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Lipocalin-2 deficiency impairs thermogenesis and potentiates diet-induced insulin resistance in mice.

Guo H, Jin D, Zhang Y, Wright W, Bazuine M, Brockman DA, Bernlohr DA, Chen X - Diabetes (2010)

Bottom Line: Lipocalin (LCN) 2 belongs to the lipocalin subfamily of low-molecular mass-secreted proteins that bind small hydrophobic molecules.LCN2 has been recently characterized as an adipose-derived cytokine, and its expression is upregulated in adipose tissue in genetically obese rodents.Gene expression patterns in white and brown adipose tissue, liver, and muscle indicate that LCN2(-/-) mice have increased hepatic gluconeogenesis, decreased mitochondrial oxidative capacity, impaired lipid metabolism, and increased inflammatory state under the HFD condition.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, University of Minnesota, Minneapolis-St. Paul, Minnesota, USA.

ABSTRACT

Objective: Lipocalin (LCN) 2 belongs to the lipocalin subfamily of low-molecular mass-secreted proteins that bind small hydrophobic molecules. LCN2 has been recently characterized as an adipose-derived cytokine, and its expression is upregulated in adipose tissue in genetically obese rodents. The objective of this study was to investigate the role of LCN2 in diet-induced insulin resistance and metabolic homeostasis in vivo.

Research design and methods: Systemic insulin sensitivity, adaptive thermogenesis, and serum metabolic and lipid profile were assessed in LCN2-deficient mice fed a high-fat diet (HFD) or regular chow diet.

Results: The molecular disruption of LCN2 in mice resulted in significantly potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance. LCN2(-/-) mice exhibit impaired adaptive thermogenesis and cold intolerance. Gene expression patterns in white and brown adipose tissue, liver, and muscle indicate that LCN2(-/-) mice have increased hepatic gluconeogenesis, decreased mitochondrial oxidative capacity, impaired lipid metabolism, and increased inflammatory state under the HFD condition.

Conclusions: LCN2 has a novel role in adaptive thermoregulation and diet-induced insulin resistance.

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Related in: MedlinePlus

Liver triacyglyceride content in LCN2−/− mice. A: Oil-red O staining of liver section of LCN2 −/− mice. B: Liver triacyglyceride levels in LCN2−/− mice on an RCD (n = 6–8, age 30 weeks) and an HFD (n = 11, age 15–16 weeks). C: The mRNA expression of gluocneogenic genes in liver (n = 6). D: The mRNA expression of lipogenic genes in liver (n = 6). The data are represented as means ± SE. *P < 0.05; **P < 0.01. (A high-quality digital color representation of this figure is available in the online issue.)
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Figure 6: Liver triacyglyceride content in LCN2−/− mice. A: Oil-red O staining of liver section of LCN2 −/− mice. B: Liver triacyglyceride levels in LCN2−/− mice on an RCD (n = 6–8, age 30 weeks) and an HFD (n = 11, age 15–16 weeks). C: The mRNA expression of gluocneogenic genes in liver (n = 6). D: The mRNA expression of lipogenic genes in liver (n = 6). The data are represented as means ± SE. *P < 0.05; **P < 0.01. (A high-quality digital color representation of this figure is available in the online issue.)

Mentions: To investigate whether increased liver weight in LCN2−/− mice is associated with the development of fatty liver and dyslipidemia, liver triglyceride content and blood lipid profiles were measured. In comparison with wild-type controls, HFD-fed and aged LCN2−/− mice demonstrated a significant increase in lipid accumulation as detected by oil-red o staining of the liver section (Fig. 6A) and the increased levels of liver triglycerides (Fig. 6B). The development of more severe fatty liver disease, together with elevated fasting blood glucose levels, suggests hepatic insulin resistance in LCN2−/− mice. To elucidate hepatic glucose production in wild-type and LCN2-deficient mice fed an HFD, mice were fasted for 18 h and gene expression of two key gluconeogenic enzymes PEPCK and glucose-6-phosphatase (G6Pase) were detected by quantitative PCR. As illustrated in Fig. 6C, expression levels of PEPCK1, PEPCK2, and G6Pase genes were significantly higher in the liver of LCN2−/− mice than that in wild-type controls, suggesting that increased hepatic glucose production is attributed to hyperglycemia in LCN2−/− mice. We next examined the hepatic capabilities for fatty acid synthesis and oxidation to explore the possible mechanism for the development of fatty liver in LCN2−/− mice. As illustrated in Fig. 6D, the lipogenic genes sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase 1 (ACC1), Spot 14 (S14), and SCD-1 were expressed at a significantly higher level in HFD-fed LCN2−/− mice compared with wild-type controls, while genes involved in fatty acid oxidation such as PPARα, CPT-1, and acetyl-CoA carboxylase 2 were similarly expressed between genotypes (data not shown). Therefore, the development of fatty liver results primarily from the increased capability for fatty acid synthesis in the liver in LCN2−/− mice.


