scholarly journals Aberrant Ca2+ homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity

2020 ◽  
Author(s):  
Ekin Guney ◽  
Ana Paula Arruda ◽  
Gunes Parlakgul ◽  
Erika Cagampan ◽  
Nina Min ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Dependent Manner ◽  
Metabolic Inflammation ◽  
Metabolic Dysregulation ◽  
Initiation And Propagation ◽  
Impaired Insulin Action

SummaryChronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+ channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposure in vitro or by obesity in vivo lead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+ and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+ is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+ homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity.

scholarly journals Exposure to the Widely Used Pyrethroid Pesticide Deltamethrin, Does Not Exacerbate High Fat Diet Induced Obesity or Insulin Resistance in C57BL/6J Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A45-A46
Author(s):  
Evangelia Evelyn Tsakiridis ◽  
Marisa Morrow ◽  
Andrea Llanos ◽  
Bo Wang ◽  
Alison Holloway ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glycemic Control ◽  
Metabolic Diseases ◽  
Uncoupling Protein ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Pyrethroid Pesticide ◽  
First Time

Abstract Deltamethrin is a commonly used pesticide for the control of mosquito populations. Despite widespread use, the effects of deltamethrin on adiposity and glucose homeostasis have been equivocal with some studies showing increased, decreased and no effect on adiposity and glycemic control. However, no study to date has investigated the effect of deltamethrin in mice housed at thermoneutral temperatures, which is important for modelling metabolic diseases in rodents due to reduced thermal stress and constitutive activation of brown adipose tissue. In the current study we demonstrate for the first time that deltamethrin reduces uncoupling protein-1 expression in brown adipocytes cultured in vitro at concentrations as low as 1pm. Meanwhile, in-vivo deltamethrin does not appear to alter glycemic control or promote adiposity at exposures equivalent to 0.01, 0.1 or 1.0 mg/kg/day. Together, our study demonstrates environmentally relevant exposure to deltamethrin does not exacerbate diet induced obesity or insulin resistance.

scholarly journals Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

2016 ◽  
Vol 291 (33) ◽  
pp. 17066-17076 ◽  
Author(s):  
Carrie M. Elks ◽  
Peng Zhao ◽  
Ryan W. Grant ◽  
Hardy Hang ◽  
Jennifer L. Bailey ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cell Types ◽  
Oncostatin M ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Fat Feeding

Oncostatin M (OSM) is a multifunctional gp130 cytokine. Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor β (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. In vivo, we generated a mouse line lacking Osmr in adiponectin-expressing cells (OSMRFKO mice). The effects of OSM on gene expression were also assessed in vitro and in vivo. OSM exerts proinflammatory effects on cultured adipocytes that are partially rescued by Osmr knockdown. Osm expression is significantly increased in adipose tissue T cells of high fat-fed mice. In addition, adipocyte Osmr expression is increased following high fat feeding. OSMRFKO mice exhibit increased insulin resistance and adipose tissue inflammation and have increased lean mass, femoral length, and bone volume. Also, OSMRFKO mice exhibit increased expression of Osm, the T cell markers Cd4 and Cd8, and the macrophage markers F4/80 and Cd11c. Interestingly, the same proinflammatory genes induced by OSM in adipocytes are induced in the adipose tissue of the OSMRFKO mouse, suggesting that increased expression of proinflammatory genes in adipose tissue arises both from adipocytes and other cell types. These findings suggest that adipocyte OSMR signaling is involved in the regulation of adipose tissue homeostasis and that, in obesity, OSMR ablation may exacerbate insulin resistance by promoting adipose tissue inflammation.

scholarly journals PPARγ regulates adipose triglyceride lipase in adipocytes in vitro and in vivo

2007 ◽  
Vol 293 (6) ◽  
pp. E1736-E1745 ◽  
Author(s):  
Erin E. Kershaw ◽  
Michael Schupp ◽  
Hong-Ping Guan ◽  
Noah P. Gardner ◽  
Mitchell A. Lazar ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Protein Synthesis Inhibitor ◽  
Adipose Triglyceride Lipase ◽  
Dependent Manner ◽  
Triglyceride Lipase ◽  
Brown Adipose

Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARγ to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARγ agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARγ-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARγ, supporting the direct transcriptional regulation of ATGL by PPARγ. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARγ positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARγ's effects on lipid metabolism.

