scholarly journals PPARγ-Independent Increase in Glucose Uptake and Adiponectin Abundance in Fat Cells

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3648-3660 ◽  
Author(s):  
Olga Dubuisson ◽  
Emily J. Dhurandhar ◽  
Rashmi Krishnapuram ◽  
Heather Kirk-Ballard ◽  
Alok K. Gupta ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glycemic Control ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Human Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Glucose Transporter 1

Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)γ induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPARγ or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPARγ, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPARγ and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected or human adenoviruses Ad36 or Ad2-infected cell types under the following conditions: 1) undifferentiated human-adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPARγ inhibitor, 4) NIH/3T3 that have impaired PPARγ expression, and 5) PPARγ-knockout mouse embryonic fibroblasts. Mouse embryonic fibroblasts with intact PPARγ served as a positive control. Additionally, to determine natural Ad36 infection, human sera were screened for Ad36 antibodies. In undifferentiated or differentiated hASC, or despite the inhibition, down-regulation, or the absence of PPARγ, Ad36 significantly enhanced glucose uptake and PPARγ, adiponectin, glucose transporter 4, and glucose transporter 1 protein abundance, compared with mock or Ad2-infected cells. This indicated that Ad36 up-regulates glucose uptake and adiponectin secretion independent of adipogenesis or without recruiting PPARγ. In humans, natural Ad36 infection predicted greater adiponectin levels, suggesting a human relevance of these effects. In conclusion, Ad36 provides a novel template to metabolically remodel human adipose tissue to enhance glycemic control without the concomitant increase in adiposity or PPARγ induction associated with TZD actions.

scholarly journals RalA controls glucose homeostasis by regulating glucose uptake in brown fat

2018 ◽  
Vol 115 (30) ◽  
pp. 7819-7824 ◽  
Author(s):  
Yuliya Skorobogatko ◽  
Morgan Dragan ◽  
Claudia Cordon ◽  
Shannon M. Reilly ◽  
Chao-Wei Hung ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Brown Fat ◽  
Specific Chemical ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Chemical Inhibitors ◽  
Glucose Transporter Glut4

Insulin increases glucose uptake into adipose tissue and muscle by increasing trafficking of the glucose transporter Glut4. In cultured adipocytes, the exocytosis of Glut4 relies on activation of the small G protein RalA by insulin, via inhibition of its GTPase activating complex RalGAP. Here, we evaluate the role of RalA in glucose uptake in vivo with specific chemical inhibitors and by generation of mice with adipocyte-specific knockout of RalGAPB. RalA was profoundly activated in brown adipose tissue after feeding, and its inhibition prevented Glut4 exocytosis. RalGAPB knockout mice with diet-induced obesity were protected from the development of metabolic disease due to increased glucose uptake into brown fat. Thus, RalA plays a crucial role in glucose transport in adipose tissue in vivo.

scholarly journals Glucocorticoids Enhance Intestinal Glucose Uptake Via the Dimerized Glucocorticoid Receptor in Enterocytes

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1783-1794 ◽  
Author(s):  
Sybille D. Reichardt ◽  
Michael Föller ◽  
Rexhep Rexhepaj ◽  
Ganesh Pathare ◽  
Kerstin Minnich ◽  
...  
Keyword(s):  
Small Intestine ◽  
Glucose Uptake ◽  
Molecular Mechanism ◽  
Glucose Transport ◽  
Transcriptional Control ◽  
Glucose Transporter ◽  
Gene Activation ◽  
Mouse Strains ◽  
Glucose Transporter 1

Glucocorticoid (GC) treatment of inflammatory disorders, such as inflammatory bowel disease, causes deranged metabolism, in part by enhanced intestinal resorption of glucose. However, the underlying molecular mechanism is poorly understood. Hence, we investigated transcriptional control of genes reported to be involved in glucose uptake in the small intestine after GC treatment and determined effects of GC on electrogenic glucose transport from transepithelial currents. GRvillinCre mice lacking the GC receptor (GR) in enterocytes served to identify the target cell of GC treatment and the requirement of the GR itself; GRdim mice impaired in dimerization and DNA binding of the GR were used to determine the underlying molecular mechanism. Our findings revealed that oral administration of dexamethasone to wild-type mice for 3 d increased mRNA expression of serum- and GC-inducible kinase 1, sodium-coupled glucose transporter 1, and Na+/H+ exchanger 3, as well as electrogenic glucose transport in the small intestine. In contrast, GRvillinCre mice did not respond to GC treatment, neither with regard to gene activation nor to glucose transport. GRdim mice were also refractory to GC, because dexamethasone treatment failed to increase both, gene expression and electrogenic glucose transport. In addition, the rise in blood glucose levels normally observed after GC administration was attenuated in both mutant mouse strains. We conclude that enhanced glucose transport in vivo primarily depends on gene regulation by the dimerized GR in enterocytes, and that this mechanism contributes to GC-induced hyperglycemia.

