Role of resistin in diet-induced hepatic insulin resistance

Muse, Evan D.; Obici, Silvana; Bhanot, Sanjay; Monia, Brett P.; McKay, Robert A.; Rajala, Michael W.; Scherer, Philipp E.; Rossetti, Luciano

doi:10.1172/jci200421270

Cited by 294 publications

(193 citation statements)

References 41 publications

(19 reference statements)

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“…The reduction in glycogen synthesis is particularly important and we went on to show that this effect correlated with decreased GSK-3β phosphorylation, whereas total protein content was unaltered. The ability of insulin to stimulate hepatic Akt and GSK-3 phosphorylation was previously shown to be enhanced by antisense-mediated knockdown of circulating resistin levels [30]. Here, our results are consistent with a mechanism involving defects in IRS-1, Akt-1 and GSK-3β leading to decreased glycogen synthesis in skeletal muscle cells.…”

Section: Discussionsupporting

confidence: 90%

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Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

et al. 2005

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Aims/hypothesis: Debate exists regarding the role of resistin in the pathophysiology of insulin resistance. The aim of this study was to directly assess the effects of resistin (0-24 h) on basal and insulin-stimulated glucose uptake and metabolism in skeletal muscle cells and to investigate the mechanisms responsible for the effects of resistin. Methods: We used L6 rat skeletal muscle cells and examined [ 3 H]2-deoxyglucose uptake, GLUT4 translocation and GLUT protein content. We assessed glucose metabolism by measuring the incorporation of D-[U-14 C] glucose into glycogen, 14 CO 2 and lactate production, as well as the phosphorylation level and total protein content of insulin signalling proteins, including insulin receptor β-subunit (IRβ), insulin receptor substrate (IRS), Akt and glycogen synthase kinase-3β (GSK-3β). Results: Treatment of L6 rat skeletal muscle cells with recombinant resistin (50 nmol/l, 0-24 h) reduced levels of basal and insulin-stimulated 2-deoxyglucose uptake and decreased insulin-stimulated GLUT4myc content at the cell surface, with no alteration in the production of GLUT4 or GLUT1. Resistin also decreased glycogen synthesis and GSK-3β phosphorylation. Insulin-stimulated oxidation of glucose via the Krebs cycle was reduced by resistin, whereas lactate production was unaltered. Although insulin receptor protein level and phosphorylation were unaltered by resistin, production of IRS-1, but not IRS-2, was downregulated and a decreased tyrosine phosphorylation of IRS-1 was detected. Reduced phosphorylation of Akt on T308 and S473 was observed, while total Akt and Akt1, but not Akt2 or Akt3, production was decreased. Conclusions/ interpretation: Our data show that resistin regulates the function of IRS-1 and Akt1 and decreases GLUT4 translocation and glucose uptake in response to insulin. Selective decreases in insulin-stimulated glucose metabolism via oxidation and conversion to glycogen were also induced by resistin. These observations highlight the potential role of resistin in the pathophysiology of type 2 diabetes in obesity.

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Section: Discussionsupporting

confidence: 90%

“…Considerable debate exists regarding the role of resistin in the pathophysiology of insulin resistance in humans and animals and as to whether resistin acts primarily in muscle, liver or fat [2,3,5,[29][30][31][32]. However, several studies provide convincing evidence for an effect of resistin in skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

et al. 2005

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“…Mice fed a high-fat diet developed hepatic insulin resistance which was accompanied by an increase in plasma resistin levels and which was completely reversed by antisense resistin [43]. In our experiment, plasma resistin levels were normal.…”

Section: Discussionsupporting

confidence: 44%

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

et al. 2006

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Aims/hypothesis: We used oestrogen receptor-α (ERα) knockout (ERKO) and receptor-β (ERβ) knockout (BERKO) mice to investigate the mechanism(s) behind the effects of oestrogens on glucose homeostasis. Methods: Endogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic-hyperinsulinaemic clamp. Insulin secretion was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding stearoyl-CoA desaturase 1 and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR. Results: ERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the adiponectin concentration was decreased in ERKO mice. Levels of both glucose-and arginine-induced insulin secretion from isolated islets were similar in ERKO and wild-type mice. The euglycaemichyperinsulinaemic clamp revealed that suppression of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release. Conclusions/interpretation: We conclude that oestrogens, acting via ERα, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity, which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.

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“…[6][7][8][9][10][11] In the current studies, we concentrated on the role of resistin in lipid metabolism. We tested the hypothesis that resistin might promote release of FFA from adipocytes by suppressing the re-esterfication of FFA into triglycerides.…”

Section: Discussionmentioning

confidence: 99%

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

et al. 2006

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Objective: To investigate the mechanism by which fat-specific transgenic expression of resistin affects fatty acid metabolism in the spontaneously hypertensive rat (SHR). Design: Basal-and adrenaline-stimulated lipolysis, basal-and insulin-stimulated lipogenesis as well as the site (glycerol versus acyl moiety) of glucose incorporated into triglycerides were determined in adipose tissue isolated from SHR-Resistin transgenic and SHR control rats. Results: A moderate expression of transgenic resistin in adipose tissue was associated with significant increase in the FFA/ glycerol ratio during adrenaline-stimulated lipolysis in the SHR-Resistin transgenic rats (3.2770.26) compared to SHR controls (2.1170.10, P ¼ 0.0005). Transgenic SHR also exhibited a significant decrease in FFA re-esterification in adipose tissue (approximately by 23%). Conclusion: These findings raise the possibility that the prodiabetic effects of transgenic resistin may be partly mediated by increased FFA release from adipose tissue due to impaired FFA re-esterification in adipocytes.

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Role of resistin in diet-induced hepatic insulin resistance

Cited by 294 publications

References 41 publications

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

Fat-specific transgenic expression of resistin in the spontaneously hypertensive rat impairs fatty acid re-esterification

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