scholarly journals The negative adipogenesis regulator DLK1 is transcriptionally regulated by TIS7 (IFRD1) and translationally by its orthologue SKMc15 (IFRD2)

2019 ◽  
Author(s):  
Ilja Vietor ◽  
Domagoj Cikes ◽  
Kati Piironen ◽  
Ronald Gstir ◽  
Matthias David Erlacher ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
High Fat Diet ◽  
Adipocyte Differentiation ◽  
Negative Regulator ◽  
Protein Levels ◽  
Diet Induced Obesity ◽  
Fatty Acid Transporter ◽  
Adipocyte Progenitors ◽  
Translational Inhibitor

AbstractDelta-like homolog 1 (DLK1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Understanding regulatory mechanisms affecting DLK1 levels is therefore of high interest. Here we identify two independent mechanisms, transcriptional and translational, by which TIS7 (IFRD1) and its orthologue SKMc15 (IFRD2) regulate DLK1 levels. Mice deficient in both TIS7 and SKMc15 (dKO) had severely reduced adipose tissue and were resistant to high fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation was significantly up regulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk-1 inhibited the expression of adipogenesis regulators PPARγ and C/EBPα, and fatty acid transporter CD36. Although both, TIS7 and SKMc15, contributed to this phenotype, they utilized two different mechanisms. TIS7 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk-1. On the other hand, here we provide experimental evidence that SKMc15 acts as a general translational inhibitor affecting DLK-1 protein levels. Our study provides data describing novel mechanisms of DLK1 regulation in adipocyte differentiation involving TIS7 and SKMc15.

scholarly journals The microRNA miR-8 is a conserved negative regulator of Wnt signaling

2008 ◽  
Vol 105 (40) ◽  
pp. 15417-15422 ◽  
Author(s):  
Jennifer A. Kennell ◽  
Isabelle Gerin ◽  
Ormond A. MacDougald ◽  
Ken M. Cadigan
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Target Genes ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Animal Development ◽  
Protein Levels ◽  
Evolutionarily Conserved ◽  
Multiple Levels

Wnt signaling plays many important roles in animal development. This evolutionarily conserved signaling pathway is highly regulated at all levels. To identify regulators of the Wnt/Wingless (Wg) pathway, we performed a genetic screen in Drosophila. We identified the microRNA miR-8 as an inhibitor of Wg signaling. Expression of miR-8 potently antagonizes Wg signaling in vivo, in part by directly targeting wntless, a gene required for Wg secretion. In addition, miR-8 inhibits the pathway downstream of the Wg signal by repressing TCF protein levels. Another positive regulator of the pathway, CG32767, is also targeted by miR-8. Our data suggest that miR-8 potently antagonizes the Wg pathway at multiple levels, from secretion of the ligand to transcription of target genes. In addition, mammalian homologues of miR-8 promote adipogenesis of marrow stromal cells by inhibiting Wnt signaling. These findings indicate that miR-8 family members play an evolutionarily conserved role in regulating the Wnt signaling pathway.

scholarly journals Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

2015 ◽  
Vol 309 (8) ◽  
pp. C511-C521 ◽  
Author(s):  
Laura Novellasdemunt ◽  
Pedro Antas ◽  
Vivian S. W. Li
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Evolutionarily Conserved

The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.

scholarly journals Salvador–Warts–Hippo pathway regulates sensory organ development via caspase-dependent nonapoptotic signaling

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Lan-Hsin Wang ◽  
Nicholas E. Baker
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Growth Regulation ◽  
Hippo Pathway ◽  
Size Control ◽  
Negative Regulator ◽  
Sensory Organ ◽  
Neural Precursor ◽  
Cell Fate Determination ◽  
Fate Determination