scholarly journals The Endogenous Cannabinoid System Stimulates Glucose Uptake in Human Fat Cells via Phosphatidylinositol 3-Kinase and Calcium-Dependent Mechanisms

2007 ◽  
Vol 92 (12) ◽  
pp. 4810-4819 ◽  
Author(s):  
Claudio Pagano ◽  
Catia Pilon ◽  
Alessandra Calcagno ◽  
Riccardo Urbanet ◽  
Marco Rossato ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Cannabinoid Receptors ◽  
Glucose Transporter ◽  
Peroxisome Proliferator ◽  
Fat Cells ◽  
Human Adipocytes ◽  
Cannabinoid System ◽  
Endogenous Cannabinoid ◽  
Endogenous Cannabinoid System

Abstract Background: The endogenous cannabinoid system participates in the regulation of energy balance, and its dysregulation may be implicated in the pathogenesis of obesity. Adipose tissue endocannabinoids may produce metabolic and endocrine effects, but very few data are available in human adipose tissue and in primary human fat cells. Experimental Design: We measured expression of type 1 and type 2 cannabinoid receptors (CNR), enzymes of cannabinoids synthesis and degradation in human omental, sc abdominal, and gluteal adipose tissue from lean and obese subjects. Furthermore, we assessed the effect of CNR1 stimulation on glucose uptake and intracellular transduction mechanisms in primary human adipocytes. Then we assessed the reciprocal regulation between CNR1 and peroxisome proliferator-activated receptor-γ (PPARγ). Finally, we tested whether leptin and adiponectin are regulated by CNR1 in human adipocytes. Results: We found that most genes of the endocannabinoid system are down-regulated in gluteal fat and up-regulated in visceral and sc abdominal adipose tissue of obese patients. Treatment of adipocytes with rosiglitazone markedly down-regulated CNR1 expression, whereas Win 55,212 up-regulated PPARγ. Win 55,212 increased (+50%) glucose uptake, the translocation of glucose transporter 4, and intracellular calcium in fat cells. All these effects were inhibited by SR141716 and wortmannin and by removing extracellular calcium. Win 55,212 and SR141716 had no effect on expression of adiponectin and leptin. Conclusions: These results indicate a role for the local endocannabinoids in the regulation of glucose metabolism in human adipocytes and suggest a role in channeling excess energy fuels to adipose tissue in obese humans.

scholarly journals Impacts of rat hindlimb Fndc5/irisin overexpression on muscle and adipose tissue metabolism

2020 ◽  
Vol 318 (6) ◽  
pp. E943-E955
Author(s):  
W. Farrash ◽  
M. Brook ◽  
H. Crossland ◽  
B. E. Phillips ◽  
J. Cegielski ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Mitochondrial Biogenesis ◽  
Glucose Transporter ◽  
Glycogen Synthase ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Subcutaneous Fat ◽  
Tolerance Test

Myokines, such as irisin, have been purported to exert physiological effects on skeletal muscle in an autocrine/paracrine fashion. In this study, we aimed to investigate the mechanistic role of in vivo fibronectin type III domain-containing 5 (Fndc5)/irisin upregulation in muscle. Overexpression (OE) of Fndc5 in rat hindlimb muscle was achieved by in vivo electrotransfer, i.e., bilateral injections of Fndc5 harboring vectors for OE rats ( n = 8) and empty vector for control rats ( n = 8). Seven days later, a bolus of D2O (7.2 mL/kg) was administered via oral gavage to quantify muscle protein synthesis. After an overnight fast, on day 9, 2-deoxy-d-glucose-6-phosphate (2-DG6P; 6 mg/kg) was provided during an intraperitoneal glucose tolerance test (2 g/kg) to assess glucose handling. Animals were euthanized, musculus tibialis cranialis muscles and subcutaneous fat (inguinal) were harvested, and metabolic and molecular effects were evaluated. Muscle Fndc5 mRNA increased with OE (~2-fold; P = 0.014), leading to increased circulating irisin (1.5 ± 0.9 to 3.5 ± 1.2 ng/mL; P = 0.049). OE had no effect on protein anabolism or mitochondrial biogenesis; however, muscle glycogen was increased, along with glycogen synthase 1 gene expression ( P = 0.04 and 0.02, respectively). In addition to an increase in glycogen synthase activation in OE ( P = 0.03), there was a tendency toward increased glucose transporter 4 protein ( P = 0.09). However, glucose uptake (accumulation of 2-DG6P) was identical. Irisin elicited no endocrine effect on mitochondrial biogenesis or uncoupling proteins in white adipose tissue. Hindlimb overexpression led to physiological increases in Fndc5/irisin. However, our data indicate limited short-term impacts of irisin in relation to muscle anabolism, mitochondrial biogenesis, glucose uptake, or adipose remodeling.

