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Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3?.

ABSTRACT: The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3? (GSK-3?) (P<0.001). No differences in the protein levels for the insulin receptor ? (IR?), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P<0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P<0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3? in the liver tissue was also decreased (P<0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggest that resistin reduces the levels of GSK-3? phosphorylated at Ser 9 leading to impaired hepatic insulin action in primary rat hepatocytes and in a mouse model with high liver-specific expression of resistin.

SUBMITTER: Song R

PROVIDER: S-EPMC3897445 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β.

Song Rongjing R Wang Xi X Mao Yiqing Y Li Hui H Li Zhixin Z Xu Wei W Wang Rong R Guo Tingting T Jin Ling L Zhang Xiaojing X Zhang Yizhuang Y Zhou Na N Hu Ruobi R Jia Jianwei J Lei Zhen Z Irwin David M DM Niu Gang G Tan Huanran H

Gene 20130713 1

The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signalin ...[more]

PMID: 23860320

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Project description:BACKGROUND: Relatively little is known about the role of specific saturated fatty acids in the development of high fat diet induced obesity and insulin resistance. Here, we have studied the effect of stearate in high fat diets (45% energy as fat) on whole body energy metabolism and tissue specific insulin sensitivity. METHODS: C57Bl/6 mice were fed a low stearate diet based on palm oil or one of two stearate rich diets, one diet based on lard and one diet based on palm oil supplemented with tristearin (to the stearate level of the lard based diet), for a period of 5 weeks. Ad libitum fed Oxidative metabolism was assessed by indirect calorimetry at week 5. Changes in body mass and composition was assessed by DEXA scan analysis. Tissue specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis and Western blot at the end of week 5. RESULTS: Indirect calorimetry analysis revealed that high levels of dietary stearate resulted in lower caloric energy expenditure characterized by lower oxidation of fatty acids. In agreement with this metabolic phenotype, mice on the stearate rich diets gained more adipose tissue mass. Whole body and tissue specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp and analysis of insulin induced PKBser473 phosphorylation. Whole body insulin sensitivity was decreased by all high fat diets. However, while insulin-stimulated glucose uptake by peripheral tissues was impaired by all high fat diets, hepatic insulin sensitivity was affected only by the stearate rich diets. This tissue-specific pattern of reduced insulin sensitivity was confirmed by similar impairment in insulin-induced phosphorylation of PKBser473 in both liver and skeletal muscle. CONCLUSION: In C57Bl/6 mice, 5 weeks of a high fat diet rich in stearate induces a metabolic state favoring low oxidative metabolism, increased adiposity and whole body insulin resistance characterized by severe hepatic insulin resistance. These results indicate that dietary fatty acid composition per sé rather than dietary fat content determines insulin sensitivity in liver of high fat fed C57Bl/6 mice.

Dataset Information

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3?.

Publications

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β.

Similar Datasets

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