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Zhen Yang
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Chunming Guo
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Ping Zhu
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Wenjiao Li
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Leslie Myatt
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Kang Sun
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The amount of cortisol available to its receptors is increased by the pre-receptor enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which converts cortisone to cortisol. We examined the molecular mechanisms of the feedback effect of cortisol on 11β-HSD1 mRNA expression in human amnion fibroblasts. Our data showed that cortisol-induced 11β-HSD1 mRNA expression dose dependently in amnion fibroblasts, which could be completely blocked both by the mRNA transcription inhibitor 5,6-dichlorobenzimidazole riboside and by the glucocorticoid receptor (GR) antagonist RU486, and partially blocked by global inhibition of CCAAT/enhancer-binding proteins (C/EBPs) with transfection of C/EBP-specific dominant-negative expression CMV500 plasmid (AC/EBP) into the cells. Likewise, the induction of the promoter activity by cortisol could also be completely blocked by RU486 and partially by AC/EBP transfection. Progressive 5′ deletion of the 11β-HSD1promoter located the region responsible for cortisol’s induction within −204 bp upstream to the transcription start site. Specific nucleotide mutations of the putative glucocorticoid responsive element or CCAAT in this promoter region attenuated the induction by cortisol. Moreover, chromatin immunoprecipitation assay and electrophoretic mobility shift assay showed that GR and C/EBPα but not C/EBPβ could bind this promoter region upon cortisol stimulation of amnion fibroblasts. In conclusion, we demonstrated that GR and C/EBPα were involved in cortisol-induced 11β-HSD1 mRNA expression via binding to 11β-HSD1 promoter in amnion fibroblasts, which may cast a feed-forward production of cortisol in the fetal membranes at the end of gestation.

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Aiying Liu
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Liping Gao
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Shoulei Kang
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Ying Liu
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Chuanying Xu
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Hong Sun
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Dongye Li Department of Physiology, Institute of Cardiovascular Disease Research, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China

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Changdong Yan
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After menopause, the development of cardiovascular disease (CVD) is due not only to estrogen decline but also to androgen decline. This study examined the effects of either estradiol (E2) or testosterone replacement alone or E2–testosterone combination on isolated myocytes in ovariectomized (Ovx) rats subjected to ischemia/reperfusion (I/R). Furthermore, we determined whether the effects are associated with β2-adrenoceptor (β2-AR). Five groups of adult female Sprague–Dawley rats were used: Sham operation (Sham) rats, bilateral Ovx rats, Ovx rats with E2 40 μg/kg per day (Ovx+E), Ovx rats with testosterone 150 μg/kg per day (Ovx+T), and Ovx rats with E2 40 μg/kg per day+testosterone 150 μg/kg per day (Ovx+E/T). We determined the lactate dehydrogenase (LDH) release, percentage of rod-shaped cells and apoptosis of ventricular myocytes from rats of all groups subjected to I/R. Then, we determined the above indices and contractile function with or without a selective β2-AR antagonist ICI 118 551. We also determined the expression of β2-AR. Our data show that either E2 or testosterone replacement alone or E2 and testosterone in combination decreased the LDH release, increased the percentage of rod-shaped cells, reduced apoptotic cells (%), and combination treatment appeared to be more effective than either E2 or testosterone replacement alone. ICI 118 551 abolished the effects of the three. Combination supplementation also enhanced the expression of β2-AR. We concluded that in Ovx rats, testosterone enhances E2's cardioprotection, while E2 and testosterone in combination was more effective and the protective effects may be associated with β2-AR. The study highlights the potential therapeutic application for CVD in postmenopausal women.

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Xiong Weng Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Hao Jiang Gene Expression and Regulation, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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David J Walker Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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Houjiang Zhou MRC Protein Phosphorylation Unit, School of Life Sciences, Dundee, Scotland, UK

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De Lin Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee, Scotland, UK

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Jing Wang Science for Life Laboratory, Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden

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Li Kang Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK

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CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

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Chunxiao Qi Department of Neurobiology, Hebei Medical University, Shijiazhuang, People’s Republic of China
Department of Human Anatomy, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Xiaoming Ji Department of Neurobiology, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Guoliang Zhang Department of Human Anatomy, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Yunxiao Kang Department of Neurobiology, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Yuanxiang Huang Grade 2015 Eight-year Clinical Medicine Program, School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Rui Cui Department of Human Anatomy, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Shuangcheng Li Department of Human Anatomy, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Huixian Cui Department of Human Anatomy, Hebei Medical University, Shijiazhuang, People’s Republic of China
Neuroscience Research Center, Hebei Medical University, Shijiazhuang, People’s Republic of China

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Geming Shi Department of Neurobiology, Hebei Medical University, Shijiazhuang, People’s Republic of China
Department of Human Anatomy, Hebei Medical University, Shijiazhuang, People’s Republic of China
Neuroscience Research Center, Hebei Medical University, Shijiazhuang, People’s Republic of China

