Journal of molecular endocrinology最新文献_第4页

Sex steroids have opposing effects on heart rate of juveniles, Gambusia holbrooki. 性类固醇对幼体的心率有相反的作用。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-06-26 Print Date: 2023-08-01 DOI: 10.1530/JME-23-0021

Seyed Ehsan Mousavi, Komeil Razmi, Jawahar G Patil

{"title":"Sex steroids have opposing effects on heart rate of juveniles, Gambusia holbrooki.","authors":"Seyed Ehsan Mousavi, Komeil Razmi, Jawahar G Patil","doi":"10.1530/JME-23-0021","DOIUrl":"10.1530/JME-23-0021","url":null,"abstract":"Abstract: Built on our recent work that heart rates (HRs) and function in Gambusia holbrooki are sexually dimorphic, this study assessed whether the species is an appropriate model to study sex-hormone effects on heart physiology. With a hypothesis that 17β-estradiol (E2) and 17α-methyltestosterone (MT) regulate the HR of juvenile G. holbrooki in a sex-specific manner, genetic males and females were treated with E2 and MT, respectively, and the HR; (bpm) was measured an hour following treatment using light-cardiogram. Results showed the HRs (bpm) of both sexes were significantly (P < 0.05) altered compared to controls. Specifically, the E2 accelerated HR in the males and conversely MT decelerated the HR in the females. The normal expression levels of estrogen (erα and erβ) and G protein-coupled estrogen (gper) receptor genes were significantly higher (P < 0.05) in female than male hearts. Interestingly, the activity of the erβ in the heart of the MT-treated females reversed and was significantly lower (P < 0.05) than those of males while erα and gper were non-responsive. In contrast, significant down- and up-regulation of erα and gper, respectively, occurred in the liver of MT-treated females. Morphological observations suggest that MT caused hepatomegaly, somewhat resembling an inflating balloon, perhaps induced by the accumulation of unexpelled gases. E2-induced ventricular angiogenesis in males was likely due to an influx of blood supply caused by the increased HRs. Collectively, the results demonstrate that the juvenile G. holbrooki heart readily responds to E2/MT in a sex-specific manner.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10069043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CLEC11A improves insulin secretion and promotes cell proliferation in human beta-cells. CLEC11A可改善人β细胞的胰岛素分泌，促进细胞增殖。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-06-21 Print Date: 2023-07-01 DOI: 10.1530/JME-22-0066

Ruifeng Shi, Jing Cen, Gunilla Westermark, Sheng Zhao, Nils Welsh, Zilin Sun, Joey Lau Börjesson

{"title":"CLEC11A improves insulin secretion and promotes cell proliferation in human beta-cells.","authors":"Ruifeng Shi, Jing Cen, Gunilla Westermark, Sheng Zhao, Nils Welsh, Zilin Sun, Joey Lau Börjesson","doi":"10.1530/JME-22-0066","DOIUrl":"10.1530/JME-22-0066","url":null,"abstract":"Beta-cell dysfunction is a hallmark of disease progression in patients with diabetes. Research has been focused on maintaining and restoring beta-cell function during diabetes development. The aims of this study were to explore the expression of C-type lectin domain containing 11A (CLEC11A), a secreted sulphated glycoprotein, in human islets and to evaluate the effects of CLEC11A on beta-cell function and proliferation in vitro. To test these hypotheses, human islets and human EndoC-βH1 cell line were used in this study. We identified that CLEC11A was expressed in beta-cells and alpha-cells in human islets but not in EndoC-βH1 cells, whereas the receptor of CLEC11A called integrin subunit alpha 11 was found in both human islets and EndoC-βH1 cells. Long-term treatment with exogenous recombinant human CLEC11A (rhCLEC11A) accentuated glucose-stimulated insulin secretion, insulin content, and proliferation from human islets and EndoC-βH1 cells, which was partially due to the accentuated expression levels of transcription factors MAFA and PDX1. However, the impaired beta-cell function and reduced mRNA expression of INS and MAFA in EndoC-βH1 cells that were caused by chronic palmitate exposure could only be partially improved by the introduction of rhCLEC11A. Based on these results, we conclude that rhCLEC11A promotes insulin secretion, insulin content, and proliferation in human beta-cells, which are associated with the accentuated expression levels of transcription factors MAFA and PDX1. CLEC11A, therefore, may provide a novel therapeutic target for maintaining beta-cell function in patients with diabetes.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9819147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of WD40 repeat-containing proteins in endocrine (dys)function. WD40重复序列蛋白在内分泌(日)功能中的作用。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-06-19 Print Date: 2023-07-01 DOI: 10.1530/JME-22-0217

