ID: 87: TRANSCRIPTION FACTOR CREB3L3 IS A NOVEL REGULATOR FOR ADIPOCYTE BIOLOGY AND METABOLISM

2016 ◽  
Vol 64 (4) ◽  
pp. 930.2-931
Author(s):  
S Duncan ◽  
M McCann ◽  
G Qiang ◽  
V Gil ◽  
H Whang Kong ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Human Subjects ◽  
Stromal Vascular Fraction ◽  
Obese Mouse ◽  
Futile Cycle ◽  
Adipose Tissues

The presence of differential metabolic risks between the metabolically-protective subcutaneous adipose tissue (SAT) and the disease-associated visceral adipose tissue (VAT) is well established, but the mechanisms that cause these differences are not well understood. Cyclic AMP responsive element binding protein 3-like 3 (CREB3L3), a previously characterized liver-specific ER-bound transcription factor, was found to be expressed in murine SAT and VAT. In obese human subjects and an obese mouse model, we found that CREB3L3 is downregulated in SAT, but not in VAT. To examine the role of CREB3L3 in adipocyte biology and metabolism, we created a fat-specific CREB3L3 knockout (KO) mouse using the AdipoQ-Cre mouse. To establish a potential role for CREB3L3 in adipocytes, we examined in vitro differentiated adipocytes from isolated WT and KO primary stromal vascular fraction. We observed that ablation of CREB3L3 in SAT adipocytes significantly upregulated expression of both lipogenic and lipolytic markers. At the same time, we also observed significantly increased expression of thermogenic markers like PGC1α and Cox8b. Taken together our data suggest potential upregulation of the fat futile cycle in SAT upon deletion of CREB3L3. Surprisingly, we found that CREB3L3 KO tends to downregulate expression of markers of both lipogenesis and lipolysis in VAT adipocytes. This observation could potentially be contributed by the tendency of CREB3l3 KO VAT to have inhibited differentiation. To investigate the in vivo function of CREB3L3, we challenged WT and KO mice with high fat diet with weekly body weight assessment. We observed that CREB3L3 ablation in adipose tissues promotes significant weight gain in mice on HFD. Unexpectedly, despite being heavier, the KO mice are not more glucose intolerant or insulin resistant. These data together suggest that ablation of CREB3L3 could potentially promote fat storage in adipose tissues to prevent metabolic diseases caused by ectopic fat deposition.

scholarly journals Long-Term Severe In Vitro Hypoxia Exposure Enhances the Vascularization Potential of Human Adipose Tissue-Derived Stromal Vascular Fraction Cell Engineered Tissues

2021 ◽  
Vol 22 (15) ◽  
pp. 7920
Author(s):  
Myroslava Mytsyk ◽  
Giulia Cerino ◽  
Gregory Reid ◽  
Laia Gili Sole ◽  
Friedrich S. Eckstein ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Therapeutic Potential ◽  
Stromal Vascular Fraction ◽  
Human Adipose Tissue ◽  
Bioreactor Culture ◽  
Proliferating Cells ◽  
Angiogenic Potential ◽  
Engineered Tissues

The therapeutic potential of mesenchymal stromal/stem cells (MSC) for treating cardiac ischemia strongly depends on their paracrine-mediated effects and their engraftment capacity in a hostile environment such as the infarcted myocardium. Adipose tissue-derived stromal vascular fraction (SVF) cells are a mixed population composed mainly of MSC and vascular cells, well known for their high angiogenic potential. A previous study showed that the angiogenic potential of SVF cells was further increased following their in vitro organization in an engineered tissue (patch) after perfusion-based bioreactor culture. This study aimed to investigate the possible changes in the cellular SVF composition, in vivo angiogenic potential, as well as engraftment capability upon in vitro culture in harsh hypoxia conditions. This mimics the possible delayed vascularization of the patch upon implantation in a low perfused myocardium. To this purpose, human SVF cells were seeded on a collagen sponge, cultured for 5 days in a perfusion-based bioreactor under normoxia or hypoxia (21% and <1% of oxygen tension, respectively) and subcutaneously implanted in nude rats for 3 and 28 days. Compared to ambient condition culture, hypoxic tension did not alter the SVF composition in vitro, showing similar numbers of MSC as well as endothelial and mural cells. Nevertheless, in vitro hypoxic culture significantly increased the release of vascular endothelial growth factor (p < 0.001) and the number of proliferating cells (p < 0.00001). Moreover, compared to ambient oxygen culture, exposure to hypoxia significantly enhanced the vessel length density in the engineered tissues following 28 days of implantation. The number of human cells and human proliferating cells in hypoxia-cultured constructs was also significantly increased after 3 and 28 days in vivo, compared to normoxia. These findings show that a possible in vivo delay in oxygen supply might not impair the vascularization potential of SVF- patches, which qualifies them for evaluation in a myocardial ischemia model.

