted to perform a meta-analysis adopting standardized RECIST criteria as end-points. Methods...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2018.00224
更新日期:2018-05-03 00:00:00
abstract::Thyrotropin hormone (TSH) was reported to exhibit biphasic regulation of cAMP production in human thyroid slices; specifically, upregulation at low TSH doses transitioning to inhibition at high doses. We observed this phenomenon in HEK293 cells overexpressing TSH receptors (TSHRs) but in only 25% of human thyrocytes (...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2020.00276
更新日期:2020-04-30 00:00:00
abstract::Pituitary adenomas (PA) are amongst the most prevalent intracranial tumors, causing complications by hormonal overproduction or deficiency and tumor mass effects, with 95% of cases occurring sporadically. Associated germline mutations (AIP, MEN1, CDKN1B, PRKAR1A, SDHx) and Xq26.3 microduplications are increasingly ide...
journal_title:Frontiers in endocrinology
pub_type:
doi:10.3389/fendo.2019.00837
更新日期:2019-12-10 00:00:00
abstract::Regenerative medicine is a multidisciplinary field that aims to determine different factors and develop various methods to regenerate impaired tissues, organs, and cells in the disease and impairment conditions. When treatment procedures are specified according to the individual's information, the leading role of pers...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2020.00396
更新日期:2020-07-17 00:00:00
abstract:BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver diseases closely associated with obesity and insulin resistance; deficient growth hormone (GH) action in liver has been implicated as a mechanism. Here, we investigated the evolution of NAFLD in aged mice with liver-sp...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2014.00218
更新日期:2014-12-18 00:00:00
abstract::Sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. Accumulating evidence shows that hippocampal neurons synthesize both estrogen and androgen. Recently, we also revealed the hippocampal synthesis of corticosteroids. The accurate concentrations of these hi...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2011.00043
更新日期:2011-10-10 00:00:00
abstract::Background: Previous studies have confirmed that APOE genotype is associated with lipid metabolism, but related studies are inconsistent. Therefore, we conducted this cross-sectional study to explore the associations between apolipoprotein E (APOE) genotypes and serum levels of fasting blood sugar, triglycerides, tota...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2019.00827
更新日期:2019-12-05 00:00:00
abstract::Human primordial germ cells (PGCs) have been described in the yolk sac wall around the beginning of the third week. From week 4 to 5, they migrate under control of SCF/c-KIT signaling pathway to the genital ridge, where they become gonocytes. PGCs and gonocytes express classic pluripotency markers, such as KIT, NANOG,...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2019.00343
更新日期:2019-06-06 00:00:00
abstract::A well-functioning hematopoietic system requires a certain robustness and flexibility to maintain appropriate quantities of functional mature blood cells, such as red blood cells and platelets. This review focuses on the cytokine receptor that plays a significant role in thrombopoiesis: the receptor for thrombopoietin...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2017.00059
更新日期:2017-03-31 00:00:00
abstract::Objectives: To evaluate the impact of metformin (MTF) use on TSH levels, thyroid volume and volume of benign thyroid nodules (TNs). Additionally, to study if iodine status influences the outcomes. Methods: A total of 23 euthyroid patients (42 TNs) with benign thyroid nodules, diagnosed by fine needle aspiration biopsy...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2019.00465
更新日期:2019-07-17 00:00:00
abstract:Background:For detecting tumor recurrence of medullary thyroid carcinoma (MTC) in the neck, an appropriate frequency and interval of postoperative ultrasonography (US) surveillance remains unclear. This study aimed to assess an appropriate interval and frequency of postoperative neck US surveillance for detecting tumor...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2018.00102
更新日期:2018-03-15 00:00:00
abstract::Responses to a high fat, high sucrose (HFHS) diet vary greatly among inbred strains of mice. We sought to examine the epigenetic (DNA methylation) changes underlying these differences as well as variation in weight loss when switched to a low-fat chow diet. We surveyed DNA methylation from livers of 45 inbred mouse st...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章
doi:10.3389/fendo.2019.00882
更新日期:2019-12-20 00:00:00
abstract::The mammalian genome contains four genes encoding GABA transporters (GAT1, slc6a1; GAT2, slc6a13; GAT3, slc6a11; BGT1, slc6a12) and five glutamate transporter genes (EAAT1, slc1a3; EAAT2, slc1a2; EAAT3, slc1a1; EAAT4, slc1a6; EAAT5, slc1a7). These transporters keep the extracellular levels of GABA and excitatory amino...
journal_title:Frontiers in endocrinology
pub_type: 杂志文章,评审
doi:10.3389/fendo.2013.00165
更新日期:2013-11-11 00:00:00