Lipocalin-2 deficiency impairs thermogenesis and potentiates diet-induced insulin resistance in mice.

Guo H, Jin D, Zhang Y, Wright W, Bazuine M, Brockman DA, Bernlohr DA, Chen X - Diabetes (2010)

Liver triacyglyceride content in LCN2−/− mice. A: Oil-red O staining of liver section of LCN2 −/− mice. B: Liver triacyglyceride levels in LCN2−/− mice on an RCD (n = 6–8, age 30 weeks) and an HFD (n = 11, age 15–16 weeks). C: The mRNA expression of gluocneogenic genes in liver (n = 6). D: The mRNA expression of lipogenic genes in liver (n = 6). The data are represented as means ± SE. *P < 0.05; **P < 0.01. (A high-quality digital color representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2874698&req=5

Figure 6: Liver triacyglyceride content in LCN2−/− mice. A: Oil-red O staining of liver section of LCN2 −/− mice. B: Liver triacyglyceride levels in LCN2−/− mice on an RCD (n = 6–8, age 30 weeks) and an HFD (n = 11, age 15–16 weeks). C: The mRNA expression of gluocneogenic genes in liver (n = 6). D: The mRNA expression of lipogenic genes in liver (n = 6). The data are represented as means ± SE. *P < 0.05; **P < 0.01. (A high-quality digital color representation of this figure is available in the online issue.)
Mentions: To investigate whether increased liver weight in LCN2−/− mice is associated with the development of fatty liver and dyslipidemia, liver triglyceride content and blood lipid profiles were measured. In comparison with wild-type controls, HFD-fed and aged LCN2−/− mice demonstrated a significant increase in lipid accumulation as detected by oil-red o staining of the liver section (Fig. 6A) and the increased levels of liver triglycerides (Fig. 6B). The development of more severe fatty liver disease, together with elevated fasting blood glucose levels, suggests hepatic insulin resistance in LCN2−/− mice. To elucidate hepatic glucose production in wild-type and LCN2-deficient mice fed an HFD, mice were fasted for 18 h and gene expression of two key gluconeogenic enzymes PEPCK and glucose-6-phosphatase (G6Pase) were detected by quantitative PCR. As illustrated in Fig. 6C, expression levels of PEPCK1, PEPCK2, and G6Pase genes were significantly higher in the liver of LCN2−/− mice than that in wild-type controls, suggesting that increased hepatic glucose production is attributed to hyperglycemia in LCN2−/− mice. We next examined the hepatic capabilities for fatty acid synthesis and oxidation to explore the possible mechanism for the development of fatty liver in LCN2−/− mice. As illustrated in Fig. 6D, the lipogenic genes sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase 1 (ACC1), Spot 14 (S14), and SCD-1 were expressed at a significantly higher level in HFD-fed LCN2−/− mice compared with wild-type controls, while genes involved in fatty acid oxidation such as PPARα, CPT-1, and acetyl-CoA carboxylase 2 were similarly expressed between genotypes (data not shown). Therefore, the development of fatty liver results primarily from the increased capability for fatty acid synthesis in the liver in LCN2−/− mice.

Bottom Line: Lipocalin (LCN) 2 belongs to the lipocalin subfamily of low-molecular mass-secreted proteins that bind small hydrophobic molecules.LCN2 has been recently characterized as an adipose-derived cytokine, and its expression is upregulated in adipose tissue in genetically obese rodents.Gene expression patterns in white and brown adipose tissue, liver, and muscle indicate that LCN2(-/-) mice have increased hepatic gluconeogenesis, decreased mitochondrial oxidative capacity, impaired lipid metabolism, and increased inflammatory state under the HFD condition.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, University of Minnesota, Minneapolis-St. Paul, Minnesota, USA.

ABSTRACT

Objective: Lipocalin (LCN) 2 belongs to the lipocalin subfamily of low-molecular mass-secreted proteins that bind small hydrophobic molecules. LCN2 has been recently characterized as an adipose-derived cytokine, and its expression is upregulated in adipose tissue in genetically obese rodents. The objective of this study was to investigate the role of LCN2 in diet-induced insulin resistance and metabolic homeostasis in vivo.

Research design and methods: Systemic insulin sensitivity, adaptive thermogenesis, and serum metabolic and lipid profile were assessed in LCN2-deficient mice fed a high-fat diet (HFD) or regular chow diet.

Results: The molecular disruption of LCN2 in mice resulted in significantly potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance. LCN2(-/-) mice exhibit impaired adaptive thermogenesis and cold intolerance. Gene expression patterns in white and brown adipose tissue, liver, and muscle indicate that LCN2(-/-) mice have increased hepatic gluconeogenesis, decreased mitochondrial oxidative capacity, impaired lipid metabolism, and increased inflammatory state under the HFD condition.

Conclusions: LCN2 has a novel role in adaptive thermoregulation and diet-induced insulin resistance.

Show MeSH
Related in: MedlinePlus