Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity

Shen, Xiaodong; Yang, Liyong; Yan, Sunjie; Zheng, Hao; Liang, Liyu; Cai, Xiuhui; Liao, Meng

doi:10.1016/j.mce.2015.05.014

Cited by 47 publications

(50 citation statements)

References 26 publications

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“…Activation of JNK may indeed inhibit insulin secretion by reduction of Ca 2+ influx [38]. In agreement with our findings, fetuin-A impaired insulin secretion of the murine cell line βTC6 [45]. Clinical data showing reduced insulin secretion in humans with increased levels of fetuin-A and the negative correlation between plasma fetuin-A and the disposition index (Fig.…”

Section: Discussionsupporting

confidence: 90%

“…Indeed, in human pancreatic resections, CD68-positive macrophages/ monocytes infiltrated the islets. In addition, we found no evidence that fetuin-A activates NF-κB in human islet cells, although a proinflammatory, TLR4-, JNK-and NF-κB-dependent effect of fetuin-A was recently ascribed to insulin secreting cells [45]. In agreement with our observations, another study identified islet resident macrophages as a source of cytokine production upon stimulation with TLR2/4 agonists [23].…”

Section: Discussionsupporting

confidence: 89%

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Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

et al. 2017

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Aims/hypothesis Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver. Methods Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining.Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RT-PCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting. Results In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic preadipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when cocultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1β. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase-and Ca 2+ -dependent, manner. Conclusions/interpretation These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

et al. 2017

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“…Physical activity is known to attenuate low-grade inflammation [139, 140]. Fetuin released from the liver targets the same receptor as lipopolysaccharide [141]. Depression is also closely associated with elevated levels of inflammatory mediators and, conversely, subclinical inflammation may promote the occurrence of depressive symptoms [142–144].…”

Section: How May Unfavourable Lifestyle and Environmental Changes Caumentioning

confidence: 99%

Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes

Kolb

Martin

2017

BMC Med

490

327

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Background: Environmental and lifestyle changes, in addition to the ageing of populations, are generally believed to account for the rapid global increase in type 2 diabetes prevalence and incidence in recent decades. Discussion: In this review, we present a comprehensive overview of factors contributing to diabetes risk, including aspects of diet quality and quantity, little physical activity, increased monitor viewing time or sitting in general, exposure to noise or fine dust, short or disturbed sleep, smoking, stress and depression, and a low socioeconomic status. In general, these factors promote an increase in body mass index. Since loss of β-cell function is the ultimate cause of developing overt type 2 diabetes, environmental and lifestyle changes must have resulted in a higher risk of β-cell damage in those at genetic risk. Multiple mechanistic pathways may come into play. Conclusions: Strategies of diabetes prevention should aim at promoting a 'diabetes-protective lifestyle' whilst simultaneously enhancing the resistance of the human organism to pro-diabetic environmental and lifestyle factors. More research on diabetes-protective mechanisms seems warranted.

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“…The combination of TLR4 and MyD88 activates the downstream high-mobility group protein 1 (HMGB-1)414243. NF-κB, a critical factor in the regulation of this inflammatory response, stimulates the production and release of inflammatory mediators, such as interleukins (IL-1β and IL-6) and TNF-α, by inflammatory cells44454647. Based on the real-time RT-PCR results), the inflammatory regulatory capability of dioscin is partially dependent on the decreased levels of NF-κB, HMGB-1, TNF-α, IL-1β and IL-6, by reducing the TLR4 signaling.…”

Section: Discussionmentioning

confidence: 99%

Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism

Yang

Chen

et al. 2017

Sci Rep

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Sepsis, in addition to causing fatality, is an independent risk factor for cognitive impairment among sepsis survivors. The pathologic mechanism of endotoxemia induced acute neuro-inflammation still has not been fully understood. For the first time, we found the disruption of neurotransmitters 5-HT, impaired neurogenesis and activation of astrocytes coupled with concomitant neuro-inflammation were the potential pathogenesis of endotoxemia induced acute neuro-inflammation in sepsis survivors. In addition, dioscin a natural steroidal saponin isolated from Chinese medicinal herbs, enhanced the serotonergic system and produced anti-depressant effect by enhancing 5-HT levels in hippocampus. What is more, this finding was verified by metabolic analyses of hippocampus, indicating 5-HT related metabolic pathway was involved in the pathogenesis of endotoxemia induced acute neuro-inflammation. Moreover, neuro-inflammation and neurogenesis within hippocampus were indexed using quantitative immunofluorescence analysis of GFAP DCX and Ki67, as well as real-time RT-PCR analysis of some gene expression levels in hippocampus. Our in vivo and in vitro studies show dioscin protects hippocampus from endotoxemia induced cascade neuro-inflammation through neurotransmitter 5-HT and HMGB-1/TLR4 signaling pathway, which accounts for the dioscin therapeutic effect in behavioral tests. Therefore, the current findings suggest that dioscin could be a potential approach for the therapy of endotoxemia induced acute neuro-inflammation.

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Fetuin A promotes lipotoxicity in β cells through the TLR4 signaling pathway and the role of pioglitazone in anti-lipotoxicity

Cited by 47 publications

References 26 publications

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes

Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism

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