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Ting Xiao, Xiuci Liang, Hailan Liu, Feng Zhang, Wen Meng and Fang Hu

ER stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction caused metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that high fat diet (HFD) or chemical induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration and decrease mitochondrial membrane potential in mouse hepatocytes. Hsp60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.

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Francesco J. DeMayo and John Lydon

Progesterone’s ability to maintain pregnancy in eutherian mammals highlighted this steroid as the “hormone of pregnancy”. It was the unique “pro-gestational” bioactivity of progesterone that enabled eventual purification of this ovarian steroid to crystalline form by Willard Myron Allen in the early 1930s. While a functional connection between normal progesterone responses (“progestational proliferation”) of the uterus with the maintenance of pregnancy was quickly appreciated, an understanding of progesterone’s involvement in the early stages of pregnancy establishment was comparatively less well understood. With the aforementioned as historical backdrop, this review focusses on a selection of key advances in our understanding of the molecular mechanisms by which progesterone, through its nuclear receptor (the progesterone receptor), drives the development of endometrial receptivity, a transient uterine state that allows for embryo implantation and the establishment of pregnancy. Highlighted in this review are the significant contributions of advanced mouse engineering and genome-wide transcriptomic and cistromic analytics to revealing the pivotal molecular mediators and modifiers that are essential to progesterone-dependent endometrial receptivity and decidualization. With a clearer understanding of the molecular landscape that underpins uterine responsiveness to progesterone during the periimplantation period, we predict that common gynecologic morbidities due to abnormal progesterone responsiveness will be more effectively diagnosed and/or treated in the future.

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Peng Xu, John J. Gildea, Chi Zhang, Prasad Konkalmatt, Santiago Santiago, Dora Bigler Wang, Hanh T. Tran, Pedro A. Jose and Robin A. Felder

Gastrin, secreted by stomach G cells in response to ingested sodium, stimulates the renal cholecystokinin B receptor (CCKBR) to increase renal sodium excretion. It is not known, how dietary sodium, independent of food, can increase gastrin secretion in human G cells. However, fenofibrate (FFB), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, increases gastrin secretion in rodents and several human gastrin-secreting cells, via a gastrin transcriptional promoter. We tested these hypotheses: 1) a sodium sensor in G cells plays a critical role in the sodium-mediated increase in gastrin expression/secretion; and 2) dopamine, via the D1R and PPAR-α, is involved. Intact human stomach antrum and G cells were compared with human gastrin-secreting gastric and ovarian adenocarcinoma cells. When extra or intracellular sodium was increased in human antrum, human G cells, and adenocarcinoma cells, gastrin mRNA and protein expression/secretion were increased. In human G cells, the PPAR-α agonist, FFB increased gastrin protein expression that was blocked by GW6471, a PPAR-α antagonist, and LE300, a D1-like receptor antagonist. LE300 prevented the ability of FFB to increase gastrin protein expression in human G cells, via the D1R, because the D5R, the other D1-like receptor, is not expressed in human G cells. Human G cells also express tyrosine hydroxylase and DOPA decarboxylase, enzymes needed to synthesize dopamine. G cells in the stomach may be the sodium sensor that stimulates gastrin secretion, which enables the kidney to eliminate, acutely, an oral sodium load. Dopamine, via the D1R, by interacting with PPAR-α, is involved in this process.

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Márcia Faria, Daniela Félix, Rita Domingues, Maria João Bugalho, Paulo Matos and Ana Luísa Silva

Thyroid cancer (TC) is the most common endocrine malignancy. The sodium–iodide symporter (NIS), responsible for active transport of iodide into thyroid cells, allows the use of radioactive iodine (RAI) as the systemic treatment of choice for TC metastatic disease. Still, patients with advanced forms of TC often lose the ability to respond to RAI therapy, which results in worse survival rates. We have shown that the overexpression of RAC1b, a tumor-related RAC1 splice variant, is associated with less favorable clinical outcomes in differentiated TCs derived from the follicular epithelial (DTCs). RAC1b overexpression is also significantly associated with the presence of MAPK-activating BRAFV600E mutation, which has been previously implicated in the loss of NIS expression. Here, we show that increased RAC1b levels are associated with NIS downregulation in DTCs and demonstrate that ectopic overexpression of RAC1b in non-transformed thyroid cells is sufficient to decrease TSH-induced NIS expression, antagonizing the positive effect of the canonically spliced RAC1 GTPase. Moreover, we clearly document for the first time in thyroid cells that both NIS expression and iodide uptake are hampered by RAC1 inhibition, highlighting the role of RAC1 in promoting TSH-induced NIS expression. Our findings support a role for RAC1 and RAC1b signaling in the regulation of NIS expression in thyroid cells and suggest that RAC1b in cooperation with other cancer-associated signaling cues may be implicated in the response of DTCs to RAI therapy.

