P735Interleukin-33 induced eosinophilia restores perivascular adipose tissue function in obesity

Abstract Background/Purpose Perivascular adipose tissue (PVAT) is essential in the modulation of vascular tone. Recently we have shown that resident eosinophils play a vital role in regulating PVAT function. In obesity, eosinophil numbers are reduced and PVAT anticontractile function is lost, resulting in increased vascular tone, which will contribute to development of hypertension and type-2 diabetes. Evidence suggests that eosinophilia resulting from parasitic infection may be useful in improving glucose tolerance; therefore, we investigated the effects of eosinophilia on PVAT function in health and obesity. Methods Control mice and a high fat fed mouse model of obesity were administered intraperitoneal injections of interleukin-33 (IL-33, 0.1μg) over a five day period. Blood pressure, blood glucose and plasma insulin were measured and compared with un-injected control and obese mice. Wire myography was used to assess the vascular contractility of mesenteric arteries (<250μm, +/− PVAT) from both injected and un-injected control and obese mice in response to noradrenaline. ELISAs and immunohistochemistry were used to examine eosinophil numbers. Results High fat feeding induced significant elevations in blood pressure, blood glucose and plasma insulin, which were reduced using IL-33 injections. Eosinophilia was confirmed in blood plasma using an eosinophil cationic protein ELISA. Using wire myography, mesenteric arteries from control mice PVAT exerted an anticontractile effect on the vessels, which was enhanced in control mice injected with IL-33. In obese mice, the PVAT anticontractile effect was lost, but was restored in IL-33 injected obese mice. Using immunohistochemistry, we confirm that eosinophils numbers in PVAT were reduced in obesity and increased in IL-33 treated PVAT. Conclusions IL-33 injections induced eosinophilia in both control and obese mice. IL-33 treatment restored PVAT function in obesity, and enhanced the anticontractile function of PVAT in healthy animals. In addition, only five consecutive injections of IL-33 reversed development of hypertension and type-2 diabetes in obese mice. These data suggest that IL-33 induced eosinophilia presents a novel approach to treatment of hypertension and type-2 diabetes in obesity. Acknowledgement/Funding British Heart Foundation

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Abstract 015: Increased 20-HETE Levels Contribute to Impaired Glucose Metabolism and Type 2 Diabetes in Cyp4a14 Knockout Mice Fed on High Fat Diet.

Hypertension ◽

10.1161/hyp.66.suppl_1.015 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Varunkumar G Pandey ◽

Lars Bellner ◽

Victor Garcia ◽

Joseph Schragenheim ◽

Andrew Cohen ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Weight Gain ◽

Blood Glucose ◽

High Fat Diet ◽

Plasma Insulin ◽

High Fat ◽

Plasma Insulin Levels

20-HETE (20-Hydroxyeicosatetraenoic acid) is a cytochrome P450 ω-hydroxylase metabolite of arachidonic acid that promotes endothelial dysfunction, microvascular remodeling and hypertension. Previous studies have shown that urinary 20-HETE levels correlate with BMI and plasma insulin levels. However, there is no direct evidence for the role of 20-HETE in the regulation of glucose metabolism, obesity and type 2 diabetes mellitus. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water-soluble 20-HETE antagonist, on blood pressure, weight gain and blood glucose in Cyp4a14 knockout (Cyp4a14-/-) mice fed high-fat diet (HFD). The Cyp4a14-/- male mice exhibit high vascular 20-HETE levels and display 20-HETE-dependent hypertension. There was no difference in weight gain and fasting blood glucose between Cyp4a14-/- and wild type (WT) on regular chow. When subjected to HFD for 15 weeks, a significant increase in weight was observed in Cyp4a14-/- as compared to WT mice (56.5±3.45 vs. 30.2±0.7g, p<0.05). Administration of 20-SOLA (10mg/kg/day in drinking water) significantly attenuated the weight gain (28.7±1.47g, p<0.05) and normalized blood pressure in Cyp4a14-/- mice on HFD (116±0.3 vs. 172.7±4.6mmHg, p<0.05). HFD fed Cyp4a14-/- mice exhibited hyperglycemia as opposed to normal glucose levels in WT on a HFD (154±1.9 vs. 96.3±3.0 mg/dL, p<0.05). 20-SOLA prevented the HFD-induced hyperglycemia in Cyp4a14-/- mice (91±8mg/dL, p<0.05). Plasma insulin levels were markedly high in Cyp4a14-/- mice vs. WT on HFD (2.66±0.7 vs. 0.58±0.18ng/mL, p<0.05); corrected by the treatment with 20-SOLA (0.69±0.09 ng/mL, p<0.05). Importantly, glucose and insulin tolerance tests showed impaired glucose homeostasis and insulin resistance in Cyp4a14-/- mice on HFD; ameliorated by treatment with 20-SOLA. This novel finding that blockade of 20-HETE actions by 20-SOLA prevents HFD-induced obesity and restores glucose homeostasis in Cyp4a14-/- mice suggests that 20-HETE contributes to obesity, hyperglycemia and insulin resistance in HFD induced metabolic disorder. The molecular mechanisms underlying 20-HETE mediated metabolic dysfunction are being currently explored.