Abstract The fundamental roles for the Salvador–Warts–Hippo (SWH) pathway are widely characterized in growth regulation and organ size control. However, the function of SWH pathway is less known in cell fate determination. Here we uncover a novel role of the SWH signaling pathway in determination of cell fate during neural precursor (sensory organ precursor, SOP) development. Inactivation of the SWH pathway in SOP of the wing imaginal discs affects caspase-dependent bristle patterning in an apoptosis-independent process. Such nonapoptotic functions of caspases have been implicated in inflammation, proliferation, cellular remodeling, and cell fate determination. Our data indicate an effect on the Wingless (Wg)/Wnt pathway. Previously, caspases were proposed to cleave and activate a negative regulator of Wg/Wnt signaling, Shaggy (Sgg)/GSK3β. Surprisingly, we found that a noncleavable form of Sgg encoded from the endogenous locus after CRISPR-Cas9 modification supported almost normal bristle patterning, indicating that Sgg might not be the main target of the caspase-dependent nonapoptotic process. Collectively, our results outline a new function of SWH signaling that crosstalks to caspase-dependent nonapoptotic signaling and Wg/Wnt signaling in neural precursor development, which might be implicated in neuronal pathogenesis.

scholarly journals Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

2011 ◽  
Vol 301 (1) ◽  
pp. E187-E195 ◽  
Author(s):  
Guillaume de Lartigue ◽  
Claire Barbier de la Serre ◽  
Elvis Espero ◽  
Jennifer Lee ◽  
Helen E. Raybould
Keyword(s):  
High Fat Diet ◽  
Leptin Resistance ◽  
Afferent Neurons ◽  
High Fat ◽  
Leptin Signaling ◽  
Protein Levels ◽  
Diet Induced Obesity ◽  
Nodose Ganglia ◽  
Vagal Afferent

Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.

scholarly journals An Akt-dependent Increase in Canonical Wnt Signaling and a Decrease in Sclerostin Protein Levels Are Involved in Strontium Ranelate-induced Osteogenic Effects in Human Osteoblasts

2011 ◽  
Vol 286 (27) ◽  
pp. 23771-23779 ◽  
Author(s):  
Mark S. Rybchyn ◽  
Michael Slater ◽  
Arthur D. Conigrave ◽  
Rebecca S. Mason
Keyword(s):  
Bone Formation ◽  
Wnt Signaling ◽  
Strontium Ranelate ◽  
Nuclear Translocation ◽  
Negative Regulator ◽  
Bone Homeostasis ◽  
Canonical Wnt Signaling ◽  
Human Osteoblasts ◽  
Protein Levels ◽  
Canonical Wnt

Sclerostin is an important regulator of bone homeostasis and canonical Wnt signaling is a key regulator of osteogenesis. Strontium ranelate is a treatment for osteoporosis that has been shown to reduce fracture risk, in part, by increasing bone formation. Here we show that exposure of human osteoblasts in primary culture to strontium increased mineralization and decreased the expression of sclerostin, an osteocyte-specific secreted protein that acts as a negative regulator of bone formation by inhibiting canonical Wnt signaling. Strontium also activated, in an apparently separate process, an Akt-dependent signaling cascade via the calcium-sensing receptor that promoted the nuclear translocation of β-catenin. We propose that two discrete pathways linked to canonical Wnt signaling contribute to strontium-induced osteogenic effects in osteoblasts.

scholarly journals Cirsium setidens Nakai extract inhibits adipocyte differentiation and High‐Fat Diet‐induced obesity in Mice

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
YoungJun Lee ◽  
Ju Hyun Cho ◽  
Bong Kyun Kim ◽  
Hyeon‐Son Choi ◽  
Boo Yong Lee ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Adipocyte Differentiation ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Obesity In Mice ◽  
Cirsium Setidens

164 POTENTIAL REGULATION OF PERI-IMPLANTATION OVINE CONCEPTUS GROWTH AND DIFFERENTIATION BY THE WNT SIGNALING SYSTEM

2007 ◽  
Vol 19 (1) ◽  
pp. 199
Author(s):  
K. Hayashi ◽  
R. C. Burghardt ◽  
F. W. Bazer ◽  
T. E. Spencer
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Density Lipoprotein ◽  
Cell Types ◽  
Negative Regulator ◽  
Beta Catenin ◽  
Canonical Wnt