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Mohamed Noureldein, Sara Bitar, Natalie Youssef, Sami T Azar and Assaad A. Eid

Diabetic dysbiosis has been described as a novel key player in diabetes and diabetic complications. However, the cellular/molecular alteration associated with dysbiosis remain poorly characterized. For that, control, non-obese type 2 diabetic MKR mice and MKR mice treated with butyrate were used to delineate the epigenetic, cellular and molecular mechanisms by which dysbiosis associated with diabetes induces colon shortening, inflammation attesting to gastrointestinal disturbance.

Our results show that dysbiosis is associated with T2DM and characterized by reduced Bacteroid fragilis population and butyrate-forming bacteria. The reduction of butyrate-forming bacteria and inadequate butyrate secretion result in alleviating HDAC3 inhibition and alter colon permeability. The observed changes are also associated with increased ROS production, a rise in NOX4 proteins, and a shift in the inflammatory markers, where IL-1 is increased and IL-10 and IL-17 are reduced. Treatment with butyrate restores the homeostatic levels of NOX4 and IL-1.

In summary, our data suggest that in T2DM, dysbiosis associates with a reduction in butyrate content leading to increased HDAC3 activity. Butyrate treatment restores the homeostatic levels of the inflammatory markers and reduces ROS production known to mediate diabetes-induced colon disturbance. Taken together our results suggest that butyrate could be a potential treatment to attenuate diabetic complications.

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Kimberly H Cox and Joseph S Takahashi

The mammalian circadian clock has evolved as an adaptation to the 24-h light/darkness cycle on earth. Maintaining cellular activities in synchrony with the activities of the organism (such as eating and sleeping) helps different tissue and organ systems coordinate and optimize their performance. The full extent of the mechanisms by which cells maintain the clock are still under investigation, but involve a core set of clock genes that regulate large networks of gene transcription both by direct transcriptional activation/repression as well as the recruitment of proteins that modify chromatin states more broadly.

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Shalinee Dhayal, Francesco P Zummo, Matthew W Anderson, Patricia Thomas, Hannah J Welters, Catherine Arden and Noel G Morgan

Long-chain saturated fatty acids are lipotoxic to pancreatic β-cells, whereas most unsaturates are better tolerated and some may even be cytoprotective. Fatty acids alter autophagy in β-cells and there is increasing evidence that such alterations can impact directly on the regulation of viability. Accordingly, we have compared the effects of palmitate (C16:0) and palmitoleate (C16:1) on autophagy in cultured β-cells and human islets. Treatment of BRIN-BD11 β-cells with palmitate led to enhanced autophagic activity, as judged by cleavage of microtubule-associated protein 1 light chain 3-I (LC3-I) and this correlated with a marked loss of cell viability in the cells. In addition, transfection of these cells with an mCherry-YFP-LC3 reporter construct revealed the accumulation of autophagosomes in palmitate-treated cells, indicating an impairment of autophagosome-lysosome fusion. This was also seen upon addition of the vacuolar ATPase inhibitor, bafilomycin A1. Exposure of BRIN-BD11 cells to palmitoleate (C16:1) did not lead directly to changes in autophagic activity or flux, but it antagonised the actions of palmitate. In parallel, palmitoleate also improved the viability of palmitate-treated BRIN-BD11 cells. Equivalent responses were observed in INS-1E cells and in isolated human islets. Taken together, these data suggest that palmitate may cause an impairment of autophagosome-lysosome fusion. These effects were not reproduced by palmitoleate which, instead, antagonised the responses mediated by palmitate suggesting that attenuation of β-cell stress may contribute to the improvement in cell viability caused by the mono-unsaturated fatty acid.

