Endothelin-1 induces lipolysis in 3T3-L1 adipocytes

Juan, Chi Chang; Chang, Chih Ling; Lai, Ying Hsiu; Ho, Low Tone

doi:10.1152/ajpendo.00481.2004

Cited by 42 publications

(50 citation statements)

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“…Our previous study (21) demonstrated that ET-1 affects lipid metabolism by stimulating adipocyte lipolysis. In the present study, we showed that ET-1 might also manipulate homeostasis of lipid metabolism by downregulating CD36 expression in VSMCs.…”

Section: Discussionmentioning

confidence: 98%

Endothelin-1 decreases CD36 protein expression in vascular smooth muscle cells

Kwok

Juan²,

2007

American Journal of Physiology-Endocrinology and Metabolism

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shown that CD36 plays important roles as a major scavenger receptor for oxidized low-density lipoproteins and as a crucial transporter for long-chain fatty acids. CD36 deficiency might be associated with insulin resistance and abnormal dynamics of long-chain fatty acids. Endothelin-1 (ET-1), which is synthesized and secreted by vascular endothelial cells, is the most potent endogenous vasoconstrictor known and also stimulates the proliferation of vascular smooth muscle cells (VSMCs) and thus is believed to play an important role in the development of various circulatory disorders, including hypertension and atherosclerosis. The aim of the present study was to investigate the regulatory effect of ET-1 on CD36 expression in cultured VSMCs. VSMCs were treated for different times (0 -24 h) with a fixed concentration (100 nM) of ET-1 or with different concentrations (0 -100 nM) for a fixed time (24 h); then CD36 expression was determined using Western blots. CD36 expression was significantly decreased by ET in a time-and dose-dependent manner. This inhibitory effect was prevented by the ET A receptor antagonist BQ-610 (10 M) but not the ET B receptor antagonist BQ-788 (10 M). To further explore the underlying mechanisms of ET-1 action, we examined the involvement of the tyrosine kinase-mediated and MAPK-mediated pathways. The inhibitory effect of ET-1 on CD36 protein expression was blocked by inhibition of tyrosine kinase activation by use of genistein (100 M) and by the ERK inhibitor PD-98059 (75 M) but not by the p38 MAPK inhibitor SB-203580 (20 M). In conclusion, we have demonstrated that ET-1, acting via the ET A receptor, suppresses CD36 protein expression in VSMCs by activation of the tyrosine kinase and ERK pathways.

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Section: Discussionmentioning

confidence: 98%

Endothelin-1 decreases CD36 protein expression in vascular smooth muscle cells

Kwok

Juan²,

2007

American Journal of Physiology-Endocrinology and Metabolism

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“…This results in the activation of signaling pathways that include, phospholipase A 2 , phospholipase C and further downstream protein kinase C, calmodulin, phosphatidylinositol 3-kinase and mitogenactivated protein kinases. [6][7][8][9] Receptors for ET-1 are expressed not only in smooth muscle cells but also in adipocytes and a number of other tissues. 6,10 It has recently been shown that ET-1 is released by human subcutaneous (s.c.) adipose tissue and that its secretion is elevated in obesity.…”

Section: Introductionmentioning

confidence: 99%

“…Earlier studies of lipolysis in primary rat fat cells and murine 3T3-L1 adipocytes have shown a lipolytic effect of ET-1. 9,11 This stimulation is time-and concentration-dependent, predominantly mediated through the ET A R and downstream activation of mitogen-activated protein kinases.…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

et al. 2008

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Objective: Levels of the vascular peptide endothelin-1 (ET-1) are significantly elevated in obesity. Adipose tissue-derived ET-1 attenuates insulin-mediated antilipolysis in human visceral adipocytes through the activation of the ET receptor B (ET B R), thereby linking ET-1 to insulin resistance. Whether ET-1 has direct effects on lipolysis in human adipocytes is not known. Research design and subjects: Endothelin-1 receptor (ETR) mRNA expression was determined by quatitative PCR in 130 nonobese and obese subjects. ET-1 mRNA in different adipose tissue regions was also assessed. ETR protein expression was analyzed by western blotting in 37 subjects. The effect of ET-1 on lipolysis was assessed in freshly isolated adipocytes and in vitro differentiated adipocytes from human donors. Results: Freshly isolated human adipocytes incubated with different concentrations of ET-1 showed no acute effect on lipolysis. In contrast, a 24 h incubation in primary cultures of human adipocytes resulted in a significant 50% increase in lipolysis. This effect was concentration dependent and could be mimicked by an agonist of the ET A receptor but not with a selective ET B R agonist. Adipocyte differentiation was not affected by any of the agonists. In subcutaneous (s.c.) adipose tissue from 19 nonobese and 18 obese subjects, the protein expression of ET A R was significantly higher in obese subjects whereas there was no difference in ET B R expression. Interestingly, the differences in protein expression were not observed at the mRNA level as ET A R expression was similar between lean and obese subjects. Conclusion: Long-term but not acute incubation of human adipocytes with ET-1 results in a significant increase in lipolysis. This appears to be mediated through the activation of ET A R, demonstrating a yet another receptor-specific effect of ET-1. In addition, the protein expression of ET A R is increased in s.c. adipose tissue in obesity, possibly through post-transcriptional mechanisms. An increased effect of ET-1 could be a mechanism that contributes to increased basal lipolysis in human obesity.

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“…The interference of ET-1 on metabolic function has been deeply investigated: ET-1 infusion results in hyperinsulinemia and insulin resistance in vivo [62], and chronically elevated ET-1 levels may contribute to desensitization of metabolic signaling pathways on adipocytes [63]. In addition, ET-1 inhibits adipocyte differentiation, reduces lipoprotein lipase activity, inhibits insulin-stimulated glucose uptake [64], and stimulates lipolysis [65]. ET-1 seems involved in production and secretion of Ad [66].…”

Section: Endothelial Dysfunction and Metaflammationmentioning

confidence: 99%

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Potenza

Nacci

Salvia

et al. 2017

Pharmacological Research

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Abstract:The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelialderived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

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Endothelin-1 induces lipolysis in 3T3-L1 adipocytes

Cited by 42 publications

References 50 publications

Endothelin-1 decreases CD36 protein expression in vascular smooth muscle cells

Endothelin-1 decreases CD36 protein expression in vascular smooth muscle cells

Endothelin-1 stimulates human adipocyte lipolysis through the ETA receptor

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

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