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Interleukin-33 rescues perivascular adipose tissue anticontractile function in obesity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00491.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. H1387-H1397

Author(s):

Sophie N. Saxton ◽

Alice S. Whitley ◽

Ryan J. Potter ◽

Sarah B. Withers ◽

Richard Grencis ◽

...

Keyword(s):

Blood Pressure ◽

Adipose Tissue ◽

Blood Glucose ◽

Plasma Insulin ◽

Obese Mice ◽

Perivascular Adipose Tissue ◽

Interleukin 33 ◽

Deficient Mice

In this study, we have shown that administering IL-33 to obese mice will restore PVAT anticontractile function, and this is accompanied by normalized blood pressure, blood glucose, and plasma insulin. Moreover, the PVAT effect is enhanced in control mice given IL-33. IL-33 induced a hypereosinophilic phenotype in our mice, and the effects of IL-33 on PVAT function, blood pressure, and blood glucose are absent in eosinophil-deficient mice, suggesting that the effects of IL-33 are mediated via eosinophils.

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Anti-Obesity Effects of Sargassum thunbergii via Downregulation of Adipogenesis Gene and Upregulation of Thermogenic Genes in High-Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu12113325 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3325

Author(s):

Min-Cheol Kang ◽

Hyo-Geun Lee ◽

Hyun-Soo Kim ◽

Kyung-Mo Song ◽

Yong-Gi Chun ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Adipose Tissue ◽

White Adipose Tissue ◽

High Fat Diet ◽

Obese Mice ◽

High Fat ◽

Sargassum Thunbergii ◽

Fat Accumulation

Obesity is a metabolic disease characterized by an increased risk of type 2 diabetes, hypertension, and cardiovascular disease. We have previously reported that compounds isolated from brown alga, Sargassum thunbergii (ST; Sargassum thunbergii (Mertens ex Roth) Kuntze), inhibit adipogenesis in 3T3-L1 cells. However, the in vivo anti-obesity effects of these compounds have not been previously reported. Therefore, the objective of this study was to determine the effects of ST on weight loss, fat accumulation, as well as risk factors for type 2 diabetes and cardiovascular disease in high-fat diet (HFD)-induced obese mice. ST treatment significantly decreased body weight and fat accumulation in HFD-induced obese mice, while reducing insulin and factors related to cardiovascular diseases (triglyceride and total cholesterol) in serum. ST-induced downregulation of PPARγ in white adipose tissue, and upregulation of the thermogenic genes, UCP-1 and UCP-3, in brown adipose tissue was also observed. In addition, oral administration of ST reduced the occurrence of fatty liver, as well as the amount of white adipose tissue in HFD mice. Cumulatively, these results suggest that ST exerts anti-obesity effects and may serve as a potential anti-obesity therapeutic agent.

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Increased mitochondrial ROS generation mediates the loss of the anti-contractile effects of perivascular adipose tissue in high-fat diet obese mice

British Journal of Pharmacology ◽

10.1111/bph.13687 ◽

2017 ◽

Vol 174 (20) ◽

pp. 3527-3541 ◽

Cited By ~ 26

Author(s):

Rafael Menezes da Costa ◽

Rafael S Fais ◽

Carlos R P Dechandt ◽

Paulo Louzada-Junior ◽

Luciane C Alberici ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Ros Generation ◽

Obese Mice ◽

High Fat ◽

Perivascular Adipose Tissue ◽

Mitochondrial Ros

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Contribution of perivascular adipose tissue to vascular dysfunction in type 2 diabetes

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2018.04.533 ◽

2018 ◽

Vol 120 ◽

pp. S162 ◽

Cited By ~ 1

Author(s):

Adriana Leandro ◽

Lara Azul ◽

Rosa Fernandes ◽

Raquel Seiça ◽

Cristina Sena

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Vascular Dysfunction ◽

Perivascular Adipose Tissue

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Aging Affects KV7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone

Frontiers in Physiology ◽

10.3389/fphys.2021.749709 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yibin Wang ◽

Fatima Yildiz ◽

Andrey Struve ◽

Mario Kassmann ◽

Lajos Markó ◽

...

