Abstract P158: Endothelin Inhibits Adiponectin Production Via ETB Receptor Activation On Adipocytes

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Osvaldo J Rivera-Gonzalez ◽  
Laura Coats ◽  
Joshua S Speed
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Receptor Activation ◽  
Peroxisome Proliferator ◽  
Receptor Blockade ◽  
Obese Mice ◽  
Potential Mechanism ◽  
Primary Mouse ◽  
Mouse Adipocytes

Endothelin-1 has been implicated in obesity related insulin resistance. Our lab recently demonstrated that ET-1 is elevated in adipose tissue of obese mice, and blockade of ET-1 receptors improves insulin sensitivity in a mouse model of diet induced obesity. One potential mechanism by which ET-1 promotes insulin resistance is through activation of the ET-1 type B receptor (ET B ). Blockade of ET B receptors improves insulin sensitivity and increases circulating adiponectin, an adipokine only released by adipose tissue. Therefore, the current hypothesis is that ET-1 causes insulin resistance and inhibits adiponectin production by adipocytes. Primary mouse adipocytes were cultured and chronically treated with ET-1 for 3 days. ET-1 treated adipocytes had significantly lower peroxisome proliferator activator gamma, a transcription factor that drive adiponectin production, and adiponectin mRNA expression and release into media. This response was attenuated by co-treatment with an ET B receptor antagonist (BQ-788; 57.2±2.0 vehicle, 42.5±4.5 ET-1, 59.8±1.5 ET-1+BQ788, ng/ml; p<0.05) and in adipocytes from adipocyte ET B receptor knockout mice. Further, expression of several genes in the insulin signaling pathway, including Glut4 and insulin receptor substrates 1 and 2 were significantly reduced in adipocytes treated with ET-1, a response that was attenuated with ET B receptor blockade or knockout of the ET B receptor. These data suggest that increased ET-1 production in adipose tissue promotes insulin resistance on adipocytes and inhibits the release of insulin sensitizing adipokines such as adiponectin, a potential mechanism by which ET-1 receptor blockade improves insulin sensitivity in obese mice.

scholarly journals Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice

2018 ◽  
Vol 315 (4) ◽  
pp. E676-E693 ◽  
Author(s):  
Valentina Caracciolo ◽  
Jeanette Young ◽  
Donna Gonzales ◽  
Yingchun Ni ◽  
Stephen J. Flowers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Zinc Finger Protein ◽  
Inflammatory Responses ◽  
Adipose Tissue Inflammation ◽  
Obese Mice ◽  
Tissue Inflammation ◽  
Mrna Binding

Obesity is associated with adipose tissue inflammation that contributes to insulin resistance. Zinc finger protein 36 (Zfp36) is an mRNA-binding protein that reduces inflammation by binding to cytokine transcripts and promoting their degradation. We hypothesized that myeloid-specific deficiency of Zfp36 would lead to increased adipose tissue inflammation and reduced insulin sensitivity in diet-induced obese mice. As expected, wild-type (Control) mice became obese and diabetic on a high-fat diet, and obese mice with myeloid-specific loss of Zfp36 [knockout (KO)] demonstrated increased adipose tissue and liver cytokine mRNA expression compared with Control mice. Unexpectedly, in glucose tolerance testing and hyperinsulinemic-euglycemic clamp studies, myeloid Zfp36 KO mice demonstrated improved insulin sensitivity compared with Control mice. Obese KO and Control mice had similar macrophage infiltration of the adipose depots and similar peripheral cytokine levels, but lean and obese KO mice demonstrated increased Kupffer cell (KC; the hepatic macrophage)-expressed Mac2 compared with lean Control mice. Insulin resistance in obese Control mice was associated with enhanced Zfp36 expression in KCs. Compared with Control mice, KO mice demonstrated increased hepatic mRNA expression of a multitude of classical (M1) inflammatory cytokines/chemokines, and this M1-inflammatory hepatic milieu was associated with enhanced nuclear localization of IKKβ and the p65 subunit of NF-κB. Our data confirm the important role of innate immune cells in regulating hepatic insulin sensitivity and lipid metabolism, challenge-prevailing models in which M1 inflammatory responses predict insulin resistance, and indicate that myeloid-expressed Zfp36 modulates the response to insulin in mice.

scholarly journals Fibroblast growth factor 21 reverses suppression of adiponectin expression via inhibiting endoplasmic reticulum stress in adipose tissue of obese mice