scholarly journals Mat1 Inhibits Peroxisome Proliferator-Activated Receptor γ-Mediated Adipocyte Differentiation

2008 ◽  
Vol 29 (2) ◽  
pp. 315-323 ◽  
Author(s):  
Katja Helenius ◽  
Ying Yang ◽  
Jukka Alasaari ◽  
Tomi P. Mäkelä
Keyword(s):  
Adipocyte Differentiation ◽  
Peroxisome Proliferator ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Adipose Tissues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mammalian Tissues ◽  
Basal Transcription Factors ◽  
Critical Differentiation

ABSTRACT Mammalian Cdk7, cyclin H, and Mat1 form the kinase submodule of transcription factor IIH (TFIIH) and have been considered ubiquitously expressed elements of the transcriptional machinery. Here we found that Mat1 and Cdk7 levels are undetectable in adipose tissues in vivo and downregulated during adipogenesis, where activation of peroxisome proliferator-activated receptor γ (PPARγ) acts as a critical differentiation switch. Using both Mat1 −/− mouse embryonic fibroblasts and Cdk7 knockdown approaches, we show that the Cdk7 complex is an inhibitor of adipogenesis and is required for inactivation of PPARγ through the phosphorylation of PPARγ-S112. The results demonstrate that the Cdk7 submodule of TFIIH acts as a physiological roadblock to adipogenesis by inhibiting PPARγ activity. The observation that components of TFIIH are absent from transcriptionally active adipose tissue prompts a reevaluation of the ubiquitous nature of basal transcription factors in mammalian tissues.

scholarly journals Characterization of Viral Insulin-Like Peptides Reveals Unique White Adipose Tissue Specific Characteristics

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A437-A438
Author(s):  
Martina Chrudinova ◽  
Moreau Francois ◽  
Hye Lim Noh ◽  
Terezie Panikova ◽  
Lenka Zakova ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Human Insulin ◽  
White Adipose Tissue ◽  
Glucose Transporter ◽  
Single Chain ◽  
Insulin Superfamily ◽  
Brown Adipose

Abstract The members of the insulin superfamily are well conserved across the evolution tree. We recently showed that four viruses in the Iridoviridae family possess genes that share high similarity with human insulin and IGF-1. By chemically synthesizing single chain (sc, IGF-1 like) forms of these viral insulin/IGF-1 like peptides (VILPs), we previously showed that sc VILPs have insulin/IGF properties in vitro and in vivo. However, characteristics of double chain (dc, insulin-like) VILPs remain unknown. In this study, we characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). We showed that GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and they bind to IGF-1R with a higher affinity than human insulin. These dcVILPs stimulate receptor phosphorylation and post-receptor signaling in vitro and in vivo. LCDV-1 dcVILP stimulated a weak response in in vitro signaling experiments, although we could not determine binding competition. Both GIV and SGIV dcVILPs stimulated glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (2.5 mU/kg/min) and GIV dcVILP (125 mU/kg/min) stimulate a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulates ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This is due to increased Akt phosphorylation and glucose transporter type 4 (GLUT4) expression compared to insulin specifically in WAT. Taken together, these results show that dc GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. This observation evokes questions about their potential roles in human disease including diabetes and cancer. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action and design new analogues that specifically target the tissues.

scholarly journals Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice

2020 ◽  
Author(s):  
Martina Chrudinová ◽  
Francois Moreau ◽  
Hye Lim Noh ◽  
Terezie Páníková ◽  
Lenka Žáková ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Human Insulin ◽  
White Adipose Tissue ◽  
Glucose Transporter ◽  
Single Chain ◽  
Lymphocystis Disease Virus ◽  
Brown Adipose