Keyword(s):

Adipose Tissue ◽

Vascular Function ◽

Vascular Tone ◽

Mesenteric Arteries ◽

Aging Effects ◽

Perivascular Adipose Tissue ◽

Kcnq Channels ◽

Age Related ◽

Cardiovascular Morbidity And Mortality

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.

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Tetrahydrocurcumin Upregulates the Adiponectin-AdipoR Pathway and Improves Insulin Signaling and Pancreatic β-Cell Function in High-Fat Diet/Streptozotocin-Induced Diabetic Obese Mice

Nutrients ◽

10.3390/nu13124552 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4552

Author(s):

Yi-Zhen Tsai ◽

Mei-Ling Tsai ◽

Li-Yin Hsu ◽

Chi-Tang Ho ◽

Ching-Shu Lai

Keyword(s):

Type 2 Diabetes ◽

Insulin Signaling ◽

High Fat Diet ◽

Cell Function ◽

Obese Mice ◽

High Fat ◽

Islet Mass ◽

Beneficial Effects ◽

Β Cell Function

Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly (p < 0.05) preserved islet mass, reduced apoptosis, and restored defective insulin expression in the pancreatic β-cells of diabetic obese mice, which was accompanied by an elevation of AdipoR1 and APPL1. These results demonstrated a potential mechanism underlying the beneficial effects of THC against hyperglycemia via the adiponectin-AdipoR pathway, and thus, may lead to a novel therapeutic use for type 2 diabetes.

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Luteolin Improves Perivascular Adipose Tissue Profile and Vascular Dysfunction in Goto-Kakizaki Rats

International Journal of Molecular Sciences ◽

10.3390/ijms222413671 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13671

Author(s):

Marcelo Queiroz ◽

Adriana Leandro ◽

Lara Azul ◽

Artur Figueirinha ◽

Raquel Seiça ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Endothelial Function ◽

Metabolic Parameters ◽

Perivascular Adipose Tissue ◽

Gk Rats ◽

Vascular Oxidative Stress ◽

Luteolin Treatment

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT−) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. Results: Endothelial function was impaired in diabetic GK rats (47% (GK − PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK − PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products’ levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. Conclusions: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.

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Abstract 211: The DPP-4 Inhibitor Linagliptan Reverses Endothelial Dysfunction of Mesenteric Arteries From Rats Fed a Western Diet

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.211 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Salheen M Salheen ◽

Jason C Nguyen ◽

Trisha A Jenkins ◽

Owen L Woodman

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Western Diet ◽

Mesenteric Arteries ◽

Standard Diet ◽

High Fat ◽

Total Fat ◽

Endothelium Dependent Relaxation ◽

Superoxide Release

A high-fat ‘western’ diet (WD), a risk factor for the development of type 2 diabetes, may cause endothelial dysfunction one of the earliest events in atherogenesis. The dipeptidyl peptidase-4 (DPP-4) inhibitors are used to lower hyperglycemia in type 2 diabetes which is also associated with endothelial dysfunction. We tested whether consumption of a WD affected endothelium-dependent relaxation (EDR) of rat mesenteric arteries (MA) and whether the DPP-4 inhibitor linagliptin (1μM) improves EDR. Wistar Hooded rats were fed a standard diet (SD, 7% total fat) or WD (21% total fat) for 10 weeks. Consumption of the WD significantly increased superoxide release from MA assayed by lucigenin chemiluminescence (WD 1210±180 counts/mg versus SD 543±156 counts/mg, n=7-8, p<0.05) and linagliptin significantly reduced the vascular superoxide release (WD+linagliptin 432±102 counts/mg, p<0.05). Acetylcholine (ACh)-induced endothelium-dependent relaxation of MA was assessed using wire myography. WD significantly reduced the sensitivity to ACh (pEC50, SD 7.72±0.08, WD, 7.32±0.05 n=8, p<0.05) and treatment with linagliptin improved endothelial function (ACh pEC50 WD+linagliptin, 7.74±0.12, n=8, p<0.05). The contribution of EDHF to ACh-induced relaxation was determined in the presence of L-NNA and ODQ to block NOS and guanylate cyclase. EDHF-mediated relaxation was improved by linagliptin (pEC50, WD 6.24±0.06, WD+linagliptin 6.95±0.12, n=4-5, p<0.05). Linagliptin also significantly improved the contribution of NO (determined in the presence of TRAM-34 + apamin to block IKCa and SKCa) to relaxation (pEC50, WD 6.50±0.13, WD+linagliptin 7.30±0.10 n=4-6, p<0.05). Linagliptin significantly reduced vascular superoxide levels and improved the contribution of both NO and EDHF to preserve endothelium-dependent relaxation in rats fed a high fat diet. DPP-4 inhibition may have effects in addition to the lowering of plasma glucose to improve vascular function in diabetes.

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