scholarly journals IL-25–induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice

PLoS Biology ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. e3001348
Author(s):  
Lingyi Li ◽  
Lei Ma ◽  
Zewei Zhao ◽  
Shiya Luo ◽  
Baoyong Gong ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Macrophage Polarization ◽  
Alternative Activation ◽  
Adrenoceptor Agonist ◽  
Beige Fat

Beige fat dissipates energy and functions as a defense against cold and obesity, but the mechanism for its development is unclear. We found that interleukin (IL)-25 signaling through its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue after cold exposure and β3-adrenoceptor agonist stimulation. IL-25 induced beige fat formation in white adipose tissue (WAT) by releasing IL-4 and IL-13 and promoting alternative activation of macrophages that regulate innervation and up-regulate tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine (NE). Blockade of IL-4Rα or depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the beige fat formation in WAT. Mice fed with a high-fat diet (HFD) were protected from obesity and related metabolic disorders when given IL-25 through a process that involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling in WAT may have therapeutic potential for controlling obesity and its associated metabolic disorders.

scholarly journals IL-25 induces beige fat to improve metabolic homeostasis via macrophage and innervation

2018 ◽  
Author(s):  
Lingyi Li ◽  
Lei Ma ◽  
Juan Feng ◽  
Baoyong Gong ◽  
Jin Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Therapeutic Potential ◽  
Uncoupling Protein ◽  
Alternative Activation ◽  
Adrenoceptor Agonist ◽  
Beige Fat ◽  
Underlying Mechanisms

SummaryBeige fat dissipates energy and functions as a defense against cold and obesity, but the underlying mechanisms remain unclear. We found that the signaling of interleukin (IL)-25 including its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue upon cold and β3-adrenoceptor agonist stimulation. IL-25 induced the browning effect in white adipose tissue (WAT) by releasing IL-4, 13 and promoting alternative activation of macrophages to regulate innervation, which characterized as tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine. Blockade of IL-4Rα and depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the browning of WAT. Obese mice administered with IL-25 were protected from obesity on a high-fat diet and the subsequent metabolic disorders, and the process involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling on beige fat might play a therapeutic potential for obesity and its associated metabolic disorders.

scholarly journals Browning Effects of a Chronic Pterostilbene Supplementation in Mice Fed a High-Fat Diet

2019 ◽  
Vol 20 (21) ◽  
pp. 5377 ◽  
Author(s):  
Martina La Spina ◽  
Eva Galletta ◽  
Michele Azzolini ◽  
Saioa Gomez Zorita ◽  
Sofia Parrasia ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Uncoupling Protein ◽  
Protein A ◽  
Health Concern ◽  
Marker Genes ◽  
High Fat ◽  
Protein Levels

Obesity and related comorbidities are a major health concern. The drugs used to treat these conditions are largely inadequate or dangerous, and a well-researched approach based on nutraceuticals would be highly useful. Pterostilbene (Pt), i.e., 3,5-dimethylresveratrol, has been reported to be effective in animal models of obesity, acting on different metabolic pathways. We investigate here its ability to induce browning of white adipose tissue. Pt (5 µM) was first tested on 3T3-L1 mature adipocytes, and then it was administered (352 µmol/kg/day) to mice fed an obesogenic high-fat diet (HFD) for 30 weeks, starting at weaning. In the cultured adipocytes, the treatment elicited a significant increase of the levels of Uncoupling Protein 1 (UCP1) protein—a key component of thermogenic, energy-dissipating beige/brown adipocytes. In vivo administration antagonized weight increase, more so in males than in females. Analysis of inguinal White Adipose Tissue (WAT) revealed a trend towards browning, with significantly increased transcription of several marker genes (Cidea, Ebf2, Pgc1α, PPARγ, Sirt1, and Tbx1) and an increase in UCP1 protein levels, which, however, did not achieve significance. Given the lack of known side effects of Pt, this study strengthens the candidacy of this natural phenol as an anti-obesity nutraceutical.

scholarly journals In vivo emergence of beige-like fat in chickens as physiological adaptation to cold environments

Amino Acids ◽  
2021 ◽  
Vol 53 (3) ◽  
pp. 381-393
Author(s):  
Rina Sotome ◽  
Akira Hirasawa ◽  
Motoi Kikusato ◽  
Taku Amo ◽  
Kyohei Furukawa ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Morphological Characteristics ◽  
Physiological Adaptation ◽  
Voltage Dependent Anion Channel ◽  
Adaptation To Cold ◽  
Cold Environments ◽  
Beige Fat