2016 ◽  
Vol 242 (4) ◽  
pp. 441-447 ◽  
Author(s):  
Qinyue Guo ◽  
Lin Xu ◽  
Jiali Liu ◽  
Huixia Li ◽  
Hongzhi Sun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Growth Factor ◽  
Er Stress ◽  
Insulin Signaling ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Obese Mice

Fibroblast growth factor 21 (FGF21) has recently emerged as a novel endocrine hormone involved in the regulation of glucose and lipid metabolism. However, the exact mechanisms whereby FGF21 mediates insulin sensitivity remain not fully understood. In the present study, FGF21was administrated in high-fat diet-induced obese mice and tunicamycin-induced 3T3-L1 adipocytes, and metabolic parameters, endoplasmic reticulum (ER) stress indicators, and insulin signaling molecular were assessed by Western blotting. The administration of FGF21 in obese mice reduced body weight, blood glucose and serum insulin, and increased insulin sensitivity, resulting in alleviation of insulin resistance. Meanwhile, FGF21 treatment reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress in adipose tissue of obese mice. Additionally, suppression of ER stress via the ER stress inhibitor tauroursodeoxycholic acid increased adiponectin expression and improved insulin resistance in obese mice and in tunicamycin-induced adipocytes. In conclusion, our results showed that the administration of FGF21 reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress under the condition of insulin resistance, demonstrating the causative role of ER stress in downregulating adiponectin levels.

scholarly journals The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-γ target genes, in dogs

2007 ◽  
Vol 98 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Constance Gayet ◽  
Veronique Leray ◽  
Masayuki Saito ◽  
Brigitte Siliart ◽  
Patrick Nguyen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Visceral Adipose

Visceral adipose tissue and skeletal muscle have central roles in determining whole-body insulin sensitivity. The peroxisome proliferator-activated receptor-γ (PPARγ) is a potential mediator of insulin sensitivity. It can directly modulate the expression of genes that are involved in glucose and lipid metabolism, including GLUT4, lipoprotein lipase (LPL) and adipocytokines (leptin and adiponectin). In this study, we aimed to determine the effects of obesity-associated insulin resistance on mRNA expression of PPARγ and its target genes. Dogs were studied when they were lean and at the end of an overfeeding period when they had reached a steady obese state. The use of a sensitive, real-time PCR assay allowed a relative quantification of mRNA expression for PPARγ, LPL, GLUT4, leptin and adiponectin, in adipose tissue and skeletal muscle. In visceral adipose tissue and/or skeletal muscle, mRNA expression of PPARγ, LPL and GLUT4 were at least 2-fold less in obese and insulin-resistant dogs compared with the same animals when they were lean and insulin-sensitive. The mRNA expression and plasma concentration of leptin was increased, whereas the plasma level and mRNA expression of adiponectin was decreased, by obesity. In adipose tissue, PPARγ expression was correlated with leptin and adiponectin. These findings, in an original model of obesity induced by a prolonged period of overfeeding, showed that insulin resistance is associated with a decrease in PPARγ mRNA expression that could dysregulate expression of several genes involved in glucose and lipid metabolism.

scholarly journals STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

2020 ◽  
Author(s):  
Ada Admin ◽  
Aaron R. Cox ◽  
Natasha Chernis ◽  
David A. Bader ◽  
Pradip K Saha ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Tca Cycle ◽  
Whole Body ◽  
Low Grade ◽  
Type I ◽  
Obese Mice ◽  
Fat Cell ◽  
Relationship Of

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). However, the causal relationship of these events remains unclear. The established dominance of signal transducer and activator of transcription 1 (STAT1) function in the immune response suggests an obligate link between inflammation and the co-morbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (<i>STAT1<sup>a-KO­­­</sup></i>) enhanced mitochondrial function and accelerated TCA cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. <i>STAT1<sup>a-KO</sup></i> reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNg) activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.

scholarly journals STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

2020 ◽  
Author(s):  
Aaron R. Cox ◽  
Natasha Chernis ◽  
David A. Bader ◽  
Pradip K Saha ◽  
Peter M. Masschelin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Tca Cycle ◽  
Whole Body ◽  
Low Grade ◽  
Type I ◽  
Obese Mice ◽  
Diet Induced Obesity ◽  
Relationship Of

AbstractObesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). However, the causal relationship of these events remains unclear. The established dominance of signal transducer and activator of transcription 1 (STAT1) function in the immune response suggests an obligate link between inflammation and the co-morbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 fKO) enhanced mitochondrial function and accelerated TCA cycle flux coupled with subcutaneous WAT hyperplasia. STAT1 fKO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNγ) activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.

scholarly journals SBP2 deficiency in adipose tissue macrophages drives insulin resistance in obesity

2019 ◽  
Vol 5 (8) ◽  
pp. eaav0198 ◽  
Author(s):  
Ning Wang ◽  
Hor-Yue Tan ◽  
Sha Li ◽  
Di Wang ◽  
Yu Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Metabolic Activation ◽  
Obese Mice ◽  
Tissue Inflammation ◽  
Adipose Tissue Macrophages ◽  
Increased Risk ◽  
Reactive Oxygen Species Content ◽  
Patients With Diabetes

Proinflammatory activation and accumulation of adipose tissue macrophages (ATMs) are associated with increased risk of insulin resistance in obesity. Here, we described the previously unidentified role of selenocysteine insertion sequence–binding protein 2 (SBP2) in maintaining insulin sensitivity in obesity. SBP2 was suppressed in ATMs of diet-induced obese mice and was correlated with adipose tissue inflammation. Loss of SBP2 initiated metabolic activation of ATMs, inducing intracellular reactive oxygen species content and inflammasome, which subsequently promoted IL-1β–associated local proliferation and infiltration of proinflammatory macrophages. ATM-specific knockdown of SBP2 in obese mice promoted insulin resistance by increasing fat tissue inflammation and expansion. Reexpression of SBP2 improved insulin sensitivity. Last, an herbal formula that specifically induced SBP2 expression in ATMs can experimentally improve insulin sensitivity. Clinical observation revealed that it improved hyperglycemia in patients with diabetes. This study identified SBP2 in ATMs as a potential target in rescuing insulin resistance in obesity.

scholarly journals Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population

2002 ◽  
pp. 495-501 ◽  
Author(s):  
JL Gonzalez Sanchez ◽  
M Serrano Rios ◽  
C Fernandez Perez ◽  
M Laakso ◽  
MT Martinez Larrad
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Ppar Gamma ◽  
Population Based ◽  
Peroxisome Proliferator ◽  
Model Assessment ◽  
Pro12ala Polymorphism ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sagittal Abdominal Diameter

OBJECTIVE: To investigate the role of the Pro12Ala peroxisome proliferator-activated receptor (PPAR) gamma-2 polymorphism in the susceptibility to the insulin resistance syndrome and its metabolic complications in a population-based nationwide multicenter study in Spain. DESIGN: 464 unrelated adults (45.3% men and 54.7% women) aged between 35 and 64 years were randomly chosen from a nationwide population-based survey of obesity and related conditions including insulin resistance and cardiovascular risk factors. METHODS: Anthropometric determinations included: body mass index (BMI), waist-to-hip ratio, sagittal abdominal diameter; biochemical determinations included: fasting plasma glucose concentration and concentration 2 h after an oral glucose tolerance test (OGTT), total cholesterol, high and low density lipoprotein-cholesterol, triglycerides, leptin and insulin. Systolic and diastolic blood pressure were also measured. Genotyping of the PPARgamma-2 Pro12Ala polymorphism was determined by polymerase chain reaction and single strand conformation polymorphism analysis. RESULTS: The Ala12 allele frequency was higher in obese men than in lean men (0.15 vs 0.08, P=0.03). Men carriers of the Ala12 allele had a higher BMI than non-carriers (38.9% vs 21.3%; adjusted odds ratio 2.36, 95% confidence interval 1.10-5.05, P=0.03). However, despite higher BMI obese men carriers of the Ala12 allele had lower sagittal abdominal diameter than Pro12 homozygotes (24.1+/-3.2 vs 26.3+/-2.5 cm, P=0.01). The Ala12 allele was associated with lower total triglycerides levels in the overall population and it was also associated with lower fasting insulin levels and a higher insulin sensitivity by homeostasis model assessment (HOMA) in women. CONCLUSIONS: Our results suggest that the Pro12Ala polymorphism of the PPARgamma-2 gene promotes peripheral deposition of adipose tissue and increased insulin sensitivity for a given BMI. The results in women might be due to their different adipose tissue distribution.

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