scholarly journals Inflammatory pathways involved in adipose tissue hypertrophy and the effect of Acai (Euterpe oleracea Martius) on the modulation of this process: a review

2020 ◽  
Vol 9 (9) ◽  
pp. e62996813
Author(s):  
Tamires Cássia de Melo Souza ◽  
Gabriel Vitor de Melo Souza ◽  
Ana Carolina Pinheiro Volp
Keyword(s):  
Adipose Tissue ◽  
Chronic Inflammation ◽  
Bioactive Compounds ◽  
Metabolic Diseases ◽  
Sample Size Calculation ◽  
Control Group ◽  
Euterpe Oleracea ◽  
Treatment And Prevention

Adipose tissue plays an important role in chronic inflammation and the presence of bioactive compounds in food has been widely discussed as a means of prevention and treatment of various pathological conditions. The aim of this review is to promote an overview and elucidate pathways involved in the chronic inflammatory process triggered by adipose tissue hypertrophy and to discuss data related to the use of Acai in the modulation of inflammation. Initially, a narrative review was carried out on metabolic and molecular pathways involved in the process of subclinical chronic inflammation (NF-κB, AP-1, cross-talk between macrophages and adipocytes, increased LPS and Nrf2 pathway). Then, an integrative review was carried out on the effect of Acai in processes of chronic subclinical inflammation in humans. The database consulted was PubMed, in which the name of the fruit was crossed with the descriptors "inflammation" and "chronic diseases", prioritizing in vivo and in vitro studies related to the human species, carried out in the last ten years. It was observed that the immunomodulatory effects of Acai are increasingly clear, however, are not enough to classify the fruit as a tool in the treatment and prevention of metabolic diseases. To make possible more comprehensive inferences, it is necessary that future studies include assessment of the bioavailability of the bioactive compounds present, in addition to being performed using more suitable methods, with humans, containing sample size calculation, control group and placebo.

scholarly journals Transcription Factor E2F1 Knockout Promotes Mice White Adipose Tissue Browning Through Autophagy Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
Mingchen Xiong ◽  
Weijie Hu ◽  
Yufang Tan ◽  
Honghao Yu ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Underlying Mechanism ◽  
Metabolic Complications ◽  
Autophagy Inhibition ◽  
Transcription Factor E2f1

Obesity is associated with energy metabolic disturbance and is caused by long-term excessive energy storage in white adipose tissue (WAT). The WAT browning potentially reduces excessive energy accumulation, contributing an attractive target to combat obesity. As a pivotal regulator of cell growth, the transcription factor E2F1 activity dysregulation leads to metabolic complications. The regulatory effect and underlying mechanism of E2F1 knockout on WAT browning, have not been fully elucidated. To address this issue, in this study, the in vivo adipose morphology, mitochondria quantities, uncoupling protein 1 (UCP-1), autophagy-related genes in WAT of wild-type (WT) and E2F1–/– mice were detected. Furthermore, we evaluated the UCP-1, and autophagy-related gene expression in WT and E2F1–/– adipocyte in vitro. The results demonstrated that E2F1 knockout could increase mitochondria and UCP-1 expression in WAT through autophagy suppression in mice, thus promoting WAT browning. Besides, adipocytes lacking E2F1 showed upregulated UCP-1 and downregulated autophagy-related genes expression in vitro. These results verified that E2F1 knockout exerted effects on inducing mice WAT browning through autophagy inhibition in vivo and in vitro. These findings regarding the molecular mechanism of E2F1-modulated autophagy in controlling WAT plasticity, provide a novel insight into the functional network with the potential therapeutic application against obesity.

