Fructose induced neurogenic hypertension mediated by overactivation of p38 MAPK to impair insulin signaling transduction caused central insulin resistance

Cheng, Pei; Lin, Yu Te; Ho, Wen Yu; Lu, Pei Jung; Chen, Hsin Hung; Lai, Chi Cheng; Sun, Gwo Ching; Yeh, Tung Chen; Hsiao, Michael; Tseng, Ching Jiunn; Liu, Chun Peng

doi:10.1016/j.freeradbiomed.2017.07.022

Cited by 16 publications

(16 citation statements)

References 49 publications

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“…The previous studies have reported that the high‐fructose consumption can cause hyperglycaemia. Chronic fructose diet also increased serum insulin concentrations . This study was observed that no difference in serum glucose levels among groups, unlike increased serum insulin levels.…”

Section: Discussionsupporting

confidence: 43%

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The protective effects of Δ9-tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia

Beydogan

Coşkun

Bolkent

2019

Journal of Pharmacy and Pharmacology

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Objectives A large amount of fructose is metabolized in the liver and causes hepatic functional damage. Δ9‐tetrahydrocannabinol (THC) is known as a therapeutic agent for clinical and experimental applications. The study aims to investigate the effects of THC treatment on inflammation, lipid profiles and oxidative stress in rat liver with hyperinsulinemia. Methods Sprague‐Dawley rats were divided into groups: control, fructose (10% fructose in drinking water for 12 weeks), THC (1.5 mg/kg/day for the last 4 weeks, intraperitoneally) and fructose+THC groups. Biochemical parameters were measured spectrophotometrically. ELISA method was used for insulin measurement. Apoptosis and inflammation markers were detected by the streptavidin‐biotin peroxidase method. Key findings The consumptions of food and fluid are inversely proportional to fructose and non‐fructose groups. Insulin levels were the highest in fructose group. The reduced glutathione‐S‐transferase level significantly increased in fructose + THC group compared with fructose group. Total cholesterol level in the fructose + THC group was higher than the fructose group. Caspase‐3 and NF‐κβ immunopositive cell numbers increased in fructose + THC rats compared with fructose group. The number of IL‐6 immunopositive cell decreased in fructose + THC group compared with fructose group. Conclusions According to the result, long‐term and low‐dose THC administration may reduce hyperinsulinemia and inflammation in rats to some extent.

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Section: Discussionsupporting

confidence: 43%

“…Chronic fructose diet also increased serum insulin concentrations. [3,27] This study was observed that no difference in serum glucose levels among groups, unlike increased serum insulin levels. It is known that increased levels of insulin maintained over long periods may cause to insulin resistance.…”

Section: Discussionmentioning

confidence: 80%

The protective effects of Δ9-tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia

Beydogan

Coşkun

Bolkent

2019

Journal of Pharmacy and Pharmacology

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“…Namely, MIF can limit GCs effects, most likely through p38 phosphorylation, while the absence of endogenous MIF is associated with increased sensitivity to GCs through decreased phosphorylation of p38 MAPK (Calandra et al 1995, Aeberli et al 2006a. Proinflammatory p38 kinase is activated by oxidative stress and inflammation in 3T3-L1 cells and human adipocytes (Merkel et al 2002, Chuang et al 2010, Vazquez Prieto et al 2015, Cheng et al 2017, and fructose diet is known to enhance the production of proinflammatory cytokines and oxidative stress mediators in rodent visceral adipose tissue (Kovačević et al 2016, Pektas et al 2016. Our results showed that fructose diet indeed led to the elevation in both total and phospho p38 protein levels in WT and Mif-deficient mice.…”

