Endothelin receptor antagonism improves glucose handling, dyslipidemia, and adipose tissue inflammation in obese mice

Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. We hypothesized that high ET-1 levels cause dyslipidemia, inflammation, and insulin resistance within the adipose tissue of obese mice. To test this hypothesis, male C57BL/6J mice were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle, atrasentan (ETA receptor antagonist, 10mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100mg/kg/day). Atrasentan and bosentan lowered circulating non-esterified free fatty acids and triglycerides seen in HFD mice, while atrasentan-treated mice had significantly lower liver triglycerides compared to non-treated HFD mice. ET-1 receptor blockade significantly improved insulin tolerance compared to insulin resistant HFD mice and lowered expression of genes in epididymal white adipose tissue (eWAT) associated with insulin resistance and inflammation. Flow cytometric analyses of eWAT indicated that HFD mice had significantly higher percentages of both CD4+ and CD8+ T cells compared to NMD mice, which was attenuated by treatment with atrasentan or bosentan. Atrasentan treatment also abolished the decrease in eosinophils seen in HFD mice. Taken together, these data indicate that ETA and ETA/ETB receptor blockade improves peripheral glucose homeostasis, dyslipidemia, and liver triglycerides, and also attenuates the proinflammatory immune profile in eWAT of mice fed a HFD. These data suggest a potential use for ETA and ETA/ETB receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.

Download Full-text

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

Hypertension ◽

10.1161/hyp.78.suppl_1.p158 ◽

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.

Download Full-text

332-OR: Pharmacological Inhibition of CREBZF Improves Insulin Resistance by Altering Activation of Macrophage in Adipose Tissue of Diet-Induced Obese Mice

Diabetes ◽

10.2337/db21-332-or ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 332-OR

Author(s):

YUXIAO LIU ◽

ZHIMIN HU ◽

ZHENGSHUAI LIU ◽

WEITONG SU ◽

ZENGPENG ZHENG ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Obese Mice ◽

Pharmacological Inhibition

Download Full-text

Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00495.2020 ◽

2021 ◽

Author(s):

Yingzi He ◽

Ruojun Qiu ◽

Beibei Wu ◽

Weiwei Gui ◽

Xihua Lin ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Inhibitory Effect ◽

Quadriceps Femoris ◽

Treadmill Training ◽

C2c12 Cells ◽

Obese Mice ◽

Insulin Resistant ◽

Ampk Activity ◽

Exercise Induced

Exercise improves obesity-induced insulin resistance and metabolic disorders via mechanisms that remain unclear. Here, we show that the levels of the hepatokine transthyretin (TTR) in circulation are elevated in insulin-resistant individuals including high-fat diet (HFD)-induced obese mice, db/db mice, and patients with metabolic syndrome. Liver Ttr mRNA and circulating TTR levels were reduced in mice by treadmill training, as was the TTR levels in quadriceps femoris muscle; however, AMPK signalling activity was enhanced. Transgenic overexpression of TTR or injection of purified TTR triggered insulin resistance in mice fed on regular chow (RC). Furthermore, TTR overexpression reduced the beneficial effects of exercise on insulin sensitivity in HFD-fed mice. TTR was internalized by muscle cells via the membrane receptor Grp78 and the internalization into the quadriceps femoris was reduced by treadmill training. The TTR/Grp78 combination in C2C12 cells was increased, whereas the AMPK activity of C2C12 cells was decreased as the TTR concentration rose. Additionally, Grp78 silencing prevented the TTR internalization and reversed its inhibitory effect on AMPK activity in C2C12 cells. Our study suggests that elevated circulating TTR may contribute to insulin resistance and counteract the exercise-induced insulin sensitivity improvement; the TTR suppression might be an adaptive response to exercise through enhancing AMPK activity in skeletal muscles.