AbstractWhile it has been hypothesized that brown adipocytes responsible for mammalian thermogenesis are absent in birds, the existence of beige fat has yet to be studied directly. The present study tests the hypothesis that beige fat emerges in birds as a mechanism of physiological adaptation to cold environments. Subcutaneous neck adipose tissue from cold-acclimated or triiodothyronine (T3)-treated chickens exhibited increases in the expression of avian uncoupling protein (avUCP, an ortholog of mammalian UCP2 and UCP3) gene and some known mammalian beige adipocyte-specific markers. Morphological characteristics of white adipose tissues of treated chickens showed increased numbers of both small and larger clusters of multilocular fat cells within the tissues. Increases in protein levels of avUCP and mitochondrial marker protein, voltage-dependent anion channel, and immunohistochemical analysis for subcutaneous neck fat revealed the presence of potentially thermogenic mitochondria-rich cells. This is the first evidence that the capacity for thermogenesis may be acquired by differentiating adipose tissue into beige-like fat for maintaining temperature homeostasis in the subcutaneous fat ‘neck warmer’ in chickens exposed to a cold environment.

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 TAF7L modulates brown adipose tissue formation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Haiying Zhou ◽  
Bo Wan ◽  
Ivan Grubisic ◽  
Tommy Kaplan ◽  
Robert Tjian
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Core Promoter ◽  
Uncoupling Protein ◽  
Dna Looping ◽  
Chromatin Interactions ◽  
Brown Adipose ◽  
Important Regulator

Brown adipose tissue (BAT) plays an essential role in metabolic homeostasis by dissipating energy via thermogenesis through uncoupling protein 1 (UCP1). Previously, we reported that the TATA-binding protein associated factor 7L (TAF7L) is an important regulator of white adipose tissue (WAT) differentiation. In this study, we show that TAF7L also serves as a molecular switch between brown fat and muscle lineages in vivo and in vitro. In adipose tissue, TAF7L-containing TFIID complexes associate with PPARγ to mediate DNA looping between distal enhancers and core promoter elements. Our findings suggest that the presence of the tissue-specific TAF7L subunit in TFIID functions to promote long-range chromatin interactions during BAT lineage specification.

scholarly journals JAZF1 heterozygous knockout mice show altered adipose development and metabolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jain Jeong ◽  
Soyoung Jang ◽  
Song Park ◽  
Wookbong Kwon ◽  
Si-Yong Kim ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Knockout Mice ◽  
Metabolic Disorders ◽  
Adipocyte Differentiation ◽  
Zinc Finger Protein ◽  
Tissue Mass ◽  
In Vivo Models ◽  
Brown Adipose

Abstract Background Juxtaposed with another zinc finger protein 1 (JAZF1) is associated with metabolic disorders, including type 2 diabetes mellitus (T2DM). Several studies showed that JAZF1 and body fat mass are closely related. We attempted to elucidate the JAZF1 functions on adipose development and related metabolism using in vitro and in vivo models. Results The JAZF1 expression was precisely regulated during adipocyte differentiation of 3T3-L1 preadipocyte and mouse embryonic fibroblasts (MEFs). Homozygous JAZF1 deletion (JAZF1-KO) resulted in impaired adipocyte differentiation in MEF. The JAZF1 role in adipocyte differentiation was demonstrated by the regulation of PPARγ—a key regulator of adipocyte differentiation. Heterozygous JAZF1 deletion (JAZF1-Het) mice fed a normal diet (ND) or a high-fat diet (HFD) had less adipose tissue mass and impaired glucose homeostasis than the control (JAZF1-Cont) mice. However, other metabolic organs, such as brown adipose tissue and liver, were negligible effect on JAZF1 deficiency. Conclusion Our findings emphasized the JAZF1 role in adipocyte differentiation and related metabolism through the heterozygous knockout mice. This study provides new insights into the JAZF1 function in adipose development and metabolism, informing strategies for treating obesity and related metabolic disorders.

scholarly journals Multinucleated giant cells in adipose tissue are specialized in adipocyte degradation

2020 ◽  
Author(s):  
Ada Admin ◽  
Julia Braune ◽  
Andreas Lindhorst ◽  
Janine Fröba ◽  
Constance Hobusch ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Giant Cells ◽  
Low Grade ◽  
Adipose Tissue Macrophages ◽  
Visceral Adipose ◽  
Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation in visceral adipose tissue (AT) characterized by an increasing number of adipose tissue macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures (CLS), as accumulation of ATMs around dying adipocytes, and the occurrence of multi-nucleated giant cells (MGCs). However to date, the function of MGCs in obesity is unknown. Hence, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. <p>We demonstrate that MGCs occur in obese patients and after 24 weeks of high fat diet (HFD) in mice, accompanying signs of AT inflammation and then represent ~3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggers MGC formation. Most importantly, MGCs in obese AT have a higher capacity to phagocytose oversized particles, such as adipocytes, as shown by live-imaging of AT, 45 µm bead uptake <i>ex vivo</i> and a higher lipid content <i>in vivo</i>. Finally, we show that IL-4 treatment is sufficient to increase the number of MGCs in AT, whereas other factors maybe more important for endogenous MGC formation <i>in vivo</i>.</p>