Section: Figurementioning

confidence: 99%

Mif deficiency promotes adiposity in fructose-fed mice

Gligorovska

Bursać

Kovačević

et al. 2019

Journal of Endocrinology

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The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic lowgrade inflammation may be caused by fructose intake, contributing to visceral adipose tissue (VAT) dysfunction. Since MIF is a known antagonist of glucocorticoid signaling, and deregulated glucocorticoid signaling can contribute to lipid metabolism disturbances, we hypothesized that altered MIF signaling might underlie fructose-induced adiposity through glucocorticoid action. We analyzed physiological and biochemical parameters, adipose tissue histology, insulin sensitivity and lipid metabolism in WT and MIF −/− C57Bl/6J mice consuming 20% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and glucocorticoid receptor (GR) protein level were examined in VAT, together with the expression of glucocorticoid-target genes involved in lipid metabolism. The expression of adipogenic and lipogenic transcriptional regulators peroxisome proliferator-activated receptor gamma (PPARG) and sterol regulatory element-binding protein 1c (SREBP1c) was also assessed. Results showed disturbed insulin sensitivity in all MIF −/− mice, regardless of the diet. Mice on fructose diet had increased energy intake, but increased visceral adiposity and enlarged adipocytes were observed only in fructose-fed MIF −/− mice. Increased VAT corticosterone level and 11 beta-hydroxysteroid dehydrogenase type 1, hexose-6-phosphate dehydrogenase and GR protein levels were observed in the same animals, together with induced expression of examined lipogenic genes and accumulation of PPARG and SREBP1c. In conclusion, the results showed that dietary fructose was associated with increased visceral adiposity through activation of GR-regulated lipogenic genes, but only in the absence of MIF, which set the state of hyperinsulinemia and insulin resistance.

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“…Insulin resistance-metabolic syndrome patients have been reported to benefit from strategies concerning stimulation of VSMC survival and reduction in FKN/ CX3CR1 signaling to promote plaque stability through an IRS2-dependent signaling [34]. We previously proposed that IRS1 is more critical than IRS2 in insulin resistance-metabolic syndrome of the NTS [6,35,36]. This study suggests that the inhibition of CX3CR1-microglia improves the defective Akt and ERK1/ 2 signaling, both of which are critical pathways for NO production in the NTS.…”

Section: Discussionmentioning

confidence: 99%

CX3CR1-microglia mediates neuroinflammation and blood pressure regulation in the nucleus tractus solitarii of fructose-induced hypertensive rats

Lin

Chen

et al. 2020

J Neuroinflammation

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Background: Inflammation is a common pathophysiological trait found in both hypertension and cardiac vascular disease. Recent evidence indicates that fractalkine (FKN) and its receptor CX3CR1 have been linked to inflammatory response in the brain of hypertensive animal models. Here, we investigated the role of CX3CR1-microglia in nitric oxide (NO) generation during chronic inflammation and systemic blood pressure recovery in the nucleus tractus solitarii (NTS). Methods: The hypertensive rat model was used to study the role of CX3CR1-microglia in NTS inflammation following hypertension induction by oral administration of 10% fructose water. The systolic blood pressure was measured by tail-cuff method of non-invasive blood pressure. The CX3CR1 inhibitor AZD8797 was administered intracerebroventricularly (ICV) in the fructose-induced hypertensive rat. Using immunoblotting, we studied the nitric oxide synthase signaling pathway, NO concentration, and the levels of FKN and CX3CR1, and pro-inflammatory cytokines were analyzed by immunohistochemistry staining. Results: The level of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, FKN, and CX3CR1 were elevated two weeks after fructose feeding. AZD8797 inhibited CX3CR1-microglia, which improved the regulation of systemic blood pressure and NO generation in the NTS. We also found that IL-1β, IL-6, and TNF-α levels were recovered by AZD8797 addition. Conclusion: We conclude that CX3CR1-microglia represses the nNOS signaling pathway and promotes chronic inflammation in fructose-induced hypertension. Collectively, our results reveal the role of chemokines such as IL-1β, IL-6, and TNF-α in NTS neuroinflammation with the involvement of FKN and CX3CR1.

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Fructose induced neurogenic hypertension mediated by overactivation of p38 MAPK to impair insulin signaling transduction caused central insulin resistance

Cited by 16 publications

References 49 publications

The protective effects of Δ9-tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia

The protective effects of Δ9-tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia

Mif deficiency promotes adiposity in fructose-fed mice

CX3CR1-microglia mediates neuroinflammation and blood pressure regulation in the nucleus tractus solitarii of fructose-induced hypertensive rats

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