scholarly journals Alterations in the Secretome of Clinically Relevant Preparations of Adipose-Derived Mesenchymal Stem Cells Cocultured with Hyaluronan

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Peter Succar ◽  
Edmond J. Breen ◽  
Donald Kuah ◽  
Benjamin R. Herbert
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Disease Progression ◽  
Proinflammatory Cytokines ◽  
Mechanism Of Action ◽  
Stromal Vascular Fraction ◽  
Slow Disease Progression

Osteoarthritis (OA) can be a debilitating degenerative disease and is the most common form of arthritic disease. There is a general consensus that current nonsurgical therapies are insufficient for younger OA sufferers who are not candidates for knee arthroplasties. Adipose-derived mesenchymal stem cells (MSCs) therapy for the treatment of OA can slow disease progression and lead to neocartilage formation. The mechanism of action is secretion driven. Current clinical preparations from adipose tissue for the treatment of OA include autologous stromal vascular fraction (SVF), SVF plus mature adipocytes, and culture-purified MSCs. Herein we have combined these human adipose-derived preparations with Hyaluronan (Hylan G-F 20: Synvisc)in vitroand measured alterations in cytokine profile. SVF plus mature adipocytes showed the greatest decreased in the proinflammatory cytokines IL-1β, IFN-γ, and VEGF. MCP-1 and MIP-1αdecreased substantially in the SVF preparations but not the purified MSCs. The purified MSC preparation was the only one to show increase in MIF. Overall the SVF plus mature adipocytes preparation may be most suited of all the preparations for combination with HA for the treatment of OA, based on the alterations of heavily implicated cytokines in OA disease progression. This will require further validation usingin vivomodels.

Dehydroepiandrosterone reduces preadipocyte proliferation via androgen receptor

2012 ◽  
Vol 302 (6) ◽  
pp. E694-E704 ◽  
Author(s):  
Kei Fujioka ◽  
Kazuo Kajita ◽  
Zhiliang Wu ◽  
Takayuki Hanamoto ◽  
Takahide Ikeda ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Stromal Vascular Fraction ◽  
Common Mechanism ◽  
Reduced Body ◽  
Quantification Analysis

Several studies have suggested that both testosterone and dehydroepiandrosterone (DHEA) have weight-reducing and antidiabetic effects, especially in rodent studies; however, the precise mechanism of their action remains unclear. Here, we investigated the effect of DHEA on cell growth in adipose tissue. The appearance of senescence-associated β-galactosidase in stromal vascular fraction (SVF) isolated from Otsuka Long-Evans Tokushima fatty rats, an animal model of inherent obese type 2 diabetes, was prevented by DHEA administration. Next, the effects of DHEA and testosterone were compared in vivo and in vitro to evaluate whether these hormones influence cell growth in adipose tissue. Both DHEA and testosterone reduced body weight and epididymal fat weight equivalently when administered for 4 wk. To assess the effect of DHEA and testosterone on cell growth in adipose tissue, 5-bromo-2′-deoxyuridine (BrdU) uptake by SVF was measured. Quantification analysis of BrdU uptake by examining DNA isolated from each SVF revealed that treatment with DHEA and testosterone reduced cell replication. These results indicated that DHEA- and testosterone-induced decreased adiposity was associated with reduced SVF growth. Incubation with DHEA and testosterone equally decreased BrdU uptake by 3T3-L1 preadipocytes. Pretreatment with the androgen receptor (AR) inhibitor flutamide, but not the estrogen receptor inhibitor fulvestrant, abolished these effects. Knockdown of AR with siRNA also inhibited DHEA-induced decreases in BrdU uptake. These results suggest that DHEA-induced growth suppression of preadipocytes is mediated via AR. Therefore, both DHEA and testosterone similarly decrease adipocyte growth possibly via a common mechanism.

scholarly journals Generation of a Novel Transgenic Zebrafish for Studying Adipocyte Development and Metabolic Control