In mice WNT signaling regulates cell fate, differentiation, and growth in the conceptus (embryo and associated extra-embryonic membranes), as well as implantation. We studied various components of the WNT signaling pathway in the ovine uterus during the estrous cycle (C) and pregnancy (P) and in the peri-implantation conceptus. Expression of WNT2, WNT2B, and WNT4 mRNAs was very low in endometria of C and P ewes from Days 10 to 16 and in conceptus trophectoderm (Tr). WNT5A/5B mRNAs were abundant in the stratum compactum stroma, whereas WNT11 mRNA was detected in endometrial epithelia of C and P ewes, but not in conceptus Tr. WNT7A mRNA was localized specifically to luminal (LE) and superficial glandular (sGE) epithelia of Day 10 C and P ewes, was undetectable by Day 12, and then increased up to Day 16 and was maximum on Day 20 only in P ewes. Frizzled receptor (FZD6/8) mRNAs were detected primarily in conceptus Tr and uterine LE and GE, whereas the co-receptor LRP5/6 (low density lipoprotein receptor-related protein) mRNAs were expressed in all uterine cell types and conceptus Tr. Dickkopf (DKK1), a negative regulator of WNT signaling, was detected in stratum compactum stroma after Day 14 in P ewes. CTNNB1 (beta-catenin), a key mediator of canonical WNT signaling, and GSK3B (glycogen synthase kinase-3 beta) and CHD1 (E-cadherin) mRNAs were abundant in endometrial epithelia and in conceptus Tr. Immunoreactive CTNNB1 protein was abundant in LE and GE, and present at lower levels in stroma and myometrium in uteri from C and P ewes. In the conceptus Tr, immunoreactive CTNNB1 protein was abundant in nuclei of the mononuclear and binuclear cells (BNC), as well as in cell adherens junctions. Nuclear CTNNB1 interacts with transcription factors, most notably LEF1/TCF7 (lymphoid enhancer-binding factor 1/transcription factor 7), to regulate gene transcription. LEF1 mRNA was detected in LE and sGE, whereas nuclear TCF7L2 protein was particularly abundant in trophoblast giant BNC. WNT/beta-catenin/TCF7 target genes were also studied. MSX2 mRNA was abundant in conceptus Tr, and MYC mRNA was abundant in BNC of conceptus Tr and endometrial epithelia. Next, ovine Tr (oTr) cells and endometrial stromal (oST) cells were used for mechanistic studies that revealed that transfection of mouse WNT7A stimulated a LEF/TCF-responsive reporter (TOPFLASH), and co-transfection of either dnTCF or SFRP2 (a secreted FZD inhibitor) inhibited WNT7A effects. WNT7A stimulated expression of MSX2 and MYC in oTr cells, and this effect was inhibited by SFRP2. These results implicate the canonical WNT system as a regulator of peri-implantation conceptus growth and differentiation in sheep. This work was supported by NIH HD38274 and 5 P30 ES09106 funding.

scholarly journals Lactobacillus fermentum promotes adipose tissue oxidative phosphorylation to protect against diet-induced obesity

2020 ◽  
Vol 52 (9) ◽  
pp. 1574-1586
Author(s):  
Youngmin Yoon ◽  
Gihyeon Kim ◽  
Myung-giun Noh ◽  
Jeong-hyeon Park ◽  
Mongjoo Jang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Oxidative Phosphorylation ◽  
High Fat Diet ◽  
Adipocyte Differentiation ◽  
Lactobacillus Fermentum ◽  
Metabolic Homeostasis ◽  
High Fat ◽  
Metabolome Analysis ◽  
Diet Induced Obesity ◽  
Glucose Clearance

Abstract The gut microbiota has pivotal roles in metabolic homeostasis and modulation of the intestinal environment. Notably, the administration of Lactobacillus spp. ameliorates diet-induced obesity in humans and mice. However, the mechanisms through which Lactobacillus spp. control host metabolic homeostasis remain unclear. Accordingly, in this study, we evaluated the physiological roles of Lactobacillus fermentum in controlling metabolic homeostasis in diet-induced obesity. Our results demonstrated that L. fermentum-potentiated oxidative phosphorylation in adipose tissue, resulting in increased energy expenditure to protect against diet-induced obesity. Indeed, oral administration of L. fermentum LM1016 markedly ameliorated glucose clearance and fatty liver in high-fat diet-fed mice. Moreover, administration of L. fermentum LM1016 markedly decreased inflammation and increased oxidative phosphorylation in gonadal white adipose tissue, as demonstrated by transcriptome analysis. Finally, metabolome analysis showed that metabolites derived from L. fermentum LM1016-attenuated adipocyte differentiation and inflammation in 3T3-L1 preadipocytes. These pronounced metabolic improvements suggested that the application of L. fermentum LM1016 could have clinical applications for the treatment of metabolic syndromes, such as diet-induced obesity.

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