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Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-gamma activation and function in lipid homeostasis and energy expenditure.

ABSTRACT: We have previously identified lipocalin 2 (Lcn2) as a cytokine playing a critical role in the regulation of body fat mass, lipid metabolism, and insulin resistance. Lcn2 deficiency reduces PPAR? gene expression in adipocytes. In this study, we investigated the role of Lcn2 in PPAR? activation and function via assessing the insulin sensitization and fatty acid (FA) homeostasis of PPAR? agonist in high-fat diet (HFD)-induced obesity in Lcn2(-/-) mice. We found that rosiglitazone (Rosi) significantly improved insulin sensitivity in Lcn2(-/-) mice as effectively as in wild-type (WT) mice; unfed-state levels of blood glucose, free FAs, and triglycerides (TGs) were significantly reduced after a 25-d treatment of Rosi in Lcn2(-/-) mice. However, Rosi action on fat deposition and FA homeostasis was altered; Rosi-induced body weight and subcutaneous fat gain and liver lipid accumulation were markedly lessened in Lcn2(-/-) mice. The results of in vivo metabolic labeling showed that Rosi markedly reduced de novo lipogenesis in adipose tissue of Lcn2(-/-) mice. In brown adipose tissue (BAT), the expression of the genes functioning in TG hydrolysis and mitochondrial oxidation was up-regulated more in Lcn2(-/-) than in WT mice. Most strikingly, Rosi stimulated significantly higher levels of uncoupling protein-1 expression in BAT, and completely rescued cold intolerance in Lcn2(-/-) mice. We demonstrate that Lcn2 is a critical selective modulator of PPAR? activation and function in lipid homeostasis and energy expenditure.

SUBMITTER: Jin D

PROVIDER: S-EPMC3023388 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-gamma activation and function in lipid homeostasis and energy expenditure.

Jin Daozhong D Guo Hong H Bu So Young SY Zhang Yuanyuan Y Hannaford Jennifer J Mashek Douglas G DG Chen Xiaoli X

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20101025 2

We have previously identified lipocalin 2 (Lcn2) as a cytokine playing a critical role in the regulation of body fat mass, lipid metabolism, and insulin resistance. Lcn2 deficiency reduces PPARγ gene expression in adipocytes. In this study, we investigated the role of Lcn2 in PPARγ activation and function via assessing the insulin sensitization and fatty acid (FA) homeostasis of PPARγ agonist in high-fat diet (HFD)-induced obesity in Lcn2(-/-) mice. We found that rosiglitazone (Rosi) significant ...[more]

PMID: 20974668

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Project description:CHS-131 is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic effects and less fluid retention and weight gain compared to thiazolidinediones in phase II clinical trials. We investigated the effects of CHS-131 on metabolic parameters and liver histopathology in a diet-induced obese (DIO) and biopsy-confirmed mouse model of nonalcoholic steatohepatitis (NASH). Male C57BL/6JRj mice were fed the amylin liver NASH diet (40% fat with trans-fat, 20% fructose, and 2% cholesterol). After 36 weeks, only animals with biopsy-confirmed steatosis and fibrosis were included and stratified into treatment groups (n = 12-13) to receive for the next 12 weeks (1) low-dose CHS-131 (10 mg/kg), (2) high-dose CHS-131 (30 mg/kg), or (3) vehicle. Metabolic parameters, liver pathology, metabolomics/lipidomics, markers of liver function and liver, and subcutaneous and visceral adipose tissue gene expression profiles were assessed. CHS-131 did not affect body weight, fat mass, lean mass, water mass, or food intake in DIO-NASH mice with fibrosis. CHS-131 improved fasting insulin levels and insulin sensitivity as assessed by the intraperitoneal insulin tolerance test. CHS-131 improved total plasma cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase and increased plasma adiponectin levels. CHS-131 (high dose) improved liver histology and markers of hepatic fibrosis. DIO-NASH mice treated with CHS-131 demonstrated a hepatic shift to diacylglycerols and triacylglycerols with a lower number of carbons, increased expression of genes stimulating fatty acid oxidation and browning, and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis, and inflammation in adipose tissue. Conclusion: CHS-131 improves liver histology in a DIO and biopsy-confirmed mouse model of NASH by altering the hepatic lipidome, reducing insulin resistance, and improving lipid metabolism and inflammation in adipose tissue.

Dataset Information

Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-gamma activation and function in lipid homeostasis and energy expenditure.

Publications

Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-gamma activation and function in lipid homeostasis and energy expenditure.

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