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Jiayu Jin, Xinhong Wang, Xiuling Zhi and Dan Meng

Cardiovascular disease (CVD), the main complication of diabetes mellitus (DM), accounts for a high percentage of mortality in diabetic patients. Endothelial dysfunction is a major causative event in the pathogenesis of diabetes-related vascular disease and the earliest symptom of vascular injury. Epigenetic modification plays a key role in the initiation, maintenance, and progression of both endothelial dysfunction and diabetes. Epigenetic alterations respond to the environment and mediate the ‘legacy effect’ of uncontrolled hyperglycaemia early in the disease despite thorough glycaemic control in a phenomenon called metabolic memory. Therefore, an understanding of the integrated system of different epigenetic mechanisms in DM and its vascular complications is urgently needed. This review summarizes aberrant epigenetic regulation under diabetic conditions, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs). Understanding the connections between these processes and DM may reveal a novel potential therapeutic target for diabetic vascular complications.

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Yun-Qing Zhu, Yun Hu, Ke He, Na Li, Peng Jiang, Yu-Qin Pan, Hong Zhou and Xiao-Ming Mao

The follicles are the minimal functional unit of the thyroid; the morphology and the function of each follicle can vary significantly. However, the reasons for the apparent follicular heterogeneity are poorly understood. Some tissue-resident regulatory T cells (Tregs) have a special phenotype that expresses unique molecules related to local tissue and regulates the tissue functions. The aim of this study was to identify the phenotype of thyroid Tregs and the roles of thyroid Tregs in thyroid physiological regulation. Thyroid tissue and peripheral blood samples were obtained from patients with benign thyroid nodules. Microarray-based gene expression, flow cytometry, immunofluorescence microscopy, and functional analysis of thyroid Tregs were performed. Here, we demonstrated that human thyroid Tregs expressed high level of thyroglobulin (Tg), both gene and protein. The immunofluorescence microscopy of thyroid section showed that the FOXP3+Tg+ cells concentrated in some of the thyroid follicles, at the side of the thyroid follicle. The peripheral blood Tregs expressed minimal levels of Tg, and low levels of Tg could effectively induce peripheral blood Tregs to express Tg, which was independent of thyrotropin simulation. Furthermore, the Tg secreted freely from thyroid Tregs that negatively regulated some thyroid-related genes expression. Our results revealed that the thyroid Tregs was a distinct population of Tregs, which expressed high level of Tg. The thyroid Tregs regulate thyroid function by Tg that is paracrine from the cells.

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Giulia Cantini, Martina Trabucco, Alessandra Di Franco, Edoardo Mannucci and Michaela Luconi

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), which are currently used for the treatment of type 2 diabetes, have recently been proposed as anti-obesity drugs, due to their relevant effects on weight loss. Furthermore, dual agonists for both GLP-1R and glucagon receptor (GCGR) are under investigation for their promising action on adiposity, although underlying mechanisms still need to be clarified. We have recently demonstrated that GLP-1 and liraglutide interfere with the proliferation and differentiation of human adipose precursors, supporting the hypothesis of a peripheral action of GLP-1RA on weight. Here, we investigated glucagon activity in an in vitro model of primary human adipose-derived stem cells (ASCs). Glucagon significantly inhibited ASC proliferation in a dose- and time-dependent manner, as evaluated by cell count and thymidine incorporation. When added during in vitro-induced adipogenesis, glucagon significantly reduced adipocyte differentiation, as demonstrated by the evaluation of intracellular fat content and quantitative expression of early and mature adipocyte markers (PPARγ and FABP4, HSL). Notably, the inhibitory effect of glucagon on cell proliferation and adipogenesis was reversed by specific GLP-1R (exendin-9) and GCGR (des-His1-Glu9-glucagon(1–29)) antagonists. The presence of both receptors was demonstrated by Western blot, immunofluorescence and cytofluorimetric analysis of ASCs. In conclusion, we demonstrated a direct inhibitory action of glucagon on the proliferation and differentiation of human adipose precursors, which seems to involve both GLP-1R and GCGR. These findings suggest that the adipose stem compartment is a novel target of glucagon, possibly contributing to the weight loss obtained in vivo with dual GLP-1R/glucagon agonists.