scholarly journals Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

Diabetes Care ◽  
2013 ◽  
Vol 36 (12) ◽  
pp. 4083-4090 ◽  
Author(s):  
H. Sell ◽  
M. Bluher ◽  
N. Kloting ◽  
R. Schlich ◽  
M. Willems ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4

scholarly journals Interleukin-6 Depletion Selectively Improves Hepatic Insulin Action in Obesity

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3417-3427 ◽  
Author(s):  
Peter J. Klover ◽  
Alicia H. Clementi ◽  
Robert A. Mooney
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Stat3 Phosphorylation ◽  
Insulin Dependent ◽  
Significant Change

Abstract Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lepob mice by injection of IL-6-neutralizing antibody. In untreated Lepob mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lepob mice, in contrast to only 32% in Lepob controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lepob mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer473) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.

scholarly journals Immunomodulatory Effects of Adipose Tissue-Derived Stem Cells on Concanavalin A-Induced Acute Liver Injury in Mice

Cell Medicine ◽  
2017 ◽  
Vol 9 (1-2) ◽  
pp. 21-33 ◽  
Author(s):  
Yasuma Yoshizumi ◽  
Hiroshi Yukawa ◽  
Ryoji Iwaki ◽  
Sanae Fujinaka ◽  
Ayano Kanou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Mouse Model ◽  
Cell Therapy ◽  
Concanavalin A ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Immunomodulatory Effects

Cell therapy with adipose tissue-derived stem cells (ASCs) is expected to be a candidate for the treatment of fulminant hepatic failure (FHF), which is caused by excessive immune responses. In order to evaluate the therapeutic effects of ASCs on FHF, the in vitro and in vivo immunomodulatory effects of ASCs were examined in detail in the mouse model. The in vitro effects of ASCs were examined by assessing their influence on the proliferation of lymphomononuclear cells (LMCs) stimulated with three kinds of mitogens: phorbol 12-myristate 13-acetate (PMA) plus ionomycin, concanavalin A (ConA), and lipopolysaccharide (LPS). The proliferation of LMCs was efficiently suppressed in a dose-dependent manner by ASCs in the cases of PMA plus ionomycin stimulation and ConA stimulation, but not in the case of LPS stimulation. The in vivo effects of transplanted ASCs were examined in the murine FHF model induced by ConA administration. The ALT levels and histological inflammatory changes in the ConA-administered mice were apparently relieved by the transplantation of ASCs. The analysis of mRNA expression patterns in the livers indicated that the expressions of the cytokines such as Il-6, Il-10, Ifn-γ, and Tnf-α, and the cell surface markers such as Cd3γ, Cd4, Cd8α, Cd11b, and Cd11c were downregulated in the ASC-transplanted mice. The immunomodulatory and therapeutic effects of ASCs were confirmed in the mouse model both in vitro and in vivo. These suggest that the cell therapy with ASCs is beneficial for the treatment of FHF.

scholarly journals Tributyrin attenuates obesity-associated inflammation and insulin resistance in high-fat-fed mice

2012 ◽  
Vol 303 (2) ◽  
pp. E272-E282 ◽  
Author(s):  
Marco Aurélio Ramirez Vinolo ◽  
Hosana G. Rodrigues ◽  
William T. Festuccia ◽  
Amanda R. Crisma ◽  
Vitor S. Alves ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Plasma Lipid ◽  
Peritoneal Macrophages ◽  
High Fat ◽  
Beneficial Effects ◽  
Treatment And Prevention ◽  
Inflammatory Status

The aim of this study was to investigate whether treatment with tributyrin (Tb; a butyrate prodrug) results in protection against diet-induced obesity and associated insulin resistance. C57BL/6 male mice fed a standard chow or high-fat diet were treated with Tb (2 g/kg body wt, 10 wk) and evaluated for glucose homeostasis, plasma lipid profile, and inflammatory status. Tb protected mice against obesity and obesity-associated insulin resistance and dyslipidemia without food consumption being affected. Tb attenuated the production of TNFα and IL-1β by peritoneal macrophages and their expression in adipose tissue. Furthermore, in the adipose tissue, Tb reduced the expression of MCP-1 and infiltration by leukocytes and restored the production of adiponectin. These effects were associated with a partial reversion of hepatic steatosis, reduction in liver and skeletal muscle content of phosphorylated JNK, and an improvement in muscle insulin-stimulated glucose uptake and Akt signaling. Although part of the beneficial effects of Tb are likely to be secondary to the reduction in body weight, we also found direct protective actions of butyrate reducing TNFα production after LPS injection and in vitro by LPS- or palmitic acid-stimulated macrophages and attenuating lipolysis in vitro and in vivo. The results, reported herein, suggest that Tb may be useful for the treatment and prevention of obesity-related metabolic disorders.