Yalan Hu, Eveline Bruinstroop, Anthony N Hollenberg, Eric Fliers, Anita Boelen

{"title":"The role of WD40 repeat-containing proteins in endocrine (dys)function.","authors":"Yalan Hu, Eveline Bruinstroop, Anthony N Hollenberg, Eric Fliers, Anita Boelen","doi":"10.1530/JME-22-0217","DOIUrl":"10.1530/JME-22-0217","url":null,"abstract":"WD40 repeat-containing proteins play a key role in many cellular functions including signal transduction, protein degradation, and apoptosis. The WD40 domain is highly conserved, and its typical structure is a β-propeller consisting of 4-8 blades which probably serves as a scaffold for protein-protein interaction. Some WD40 repeat-containing proteins form part of the corepressor complex of nuclear hormone receptors, a family of ligand-dependent transcription factors that play a central role in the regulation of gene transcription. This explains their involvement in endocrine physiology and pathology. In the present review, we first touch upon the structure of WD40 repeat-containing proteins. Next, we describe our current understanding of the role of WD40 domain-containing proteins in nuclear receptor signaling, e.g., as corepressor or coactivator. In the final part of this review, we focus on WD40 domain-containing proteins that are associated with endocrine pathologies. These pathologies vary from isolated dysfunction of one endocrine axis, e.g., congenital isolated central hypothyroidism, to more complex congenital syndromes comprising endocrine phenotypes, such as the Triple-A syndrome.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9741563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants. 一种独特的黑素皮质素-4受体信号传导谱与肥胖相关的组成活性变异。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-06-12 Print Date: 2023-07-01 DOI: 10.1530/JME-23-0008

Rikus Botha, Shree S Kumar, Natasha L Grimsey, Kathleen G Mountjoy

{"title":"A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants.","authors":"Rikus Botha, Shree S Kumar, Natasha L Grimsey, Kathleen G Mountjoy","doi":"10.1530/JME-23-0008","DOIUrl":"10.1530/JME-23-0008","url":null,"abstract":"The melanocortin-4 receptor (MC4R) plays a critical role in regulating energy homeostasis. Studies on obesogenic human MC4R (hMC4R) variants have not yet revealed how hMC4R maintains body weight. Here, we identified a signaling profile for obesogenic constitutively active H76R and L250Q hMC4R variants transfected in HEK293 cells that included constitutive activity for adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP) response element (CRE)-driven transcription, and calcium mobilization but not phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) activity. Importantly, the signaling profile included impaired α-melanocyte-stimulating hormone-induced CRE-driven transcription but not impaired α-melanocyte-stimulating hormone-induced AC, calcium, or pERK1/2. This profile was not observed for transfected H158R, a constitutively active hMC4R variant associated with overweight but not obesity. We concluded that there is potential for α-melanocyte-stimulating hormone-induced CRE-driven transcription in HEK293 cells transfected with obesogenic hMC4R variants to be the key predictive tool for determining whether they exhibit loss of function. Furthermore, in vivo, α-melanocyte-stimulating hormone-induced hMC4R CRE-driven transcription may be key for maintaining body weight.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10082181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

A time- and space-resolved nuclear receptor atlas in mouse liver. 小鼠肝脏核受体图谱的时空分辨。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-18 Print Date: 2023-07-01 DOI: 10.1530/JME-23-0017

Francesco Paolo Zummo, Alexandre Berthier, Céline Gheeraert, Manjula Vinod, Marie Bobowski-Gérard, Olivier Molendi-Coste, Laurent Pineau, Matthieu Jung, Loic Guille, Julie Chevalier-Dubois, David Dombrowicz, Bart Staels, Jérôme Eeckhoute, Philippe Lefebvre