2021 ◽  
Vol 22 (8) ◽  
pp. 3994
Author(s):  
Yousheng Mao ◽  
Kwang-Heum Hong ◽  
Weifang Liao ◽  
Li Li ◽  
Seong-Jin Kim ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Fluorescent Protein ◽  
Therapeutic Interventions ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Adipose Tissues ◽  
Green Fluorescent

Zebrafish have become a popular animal model for studying various biological processes and human diseases. The metabolic pathways and players conserved among zebrafish and mammals facilitate the use of zebrafish to understand the pathological mechanisms underlying various metabolic disorders in humans. Adipocytes play an important role in metabolic homeostasis, and zebrafish adipocytes have been characterized. However, a versatile and reliable zebrafish model for long-term monitoring of adipose tissues has not been reported. In this study, we generated stable transgenic zebrafish expressing enhanced green fluorescent protein (EGFP) in adipocytes. The transgenic zebrafish harbored adipose tissues that could be detected using GFP fluorescence and the morphology of single adipocyte could be investigated in vivo. In addition, we demonstrated the applicability of this model to the long-term in vivo imaging of adipose tissue development and regulation based on nutrition. The transgenic zebrafish established in this study may serve as an excellent tool to advance the characterization of white adipose tissue in zebrafish, thereby aiding the development of therapeutic interventions to treat metabolic diseases in humans.

scholarly journals Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lisa Suwandhi ◽  
Irem Altun ◽  
Ruth Karlina ◽  
Viktorian Miok ◽  
Tobias Wiedemann ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Stromal Vascular Fraction ◽  
Tissue Expansion ◽  
White Adipocyte ◽  
The Metabolic Syndrome ◽  
Beige Adipocytes ◽  
Subcutaneous Adipose ◽  
Old Mice

AbstractAdipose tissue expansion, as seen in obesity, is often metabolically detrimental causing insulin resistance and the metabolic syndrome. However, white adipose tissue expansion at early ages is essential to establish a functional metabolism. To understand the differences between adolescent and adult adipose tissue expansion, we studied the cellular composition of the stromal vascular fraction of subcutaneous adipose tissue of two and eight weeks old mice using single cell RNA sequencing. We identified a subset of adolescent preadipocytes expressing the mature white adipocyte marker Asc-1 that showed a low ability to differentiate into beige adipocytes compared to Asc-1 negative cells in vitro. Loss of Asc-1 in subcutaneous preadipocytes resulted in spontaneous differentiation of beige adipocytes in vitro and in vivo. Mechanistically, this was mediated by a function of the amino acid transporter ASC-1 specifically in proliferating preadipocytes involving the intracellular accumulation of the ASC-1 cargo D-serine.

scholarly journals Brown preadipocyte transplantation locally ameliorates obesity

2021 ◽  
Vol 48 (4) ◽  
pp. 440-447
Author(s):  
Kento Takaya ◽  
Naruhito Matsuda ◽  
Toru Asou ◽  
Kazuo Kishi
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Uncoupling Protein ◽  
Tissue Loss ◽  
Whole Body ◽  
Obese Mouse ◽  
Fat Pad ◽  
Brown Adipose

Background Brown adipose tissue (BAT) is a potential target for anti-obesity treatments. Previous studies have shown that BAT activation causes an acute metabolic boost and reduces adiposity. Furthermore, BAT and BAT-derived cell transplantation reportedly help treat obesity by regulating glucose and fatty acid metabolism. However, since BAT transplantation leads to whole-body weight loss, we speculated that earlier approaches cause a generalized and unnecessary fat tissue loss, including in breast and hip tissues.Methods We transplanted white adipose tissue-derived or BAT-derived preadipocytes prepared from C57BL/6 mice into one side of the inguinal fat pads of an obese mouse model (db/ db mice) to examine whether it would cause fat loss at the peri-transplant site (n=5 each). The same volume of phosphate-buffered saline was injected as a control on the other side. Six weeks after transplantation, the inguinal fat pad was excised and weighed. We also measured the concentrations of glucose, triglycerides, fatty acids, and total cholesterol in the peripheral blood.Results BAT-derived preadipocytes showed abundant mitochondria and high levels of mitochondrial membrane uncoupling protein 1 expression, both in vivo and in vitro, with a remarkable reduction in weight of the inguinal fat pad after transplantation (0.17±0.12 g, P=0.043). Only free fatty acid levels tended to decrease in the BAT-transplanted group, but the difference was not significant (P=0.11).Conclusions Our results suggest that brown adipocytes drive fat degradation around the transplantation site. Thus, local transplantation of BAT-derived preadipocytes may be useful for treating obesity, as well as in cosmetic treatments.