Effects of intravenous isoproterenol (β-agonist) administration on expression and synthesis of ovine uncoupling protein-1

1999 ◽  
Vol 1999 ◽  
pp. 164-164
Author(s):  
D.S. Finn ◽  
P. Trayhurn ◽  
J. Struthers ◽  
M.A. Lomax
Keyword(s):  
Adipose Tissue ◽  
Cold Stress ◽  
Uncoupling Protein ◽  
Uncoupling Protein 1 ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Uncoupling Protein ◽  
Neonatal Life ◽  
Adrenoceptor Agonist ◽  
Brown Adipose

A crucial factor in the prevention of hypothermia in the neonatal lamb is the functional activitation of a mitochondrial uncoupling protein (UCP1) in brown adipose tissue. UCP1 disappears from lamb brown fat over the first 14 days of life (Finn et al., 1998), but it is not known whether this process can be modulated in lambs by the release of catecholamines which have been established in rodents as a mediator of the response to cold stress. This study examines the effect of administering a β-adrenoceptor agonist on the disappearance of UCP1 and UCP1 mRNA during early neonatal life, using immunohistochemistry and in situ hybridization.

P2572Human iPSC-derived cardiomyocytes preserve murine heart function after myocardial infarction unlike adipose tissue-derived stromal cells

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Dulak ◽  
J Stepniewski ◽  
M Tomczyk ◽  
K Andrysiak ◽  
I Kraszewska ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Adipose Tissue ◽  
Stromal Cells ◽  
Luciferase Activity ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Rational Approach ◽  
Acute Mi ◽  
In Vivo Administration

Abstract Introduction Despite progress in pharmacological treatment of myocardial infarction (MI), there is still an immense need for novel therapies for this life-threatening condition. Accordingly, cell-based therapies have been extensively investigated with most studies focusing on mesenchymal stromal cells. However due to their inability to differentiate into cardiomyocytes as well as limited survival upon in vivo administration, no effective treatment of MI has been developed. In contrast, application of hiPSC-derived cardiomyocytes (hiPSC-CM) represent biologically rational approach with pre-clinical studies confirming their therapeutic potential in various models of MI. However further optimization is required due to limited survival of hiPSC-CM upon in vivo administration. Therefore, we evaluated the therapeutic potential of genetically modified hiPSC-CM in murine model of acute MI and compared it to the effect of adipose tissue-derived stromal cells (ADSC). Methods In the first step hiPSC overexpressing GFP, luciferase (Luc) and pro-angiogenic and cardioprotective factors: heme oxygenase-1 (HO-1, heme degrading enzyme) or stromal cell-derived factor-1 (SDF-1, pro-angiogenic chemokine) were subjected to cardiac differentiation which yielded in each group 70–90% cardiac troponin T-positive contracting cells. hiPSC-CM (5x105 in 10 μl) were administered into NOD-SCID mice which underwent permanent ligation of left anterior descending (LAD) coronary artery. The cells were injected into the peri-infarct zone. Mice subjected to sham operation as well as injected with saline after MI were used as controls. The ultrasonography of hearts was performed on day 7, 14, 28 and 42 whereas the presence of hiPSC-CM was monitored using IVIS Spectrum system upon administration of luciferin and analysed in sections of collected hearts. The same experimental scheme was used to assess therapeutic potential of ADSC (CD105+CD73+CD90+CD44+CD146-CD34-) overexpressing luciferase and GFP. Results Ultrasonography demonstrated that upon delivery of hiPSC-CM the left ventricle ejection fraction (LVEF) was very significantly higher in comparison to control group injected with saline after induction of MI. In contrast, no improvement of LVEF was observed after administration of ADSC. Interestingly, measurements of luciferase activity revealed the strongest bioluminescent signal in the hearts of mice transplanted with iPSC-CM-HO1 42 days after MI. Importantly, the survival of hiPSC-CM in murine myocardium six weeks upon administration was further confirmed with immunofluorescent analysis of heart sections using human specific anti-Ku80 antibody. Again, luciferase activity was not observed upon delivery of ADSC. Conclusion These results strongly indicate that administration of hiPSC-CM, unlike ADSC, preserve murine heart function in acute MI model. Additionally, overexpression of HO-1 may positively influence their survival upon in vivo delivery into infarcted tissue. Acknowledgement/Funding The National Centre for Research and Development (STRATEGMED 2/269415/11/NCBR/2015), National Science Centre of Poland (HARMONIA 2014/14/M/NZ1/00010)

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