Download Full-text

AT1 receptor antagonist induces thermogenic beige adipocytes in the inguinal white adipose tissue of obese mice

Endocrine ◽

10.1007/s12020-016-1213-1 ◽

2016 ◽

Vol 55 (3) ◽

pp. 786-798 ◽

Cited By ~ 6

Author(s):

Francielle Graus-Nunes ◽

Tamiris Lima Rachid ◽

Felipe de Oliveira Santos ◽

Sandra Barbosa-da-Silva ◽

Vanessa Souza-Mello

Keyword(s):

Adipose Tissue ◽

Receptor Antagonist ◽

White Adipose Tissue ◽

At1 Receptor ◽

Obese Mice ◽

Beige Adipocytes

Download Full-text

BCAA Supplementation in Mice with Diet-Induced Obesity Alters the Metabolome Without Impairing Glucose Homeostasis

Endocrinology ◽

10.1210/endocr/bqab062 ◽

2021 ◽

Author(s):

Jennifer Lee ◽

Archana Vijayakumar ◽

Phillip J White ◽

Yuping Xu ◽

Olga Ilkayeva ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Homeostasis ◽

Obese Mice ◽

High Fat ◽

Leucine Oxidation ◽

Insulin Resistant ◽

Diet Induced Obesity ◽

Chain Acyl ◽

Branched Chain ◽

Relationship Of

Abstract Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is still ill-defined. Here we examined how high-fat high-sucrose (HFHS) or high-fat diet (HFD) feeding, with or without BCAA supplementation in water, alters the metabolome in serum/plasma and tissues in mice and whether raising circulating BCAA levels worsens insulin resistance and glucose intolerance. Neither HFHS nor HFD-feeding raised circulating BCAA levels in insulin-resistant diet-induced obese mice. BCAA supplementation raised circulating BCAA and BCKA levels and C5-OH/C3-DC acylcarnitines (AC) in muscle from HFHS or HFD-fed mice, but did not worsen insulin resistance. A set of short and long-chain acyl CoAs were elevated by diet alone in muscle, liver and WAT, but not increased further by BCAA supplementation. HFD feeding reduced valine and leucine oxidation in WAT but not in muscle. BCAA supplementation markedly increased valine oxidation in muscle from HFD-fed mice while leucine oxidation was unaffected by diet or BCAA treatment. Here we establish an extensive metabolome database showing tissue-specific changes in mice on two different HFDs, with or without BCAA supplementation. We conclude that mildly elevating circulating BCAAs and a subset of ACs by BCAA supplementation does not worsen insulin resistance or glucose tolerance in mice. This work highlights major differences in the effects of BCAAs on glucose homeostasis in diet-induced obese mice versus data reported in obese rats and in humans.

Download Full-text

Specific Preservation of Biosynthetic Responses to Insulin in Adipose Tissue May Contribute to Hyperleptinemia in Insulin-Resistant Obese Mice

Journal of Nutrition ◽

10.1093/jn/134.5.1045 ◽

2004 ◽

Vol 134 (5) ◽

pp. 1045-1050 ◽

Cited By ~ 6

Author(s):

Tooru M. Mizuno ◽

Toshiya Funabashi ◽

Steven P. Kleopoulos ◽

Charles V. Mobbs

Keyword(s):

Adipose Tissue ◽

Obese Mice ◽

Insulin Resistant

Download Full-text

Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00664.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. E1433-E1440 ◽

Cited By ~ 48

Author(s):

Jinhui Zhang ◽

Wendy Wright ◽

David A. Bernlohr ◽

Samuel W. Cushman ◽

Xiaoli Chen

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Epididymal Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Insulin Resistant ◽

Obese Rats ◽

Initial Activation ◽

Adipose Cells ◽

Classic Pathway

Adipose tissue inflammation has recently been linked to the pathogenesis of obesity and insulin resistance. C1 complex comprising three distinct proteins, C1q, C1r, and C1s, involves the key initial activation of the classic pathway of complement and plays an important role in the initiation of inflammatory process. In this study, we investigated adipose expression and regulation of C1 complement subcomponents and C1 activation regulator decorin in obesity and insulin resistance. Expression of C1q in epididymal adipose tissue was increased consistently in ob/ob mice, Zucker obese rats, and high fat-diet-induced obese (HF-DIO) mice. Decorin was found to increase in expression in Zucker obese rats and HF-DIO mice but decrease in ob/ob mice. After TZD administration, C1q and decorin expression was reversed in Zucker obese rats and HF-DIO mice. Increased expression of C1 complement and decorin was observed in both primary adipose and stromal vascular cells isolated from Zucker obese rats. Upregulation of C1r and C1s expression was also perceived in adipose cells from insulin-resistant humans. Furthermore, expression of C1 complement and decorin is dysregulated in TNF-α-induced insulin resistance in 3T3-L1 adipocytes and cultured rat adipose cells as they become insulin resistant after 24-h culture. These data suggests that both adipose and immune cells are the sources for abnormal adipose tissue production of C1 complement and decorin in obesity. Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance.