{"title":"A time- and space-resolved nuclear receptor atlas in mouse liver.","authors":"Francesco Paolo Zummo, Alexandre Berthier, Céline Gheeraert, Manjula Vinod, Marie Bobowski-Gérard, Olivier Molendi-Coste, Laurent Pineau, Matthieu Jung, Loic Guille, Julie Chevalier-Dubois, David Dombrowicz, Bart Staels, Jérôme Eeckhoute, Philippe Lefebvre","doi":"10.1530/JME-23-0017","DOIUrl":"10.1530/JME-23-0017","url":null,"abstract":"The functional versatility of the liver is paramount for organismal homeostasis. Adult liver functions are controlled by a tightly regulated transcription factor network including nuclear receptors (NRs), which orchestrate many aspects of hepatic physiology. NRs are transcription factors sensitive to extracellular cues such as hormones, lipids, xenobiotics, etc. and are modulated by intracellular signaling pathways. While liver functional zonation and adaptability to fluctuating conditions rely on a sophisticated cellular architecture, a comprehensive knowledge of NR functions within liver cell populations is still lacking. As a step toward the accurate mapping of NR functions in the liver, we characterized their levels of expression in the whole liver from C57Bl6/J male mice as a function of time and diet. Nr1d1 (Rev-erba), Nr1d2 (Rev-erbb), Nr1c2 (Pparb/d), and Nr1f3 (Rorg) exhibited a robust cyclical expression in ad libitum-fed mice which was, like most cyclically expressed NRs, reinforced upon time-restricted feeding. In a few instances, cyclical expression was lost or gained as a function of the feeding regimen. NR isoform expression was explored in purified hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal cells. The expression of some NR isoforms, such as Nr1h4 (Fxra) and Nr1b1 (Rara) isoforms, was markedly restricted to a few cell types. Leveraging liver single-cell RNAseq studies yielded a zonation pattern of NRs in hepatocytes, liver sinusoidal cells, and stellate cells, establishing a link between NR subtissular localization and liver functional specialization. In summary, we provide here an up-to-date compendium of NR expression in mouse liver in space and time.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10061198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CEBPB/POU2F2 modulates endothelin 1 expression in prehypertensive SHR vascular smooth muscle cells. CEBPB/POU2F2调节高血压前期SHR血管平滑肌细胞内皮素1的表达。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-02 Print Date: 2023-07-01 DOI: 10.1530/JME-22-0178

Tien-Chun Yang, Mei-Hua Lu, Wei-Jie Wang, Jang-Yi Chen

{"title":"CEBPB/POU2F2 modulates endothelin 1 expression in prehypertensive SHR vascular smooth muscle cells.","authors":"Tien-Chun Yang, Mei-Hua Lu, Wei-Jie Wang, Jang-Yi Chen","doi":"10.1530/JME-22-0178","DOIUrl":"10.1530/JME-22-0178","url":null,"abstract":"The pathogenesis of hypertension is not fully understood; endothelin 1 (EDN1) is involved in developing essential hypertension. EDN1 can promote vascular smooth muscle cell (VSMC) proliferation or hypertrophy through autocrine and paracrine effects. Proliferating smooth muscle cells in the aorta are 'dedifferentiated' cells that cause increased arterial stiffness and remodeling. Male SHRs had higher aortic stiffness than normal control male WKY rats. Male SHR VSMCs expressed high levels of the EDN1 gene, but endothelial cells did not. Therefore, it is necessary to understand the molecular mechanism of enhanced EDN1 expression in SHR VSMCs. We identified POU2F2 and CEBPB as the main molecules that enhance EDN1 expression in male SHR VSMCs. A promoter activity analysis confirmed that the enhancer region of the Edn1 promoter in male SHR VSMCs was from -1309 to -1279 bp. POU2F2 and CEBPB exhibited an additive role in the enhancer region of the EdnET1 promoter. POU2F2 or CEBPB overexpression sufficiently increased EDN1 expression, and co-transfection with the CEBPB and POU2F2 expression plasmids had additive effects on the activity of the Edn1 promoter and EDN1 secretion level of male WKY VSMCs. In addition, the knockdown of POU2F2 also revealed that POU2F2 is necessary to enhance EDN1 expression in SHR VSMCs. The enhancer region of the Edn1 promoter is highly conserved in rats, mice, and humans. POU2F2 and CEBPB mRNA levels were significantly increased in remodeled human VMSCs. In conclusion, the novel regulation of POU2F2 and CEBPB in VSMCs will help us understand the pathogenesis of hypertension and support the development of future treatments for hypertension.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10235928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9687286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

βHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids. βHB抑制葡萄糖诱导的GLP-1分泌在GLUTag和人空肠肠。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-01 DOI: 10.1530/JME-22-0115