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.

Abstract 630: Novel Chimeric Anti-proteoglycan Antibody Inhibits Arterial Retention of Proatherogenic Lipoproteins in a Rat Model of Insulin Resistance

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Yosdel Soto ◽  
Rabban Mangat ◽  
Ana M Vázquez ◽  
Spencer D Proctor
Keyword(s):  
Insulin Resistance ◽  
Monoclonal Antibody ◽  
Ex Vivo ◽  
Dependent Manner ◽  
Insulin Resistant ◽  
Remnant Lipoproteins ◽  
Preferential Binding ◽  
Carotid Vessels

Background: The response-to-retention hypothesis for atherosclerosis describes subendothelial retention of apolipoprotein B-containing lipoproteins mediated by proteoglycans (PG). Further we know that diabetes is also associated with both increased circulating chylomicron remnants and remodeling of proatherogenic PGs. We have recently reported antiatherogenic properties of a novel chimeric monoclonal antibody (chP3R99) that recognizes PG sulfated molecules. Hypothesis: chP3R99 monoclonal antibody may interfere with the interaction of atherogenic lipoproteins with arterial sulfated PGs during insulin resistance. Methods and Results: chP3R99 antibody recognized sulfated glycosaminoglycans by ELISA showing a preferential binding to chondroitin sulfate. Also, chP3R99 blocked the interaction of proatherogenic lipoproteins with this glycosaminoglycan in vitro in a dose-dependent manner and its intravenous injection into healthy Sprague-Dawly rats (n=6, 1 mg/animal) inhibited LDL (4 mg/kg; intraperitoneally) aortic retention. To further assess this property in an insulin resistant condition, carotid arteries from control and JCR:LA-cp rats (n=4) were perfused ex vivo with apoB48 containing remnant lipoproteins (prepared via rabbit hepatectomy procedure), with or without Cy3-LDL (150 μg/mL) for 20 minutes. Confocal microscopy analysis revealed an increased arterial retention of both remnants (3.6 fold) and LDL (2.8 fold) in carotid vessels from insulin resistant rats relative to control. However, chP3R99 pre-perfusion resulted in decreased retention of remnants (-30%) and LDL (-60%) associated arterial cholesterol. Data suggests that the chP399 antibody may interfere with the arterial attachment of both remnants and LDL in vivo, but with differential efficacy. Conclusions: Relative to LDL, remnant lipoproteins had preferential accumulation in arterial vessels from insulin resistant rats ex vivo , which could then be inhibited by acute pre-exposure to the chP3R99 antibody. These in vivo data support the concept for an innovative approach to target the retention of proatherogenic lipoproteins in a pre-clinical setting.

Impaired insulin action in subcutaneous adipocytes from women with visceral obesity

2001 ◽  
Vol 280 (1) ◽  
pp. E40-E49 ◽  
Author(s):  
Julia A. Johnson ◽  
Susan K. Fried ◽  
F. Xavier Pi-Sunyer ◽  
Jeanine B. Albu
Keyword(s):  
Insulin Resistance ◽  
Visceral Obesity ◽  
Nonesterified Fatty Acid ◽  
Obese Women ◽  
Black And White ◽  
Adenosine Receptor Agonist ◽  
Impaired Insulin Action ◽  
Visceral Adipose

Visceral obesity is associated with resistance to the antilipolytic effect of insulin in vivo. We investigated whether subcutaneous abdominal and gluteal adipocytes from viscerally obese women exhibit insulin resistance in vitro. Subjects were obese black and white premenopausal nondiabetic women matched for visceral adipose tissue (VAT), total adiposity, and age. Independently of race and adipocyte size, increased VAT was associated with decreased sensitivity to insulin's antilipolytic effect in subcutaneous abdominal and gluteal adipocytes. Absolute lipolytic rates at physiologically relevant concentrations of insulin or the adenosine receptor agonist N 6-(phenylisopropyl)adenosine were higher in subjects with the highest vs. lowest VAT area. Independently of cell size, abdominal adipocytes were less sensitive to the antilipolytic effect of insulin than gluteal adipocytes, which may partly explain increased nonesterified fatty acid fluxes in upper vs. lower body obese women. Moreover, increased VAT was associated with decreased responsiveness, but not decreased sensitivity, to insulin's stimulatory effect on glucose transport in abdominal adipocytes. These data suggest that insulin resistance of subcutaneous abdominal and, to a lesser extent, gluteal adipocytes may contribute to increased systemic lipolysis in both black and white viscerally obese women.

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