scholarly journals Antiobesity Effects of Gentiana lutea Extract on 3T3-L1 Preadipocytes and a High-Fat Diet-Induced Mouse Model

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2453 ◽  
Author(s):  
Eunkuk Park ◽  
Chang Gun Lee ◽  
Junho Kim ◽  
Subin Yeo ◽  
Ji Ae Kim ◽  
...  
Keyword(s):  
Mouse Model ◽  
High Fat Diet ◽  
Glucose Transporter ◽  
Metabolic Diseases ◽  
Obese Mouse ◽  
High Fat ◽  
Messenger Ribonucleic Acid ◽  
Gentiana Lutea

Obesity is one of the most common metabolic diseases resulting in metabolic syndrome. In this study, we investigated the antiobesity effect of Gentiana lutea L. (GL) extract on 3T3-L1 preadipocytes and a high-fat-diet (HFD)-induced mouse model. For the induction of preadipocytes into adipocytes, 3T3-L1 cells were induced by treatment with 0.5 mM 3-isobutyl-1-methylxanthine, 1 mM dexamethasone, and 1 μg/mL insulin. Adipogenesis was assessed based on the messenger ribonucleic acid expression of adipogenic-inducing genes (adiponectin (Adipoq), CCAAT/enhancer-binding protein alpha (Cebpa), and glucose transporter type 4 (Slc2a4)) and lipid accumulation in the differentiated adipocytes was visualized by Oil Red O staining. In vivo, obese mice were induced with HFD and coadministered with 100 or 200 mg/kg/day of GL extract for 12 weeks. GL extract treatment inhibited adipocyte differentiation by downregulating the expression of adipogenic-related genes in 3T3-L1 cells. In the obese mouse model, GL extract prevented HFD-induced weight gain, fatty hepatocyte deposition, and adipocyte size by decreasing the secretion of leptin and insulin. In conclusion, GL extract shows antiobesity effects in vitro and in vivo, suggesting that this extract can be beneficial in the prevention of obesity.

scholarly journals HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signalling

Diabetologia ◽  
2021 ◽  
Author(s):  
Maude Giroud ◽  
Foivos-Filippos Tsokanos ◽  
Giorgio Caratti ◽  
Stefan Kotschi ◽  
Sajjad Khani ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adipose Tissue ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Gene Clusters ◽  
Data Availability ◽  
Primary Mouse

Abstract Aims/hypothesis Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of heart and neural crest derivatives-expressed 2 (HAND2) in adipogenesis. Methods Human white adipose tissue (WAT) was collected from two cross-sectional studies of 318 and 96 individuals. In vitro, for mechanistic experiments we used primary adipocytes from humans and mice as well as human multipotent adipose-derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from loxP and or tamoxifen-inducible Cre-ERT2 mouse models with Cre-encoding mRNA or tamoxifen, respectively. Adipogenesis and adipocyte metabolism were measured by Oil Red O staining, quantitative PCR (qPCR), microarray, glucose uptake assay, western blot and lipolysis assay. A combinatorial RNA sequencing (RNAseq) and ChIP qPCR approach was used to identify target genes regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (Hand2AdipoqCre) and performed a large panel of metabolic tests. Results We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was necessary but insufficient for adipocyte differentiation in vitro. In a large cohort of humans, WAT HAND2 expression was correlated to BMI. The HAND2 gene was enriched in white adipocytes compared with brown, induced early in differentiation and responded to dexamethasone (DEX), a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS cells or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR–HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that HAND2 was required at stages prior to Adipoq expression. Conclusions/interpretation In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in humans and mice. Data availability Array data have been submitted to the GEO database at NCBI (GSE148699). Graphical abstract

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