Erik Elebring, Anna Casselbrant, Sara M T Persson, Lars Fändriks, Ville Wallenius

{"title":"βHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids.","authors":"Erik Elebring, Anna Casselbrant, Sara M T Persson, Lars Fändriks, Ville Wallenius","doi":"10.1530/JME-22-0115","DOIUrl":"https://doi.org/10.1530/JME-22-0115","url":null,"abstract":"Ingestion of nutrients stimulates incretin secretion from enteroendocrine cells (EECs) of the epithelial layer of the gut. Glucagon-like peptide-1 (GLP-1) is one of these incretins that stimulate postprandial insulin release and signal satiety to the brain. Understanding the regulation of incretin secretion might open up new therapeutic options for obesity and type-2 diabetes mellitus. To investigate the inhibitory effect of the ketone body β-hydroxybutyrate (βHB) on glucose-induced GLP-1 secretion from EECs, in vitro cultures of murine GLUTag cells and differentiated human jejunal enteroid monolayers were stimulated with glucose to induce GLP-1 secretion. The effect of βHB on GLP-1 secretion was studied using ELISA and ECLIA methods. GLUTag cells stimulated with glucose and βHB were analysed using global proteomics focusing on cellular signalling pathways and the results were verified by Western blot. Results demonstrated βHB had a significant inhibitory effect on glucose-induced GLP-1 secretion at a dose of 100 mM in GLUTag cells. In differentiated human jejunal enteroid monolayers, glucose-induced secretion of GLP-1 was inhibited at a much lower dose of 10 mM βHB. The addition of βHB to GLUTag cells resulted in decreased phosphorylation of kinase AKT and transcription factor STAT3 and also influenced the expressions of signalling molecule IRS-2, kinase DGKε and receptor FFAR3. In conclusion, βHB displays an inhibitory effect on glucose-induced GLP-1 secretion in vitro in GLUTag cells and in differentiated human jejunal enteroid monolayers. This effect may be mediated through multiple downstream mediators of G-protein coupled receptor activation, such as PI3K signalling.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9684446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BMAL1 regulates osteoblast differentiation through mTOR/GSK3β/β-catenin pathway. BMAL1通过mTOR/GSK3β/β-catenin通路调控成骨细胞分化。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-01 DOI: 10.1530/JME-22-0181

Huixia Li, Hui Meng, Min Xu, Xin Gao, Xulei Sun, Xinxin Jin, Hongzhi Sun

{"title":"BMAL1 regulates osteoblast differentiation through mTOR/GSK3β/β-catenin pathway.","authors":"Huixia Li, Hui Meng, Min Xu, Xin Gao, Xulei Sun, Xinxin Jin, Hongzhi Sun","doi":"10.1530/JME-22-0181","DOIUrl":"https://doi.org/10.1530/JME-22-0181","url":null,"abstract":"Bone mass declines with age and its maintenance is tightly linked to osteoblasts (crucial bone-building cells). Although disruption of the peripheral circadian clock is involved in various pathologies including aging-related diseases, evidence regarding how the peripheral clock regulates bone mass remains elusive. In the present study, we aimed to elucidate the effects of Bmal1 (the key activator of the peripheral circadian clock system) knockdown by lentivirus-mediated shRNA on osteoblast differentiation and its related mechanisms. We found that the expression of osteogenic markers, alkaline phosphatase activity, and mineralization were decreased, whereas apoptosis and inflammatory response were increased in Bmal1 knockdown osteoblasts. In addition, Bmal1 knockdown promoted ERK and JNK phosphorylation, as well as mTOR activity, whereas mTOR inhibition by rapamycin abrogated Bmal1 knockdown-mediated effects on osteoblast differentiation and mineralization capacity. Remarkably, Bmal1 knockdown in osteoblasts inhibited GSK3β/β-catenin signaling with decreased β-catenin expression and GSK-3β phosphorylation at serine 9, while GSK3β inhibition with TDZD-8, but not WNT3a or SKL2001, rescued Bmal1 knockdown-induced defects in osteoblast differentiation. Moreover, rapamycin partly nullified the suppression of Bmal1 knockdown on β-catenin expression and GSK-3β phosphorylation. Collectively, overall data indicated that circadian gene Bmal1 regulated osteoblast differentiation and inflammatory response in an mTOR/GSK3β/β-catenin-dependent manner, and thereby may contribute to the mineralization process and bone modeling/remodeling.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9687285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis. 冉冉升起的新星:靶向G蛋白偶联受体调节能量稳态。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-04-19 Print Date: 2023-05-01 DOI: 10.1530/JME-23-0014