ABSTRACTMembers of the insulin/IGF superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single chain (sc), i.e. IGF-1-like, forms of the viral insulin/IGF-1 like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e. more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and to the IGF1R, and for the latter show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75nmol/kg/min) stimulated a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulated ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin. Taken together, these results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogues that specifically target the tissues, and provide new insights into their potential role in disease.

scholarly journals Quercetin-3-O-glucoside Improves Glucose Tolerance in Rats and Decreases Intestinal Sugar Uptake in Caco-2 Cells

2017 ◽  
Vol 12 (11) ◽  
pp. 1934578X1701201 ◽  
Author(s):  
Denys Torres-Villarreal ◽  
Alberto Camacho ◽  
Fermín I. Milagro ◽  
Rocío Ortiz-Lopez ◽  
Ana Laura de la Garza
Keyword(s):  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
In Vivo Studies ◽  
Sugar Uptake ◽  
Oral Glucose ◽  
Rt Pcr ◽  
Glucose Transporter 1 ◽  
Glucose Transporter 2

Flavonoid-rich foods intake has been associated with lower risk of non-communicable chronic diseases. Quercetin is the most abundant flavonoid in nature (fruits, vegetables, leaves and grains) as well as the most consumed flavonol. This study aims to investigate the potential effects of its conjugated form quercetin-3- O-glucoside (or isoquercetin) on glucose metabolism in rats and Caco-2 cells. To analyse the effect of quercetin-3- O-glucoside on postprandial hyperglycemia, an oral glucose tolerance test (OGTT) was conducted in Wistar rats. Additionally, Caco-2 cells were used to determine the effect of quercetin-3- O-glucoside (30 to 60 μM) on mRNA expression of genes involved in glucose uptake by RT-PCR. Thereby, in vivo studies demonstrated that quercetin-3- O-glucoside decreased blood glucose levels evaluated by OGTT in rats. Furthermore, in the presence of Na+, quercetin-3- O-glucoside inhibited methylglucoside (MG) uptake in enterocytes and both sodium dependent glucose transporter-1 (SGLT1)- and glucose transporter-2 (GLUT2)-mediated glucose uptake were downregulated in Caco-2 cells incubated with quercetin-3- O-glucoside. In summary, our results show that quercetin-3- O-glucoside improves postprandial glycemic control in rats and reduces sugar uptake in Caco-2 cells, possible by decreasing the expression of glucose transporters (SGLT1 and GLUT2) according to the results obtained through RT-PCR.

scholarly journals INSULIN GROWTH FACTOR I AND ITS RECEPTOR ARE ANTAGONISTIC MODULATORS OF GLUCOSE HANDLING BY ASTROCYTES

2015 ◽  
Author(s):  
Edwin Hernandez ◽  
Ana M Fernandez ◽  
Alberto Perez Alvarez ◽  
Sara Mederos ◽  
Paloma Perez Domper ◽  
...  
Keyword(s):  
Growth Factor ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Brain Slices ◽  
Glucose Transporter 1 ◽  
Factor I ◽  
Igf I ◽  
Pharmacological Blockade ◽  
Growth Factor I

Reducing insulin-like growth factor I receptor (IGF-IR) levels or administration of IGF-I show beneficial effects in the brain. We now provide evidence to help resolve this paradox. The unliganded IGF-IR inhibits glucose uptake by astrocytes while its stimulation with IGF-I, in concert with insulin activation of the insulin receptor, produces the opposite effect. In vivo imaging showed that shRNA interference of brain IGF-IR increased glucose uptake by astrocytes while pharmacological blockade of IGF-IR reduced it. Brain 18FGlucose-PET of IGF-IR shRNA injected mice confirmed an inhibitory role of unliganded IGF-IR on glucose uptake, whereas glucose-dependent recovery of neuronal activity in brain slices was blunted by pharmacological blockade of IGF-IR. Mechanistically, we found that the unliganded IGF-IR retains glucose transporter 1 (GLUT1), the main glucose transporter in astrocytes, inside the cell while IGF-I, in cooperation with insulin, synergistically stimulates MAPK/PKD to promote association of IGF-IR with GLUT 1 via Rac1/GIPC1 and increases GLUT1 availability at the cell membrane. These findings identify IGF-I and its receptor as antagonistic modulators of brain glucose uptake.

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.

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