Download Full-text

Visfatin levels in non-obese, obese, and insulin resistant adolescents

Paediatrica Indonesiana ◽

10.14238/pi56.5.2016.291-6 ◽

2017 ◽

Vol 56 (5) ◽

pp. 291

Author(s):

Indra Ihsan ◽

Eka Agustia Rini ◽

Rismawati Yaswir

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Serum Insulin ◽

Enzyme Linked Immunosorbent Assay ◽

Model Assessment ◽

Fasting Serum ◽

Obese Adolescents ◽

Insulin Resistant ◽

Resistant Group ◽

Visfatin Level

Background Adipose tissue is not merely a site for energy storage, but is also the largest endocrine organ, secreting various adipocytokines. Plasma visfatin, an adipocytokine predominantly secreted from visceral adipose tissue, has insulin-mimetic effects, and has been closely linked to insulin resistance.Objective To compare plasma visfatin levels between obese and non-obese adolescents, as well as between obese adolecents with and without insulin resistance.Methods This cross-sectional study was conducted in students who attended three senior high schools in Padang. Subjects comprised 28 obese and 28 non-obese adolescents. The age of the subjects ranged from 14-18 years. Obesity criteria were based on body mass index (BMI) measurements. Fasting serum glucose level was measured by glucose hexokinase photometry and serum insulin was measured by chemiluminesence immunoassay. Plasma visfatin was measured by enzyme-linked immunosorbent assay (ELISA). The insulin resistance index was estimated from fasting serum insulin and glucose levels using the homeostatic model assessment for insulin resistance (HOMA-IR). Differences in the variables were tested using independent T-test and Mann-Whitney test, depending on the distribution of the variables.Results The mean plasma visfatin level was significantly higher in the obese than in the control group [2.55 (SD 1.54) vs. 1.61 (SD 0.64) ng/mL, respectively; (P=0.005)]. The insulin resistant group had significantly higher mean plasma visfatin level than the non-resistant group [3.61 (SD 1.59) vs. 1.96 (SD 1.18) ng/mL, respectively; (P=0.004)].Conclusion Obese adolescents with insulin resistance have signifcantly higher plasma visfatin levels compared to those without insulin resistance.

Download Full-text

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00224.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. E676-E693 ◽

Cited By ~ 2

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.

Download Full-text

Prebiotic prevents impaired kidney and renal Oat3 functions in obese rats

Journal of Endocrinology ◽

10.1530/joe-17-0471 ◽

2018 ◽

Vol 237 (1) ◽

pp. 29-42 ◽

Cited By ~ 12

Author(s):

Keerati Wanchai ◽

Sakawdaurn Yasom ◽

Wannipa Tunapong ◽

Titikorn Chunchai ◽

Parameth Thiennimitr ◽

...

Keyword(s):

Insulin Resistance ◽

Renal Function ◽

High Fat Diet ◽

Organic Anion ◽

Normal Diet ◽

Organic Anion Transporter ◽

High Fat ◽

Insulin Resistant ◽

Beneficial Effects ◽

Anion Transporter

Obesity is health issue worldwide, which can lead to kidney dysfunction. Prebiotics are non-digestible foods that have beneficial effects on health. This study aimed to investigate the effects of xylooligosaccharide (XOS) on renal function, renal organic anion transporter 3 (Oat3) and the mechanisms involved. High-fat diet was provided for 12 weeks in male Wistar rats. After that, the rats were divided into normal diet (ND); normal diet treated with XOS (NDX); high-fat diet (HF) and high-fat diet treated with XOS (HFX). XOS was given daily at a dose of 1000 mg for 12 weeks. At week 24, HF rats showed a significant increase in obesity and insulin resistance associated with podocyte injury, increased microalbuminuria, decreased creatinine clearance and impaired Oat3 function. These alterations were improved by XOS supplementation. Renal MDA level and the expression of AT1R, NOX4, p67phox, 4-HNE, phosphorylated PKCα and ERK1/2 were significantly decreased after XOS treatment. In addition, Nrf2-Keap1 pathway, SOD2 and GCLC expression as well as renal apoptosis were also significantly reduced by XOS. These data suggest that XOS could indirectly restore renal function and Oat3 function via the reduction of oxidative stress and apoptosis through the modulating of AT1R-PKCα-NOXs activation in obese insulin-resistant rats. These attenuations were instigated by the improvement of obesity, hyperlipidemia and insulin resistance.

Download Full-text