Resistin reduces mitochondria and induces hepatic steatosis in mice by the protein kinase C/protein kinase G/p65/PPAR gamma coactivator 1 alpha pathway

Zhou, Lei; Yu, Xiaolan; Meng, Qi; Li, Hongqiang; Niu, Congcong; Jiang, Yun; Cai, Yuxi; Li, Minghui; Li, Qiang; An, Chaoqiang; Shu, Le; Chen, Ao; Su, Handong; Tang, Yin; Shen, Yin; Raschke, Silja; Eckardt, Kristin; Eckel, Jürgen; Zhou, Yang

doi:10.1002/hep.26167

Cited by 44 publications

(34 citation statements)

References 32 publications

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“…This resulting state of reduced mitochondrial respiration is a sign of injury, which has also been confirmed in experimental CLP models [14]. In the mouse liver, the loss of PGC1α and reduced mitochondrial activity have been reported to manifest in enhanced vacuole formation and fatty liver disease [39]. This is also reported for septic patients: morphologically, post mortem liver sections from these patients show increased hepatic vacuolization [16].…”

Section: Discussionmentioning

confidence: 73%

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Impact of hyperglycemia on cystathionine-γ-lyase expression during resuscitated murine septic shock

Merz

Vogt

Wachter

et al. 2017

ICMx

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BackgroundCystathionine-γ-lyase (CSE) was shown to have a regulatory role in glucose metabolism. Circulatory shock can induce metabolic stress, thereby leading to hyperglycemia and mitochondrial dysfunction. In vitro data suggest an effect of high glucose on CSE expression. Therefore, the aim of this study was to investigate the effects of hyperglycemia on CSE expression in resuscitated murine septic shock.MethodsNormo- (80–150 mg/dl) and hyperglycemic (>200 mg/dl) male C57/BL6J mice (n = 5-6 per group) underwent cecal ligation and puncture (CLP)-induced polymicrobial sepsis or sham procedure (n = 6 per group) and, 15 h afterwards, were anesthetized again, surgically instrumented and received intensive care treatment, including antibiotics, lung protective mechanical ventilation, circulatory support, and intravenous (i.v.) glucose infusion (50% as stable-isotope labeled 1,2,3,4,5,6–13C6 glucose). Blood and breath gas were sampled hourly to quantify parameters of glucose metabolism. 5 h later, mice were sacrificed and organs were harvested. The liver mitochondrial respiratory activity was determined via high resolution respirometry; CSE, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and adipocyte differentiation-related protein (ADRP) expression was immunohistochemically investigated.ResultsIn sepsis combined with hyperglycemia the least CSE and PGC1α expression could be detected, along with reduced mitochondrial respiratory activity, and enhanced ADRP expression, a marker of lipid droplet formation, in the liver. A novel in vivo finding is the CSE translocation from the cytosol to the nucleus triggered by metabolic stress.ConclusionsA relationship between CSE and glucose metabolism was established, which, when dysregulated, may contribute to fatty liver disease and hepatic steatosis.

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Section: Discussionmentioning

confidence: 73%

“…The reduction of PGC1α may not only lead to impaired function but to a total decrease in the number of mitochondria [39]. This resulting state of reduced mitochondrial respiration is a sign of injury, which has also been confirmed in experimental CLP models [14].…”

Section: Discussionmentioning

confidence: 99%

Impact of hyperglycemia on cystathionine-γ-lyase expression during resuscitated murine septic shock

Merz

Vogt

Wachter

et al. 2017

ICMx

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“…These effects appear to be independent of the demonstrated effects of central resistin action on thermogenesis [21, 22]. While central effects and/or reduced SNS activity in the Retn tg BAT might cause epigenetic imprinting detectable even ex vivo, it seems most likely that the transgene-mediated overexpression of the characteristically white adipocyte-associated protein resistin in brown adipocytes may push these cells towards a ‘whiter’—though still responsive—functional phenotype with increased endoplasmic reticulum stress or reduced mitochondrial activity [24, 25]. …”