Aqfan Jamaluddin, Caroline M Gorvin

{"title":"RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis.","authors":"Aqfan Jamaluddin, Caroline M Gorvin","doi":"10.1530/JME-23-0014","DOIUrl":"10.1530/JME-23-0014","url":null,"abstract":"G protein-coupled receptors (GPCRs) have a critical role in energy homeostasis, contributing to food intake, energy expenditure and glycaemic control. Dysregulation of energy expenditure can lead to metabolic syndrome (abdominal obesity, elevated plasma triglyceride, LDL cholesterol and glucose, and high blood pressure), which is associated with an increased risk of developing obesity, diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular complications. As the prevalence of these chronic diseases continues to rise worldwide, there is an increased need to understand the molecular mechanisms by which energy expenditure is regulated to facilitate the development of effective therapeutic strategies to treat and prevent these conditions. In recent years, drugs targeting GPCRs have been the focus of efforts to improve treatments for type-2 diabetes and obesity, with GLP-1R agonists a particular success. In this review, we focus on nine GPCRs with roles in energy homeostasis that are current and emerging targets to treat obesity and diabetes. We discuss findings from pre-clinical models and clinical trials of drugs targeting these receptors and challenges that must be overcome before these drugs can be routinely used in clinics. We also describe new insights into how these receptors signal, including how accessory proteins, biased signalling, and complex spatial signalling could provide unique opportunities to develop more efficacious therapies with fewer side effects. Finally, we describe how combined therapies, in which multiple GPCRs are targeted, may improve clinical outcomes and reduce off-target effects.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10160555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9687287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PPP2R2A promotes testosterone secretion in Hu sheep Leydig cells via activation of the AKT/mTOR signaling pathway. PPP2R2A通过激活AKT/mTOR信号通路促进虎羊间质细胞睾酮分泌。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-04-17 Print Date: 2023-05-01 DOI: 10.1530/JME-22-0130

Xiaodan Li, Xiaolei Yao, Yongjin Bao, Kaiping Deng, Mingtian Deng, Fan Yang, Xuan Sun, Peihua You, Qingxian Cai, Feng Wang

{"title":"PPP2R2A promotes testosterone secretion in Hu sheep Leydig cells via activation of the AKT/mTOR signaling pathway.","authors":"Xiaodan Li, Xiaolei Yao, Yongjin Bao, Kaiping Deng, Mingtian Deng, Fan Yang, Xuan Sun, Peihua You, Qingxian Cai, Feng Wang","doi":"10.1530/JME-22-0130","DOIUrl":"10.1530/JME-22-0130","url":null,"abstract":"The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme complex that plays a vital role in regulating male reproductive activities. However, as an essential member of the PP2A family, the physiological functions of PP2A regulatory subunit B55α (PPP2R2A) in testis remain inconclusive. Hu sheep are noted for their reproductive precocity and fertility, and are ideal models for the study of male reproductive physiology. Here, we analyzed the expression patterns of PPP2R2A in the male Hu sheep reproductive tract at different developmental stages and further investigated its role in testosterone secretion and its underlying mechanisms. In this study, we found that there were temporal and spatial differences in PPP2R2A protein expression in the testis and epididymis, especially the expression abundance in the testis at 8 months old (8M) was higher than that at 3 months old (3M). Interestingly, we observed that PPP2R2A interference reduced the testosterone levels in the cell culture medium, which is accompanied by a reduction in Leydig cell proliferation and an elevation in Leydig cell apoptosis. The level of reactive oxygen species in cells increased significantly, while the mitochondrial membrane potential (ΔΨm) decreased significantly after PPP2R2A deletion. Meanwhile, the mitochondrial mitotic protein DNM1L was significantly upregulated, while the mitochondrial fusion proteins MFN1/2 and OPA1 were significantly downregulated after PPP2R2A interference. Furthermore, PPP2R2A interference suppressed the AKT/mTOR signaling pathway. Taken together, our data indicated that PPP2R2A enhanced testosterone secretion, promoted cell proliferation, and inhibited cell apoptosis in vitro, all of which were associated with the AKT/mTOR signaling pathway.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10043368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0