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The purpose of present study was to infer the potential effects of testosterone increase in some male-based childhood-onset neuropsychiatric disorders, such as Tourette syndrome. Thus, the influence of early postnatal androgen exposure upon the neurobehaviors and its possible neural basis were investigated in the study. Male pup rats received consecutive 14-day testosterone propionate (TP) subcutaneous injection from postnatal day (PND) 7. The TP treatment produced the hyperactive motor behavior and grooming behavior as well as the increased levels of dopamine, tyrosine hydroxylase and dopamine transporter in the mesodopaminergic system and the elevated levels of serotonin in the nucleus accumbens, without affecting the levels of glutamate, γ-aminobutyric acid, norepinephrine and histamine in the caudate putamen and nucleus accumbens of PND21 and PND49 rats. Dopamine D2 receptor antagonist haloperidol was administered to the early postnatal TP-exposed PND21 and PND49 male rats 30 min prior to open field test. Haloperidol significantly ameliorated the motor behavioral and grooming behavioral defects induced by early postnatal TP exposure. The results demonstrated that early postnatal androgen exposure significantly disturbed the brain activity of developing male rats via enhancing the mesodopaminergic activity. It was suggested that abnormal increments of testosterone levels during the early postnatal development might be a potential risk factor for the incidence of some male-based childhood-onset neuropsychiatric disorders by affecting the mesodopaminergic system.

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Shu-Fang Xia Wuxi School of Medicine, Jiangnan University, Wuxi, China
State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China

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Xiao-Mei Duan State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China
Shandong Sport Training Center, Jinan, China

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Xiang-Rong Cheng State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China

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Li-Mei Chen Wuxi School of Medicine, Jiangnan University, Wuxi, China

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Yan-Jun Kang Wuxi School of Medicine, Jiangnan University, Wuxi, China

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Peng Wang COFCO Corporation Oilseeds Processing Division, Beijing, China

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Xue Tang State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China

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Yong-Hui Shi State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China

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Guo-Wei Le State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China

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The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD)-induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed HFD for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic TH receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb. When mice were fed for 17 weeks, OR mice had mild hepatic steatosis and increased Dio1 and TRb expression than OP mice, with downregulation of T3 target genes (including Srebp1c, Acc1, Scd1 and Fasn) and upregulation of Cpt1α, Atp5c1, Cox7c and Cyp7a1. A stem-loop qRT-PCR analysis confirmed that the levels of miR-383, miR-34a and miR-146b were inversely correlated with those of DIO1 or TRb. Down-regulated expression of miR-383 or miR-146b by miR-383 inhibitor (anti-miR-383) or miR-146b inhibitor (anti-miR-146b) in free fatty acid-treated primary mouse hepatocytes led to increased DIO1 and TRb expressions, respectively, and subsequently decreased cellular lipid accumulation, while miR-34a inhibitor (anti-miR-34a) transfection had on effects on TRb expression. Luciferase reporter assay illustrated that miR-146b could directly target TRb 3′untranslated region (3′UTR). These findings suggested that miR-383 and miR-146b might play critical roles in different propensities to diet-induced obesity via targeting on Dio1 and TRb, respectively.

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Galya Vassileva
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Weiwen Hu
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Lizbeth Hoos Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Glen Tetzloff Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Shijun Yang
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Li Liu Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Ling Kang Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Harry R Davis Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Joseph A Hedrick Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Hong Lan Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Timothy Kowalski Merck Research Laboratories, Merck Research Laboratories, Department of Discovery Technologies, Kenilworth, New Jersey 07033, USA

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Eric L Gustafson
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G-protein-coupled bile acid receptor 1 (GPBAR1/TGR5/M-Bar/GPR131) is a cell surface receptor involved in the regulation of bile acid metabolism. We have previously shown that Gpbar1-null mice are resistant to cholesterol gallstone disease when fed a lithogenic diet. Other published studies have suggested that Gpbar1 is involved in both energy homeostasis and glucose homeostasis. Here, we examine the functional role of Gpbar1 in diet-induced obese mice. We found that body weight, food intake, and fasted blood glucose levels were similar between Gpbar1-null mice and their wild-type (WT) littermates when fed a chow or high-fat diet (HFD) for 2 months. However, insulin tolerance tests revealed improved insulin sensitivity in male Gpbar1 −/− mice fed chow, but impaired insulin sensitivity when fed a HFD. In contrast, female Gpbar1 −/− mice exhibited improved insulin sensitivity when fed a HFD compared with their WT littermates. Female Gpbar1 −/− mice had significantly lower plasma cholesterol and triglyceride levels than their WT littermates on both diets. Male Gpbar1 −/− mice on HFD displayed increased hepatic steatosis when compared with Gpbar1 + / + males and Gpbar1 −/− females on HFD. These results suggest a gender-dependent regulation of Gpbar1 function in metabolic disease.

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