Section: Discussionmentioning

confidence: 99%

Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice

et al. 2014

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Aims/hypothesis Resistin was originally identified as an adipocyte-derived factor upregulated during obesity and as a contributor to obesity-associated insulin resistance. Clinically, resistin has also been implicated in cardiovascular disease in a number of different patient populations. Our aim was to simultaneously address these phenomena. Methods We generated mice with modest adipocyte-specific resistin overexpression. These mice were crossed with mice deficient in the LDL receptor (Ldlr−/−) to probe the physiological role of resistin. Both metabolic and atherosclerotic assessments were performed. Results Resistin overexpression led to increased atherosclerotic progression in Ldlr−/− mice. This was in part related to elevated serum triacylglycerol levels and a reduced ability to clear triacylglycerol upon a challenge. Additional phenotypic changes, such as increased body weight and reduced glucose clearance, independent of the Ldlr−/− background, confirmed increased adiposity associated with a more pronounced insulin resistance. A hallmark of elevated resistin was the disproportionate increase in circulating leptin levels. These mice thus recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. A unifying mechanism for this complex phenotype was a resistin-mediated central leptin resistance, which we demonstrate directly both in vivo and in organotypic brain slices. In line with reduced sympathetic nervous system outflow, we found decreased brown adipose tissue (BAT) activity. The resulting elevated triacylglycerol levels provide a likely explanation for accelerated atherosclerosis. Conclusions/interpretation Resistin overexpression leads to a complex metabolic phenotype driven by resistin-mediated central leptin resistance and reduced BAT activity. Hypothalamic leptin resistance thus provides a unifying mechanism for both resistin-mediated insulin resistance and enhanced atherosclerosis.

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“…Although adipocyte-derived murine resistin has been shown to link insulin resistance to obesity and even type-2 diabetes [Gabriely et al, 2002;Levy et al, 2002;Sánchez-Solana et al, 2012;Steppan et al, 2001;Zhou et al, 2012] 2009; Bauer et al, 2011;Degawa-Yamauchi et al, 2003;Lee et al, 2003;McTernan et al, 2002;Nagaev & Smith, 2001;Pfützner et al, 2003;Savage et al, 2001;Schwartz & Lazar, 2011]. Experiments with transgenic mice expressing human resistin indicate that human resistin is the key in the development of insulin resistance and in adipose tissue inflammation [Park et al, 2011;Qatanani et al, 2009].…”

Section: Introductionmentioning

confidence: 95%

Rapid cloning and comparative sequence analysis of full‐length cDNA of Rhesus monkey (Macaca mulatta) resistin

Sun

et al. 2013

American J Primatol

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Resistin protein is thought to link insulin resistance in murine models of obesity and type-2 diabetes, but the role of resistin in human studies of inflammatory metabolic disorders have generated conflicting data. Here, we describe the structure of the resistin gene using adipose tissue from non-human primates (NHPs), which have been used extensively to model a host of human diseases. Full-length cDNA from rhesus macaque resistin obtained by rapid amplification of cDNA ends (RACE) is comprised of 526 nucleotides covering an open-reading frame (ORF) that encodes a 108-amino-acid protein that is 92% homologous with the human counterpart but only 60% homologous with the murine counterpart. Using a modified polymerase chain reaction technique, we identified single nucleotide polymorphisms and a 78-bp deletion within resistin cDNA of nine rhesus macaques. Comparisons of the full-length cDNA sequence and an amplified 569-bp genomic DNA sequence revealed an error in published predictions arising from genomic studies about the gene's exon 3 region. Our data show, for the first time, the full-length macaque resistin cDNA sequence (GenBank: JF740676.1). These findings will illuminate future studies into the role of resistin in NHP models of inflammatory metabolic diseases.

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Resistin reduces mitochondria and induces hepatic steatosis in mice by the protein kinase C/protein kinase G/p65/PPAR gamma coactivator 1 alpha pathway

Cited by 44 publications

References 32 publications

Impact of hyperglycemia on cystathionine-γ-lyase expression during resuscitated murine septic shock

Impact of hyperglycemia on cystathionine-γ-lyase expression during resuscitated murine septic shock

Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice

Rapid cloning and comparative sequence analysis of full‐length cDNA of Rhesus monkey (Macaca mulatta) resistin

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