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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

Assessment of insulin sensitivity. GTTs (A) and ITTs (C) conducted in LCN2−/− mice on an HFD (n = 10–12, age 14–15 weeks). GTTs (B) and ITTs (D) conducted in LCN2−/− mice on an RCD (n = 10–12, age 28–29 weeks). Data are represented as means ± SE. Experiments were repeated on two independent sets of mice, yielding similar results. *P < 0.05; **P < 0.01.
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Figure 3: Assessment of insulin sensitivity. GTTs (A) and ITTs (C) conducted in LCN2−/− mice on an HFD (n = 10–12, age 14–15 weeks). GTTs (B) and ITTs (D) conducted in LCN2−/− mice on an RCD (n = 10–12, age 28–29 weeks). Data are represented as means ± SE. Experiments were repeated on two independent sets of mice, yielding similar results. *P < 0.05; **P < 0.01.

Mentions: To assess the effects of LCN2 deficiency on systemic insulin sensitivity, GTTs and ITTs were performed. Glucose clearance curves in response to glucose administration were significantly increased in HFD-fed (Fig. 3A) but not RCD-fed LCN2−/− mice (Fig. 3B), indicating that LCN2−/− mice are more glucose intolerant upon HFD feeding. In the ITT, increased insulin-stimulated glucose disposal curve was observed in LCN2−/− mice, indicating that LCN2−/− mice are more insulin resistant than wild-type controls when fed an HFD (Fig. 3C) or aged (Fig. 3D). Analysis of serum metabolic parameters, as shown in Table 1, demonstrated that levels of fasting serum glucose and insulin were significantly elevated, while adiponectin levels were reduced in HFD-fed LCN2−/− mice when compared with wild-type controls. Serum levels of leptin and plasminogen activator inhibitor-1 were not significantly changed in LCN2−/− mice on an RCD, although serum leptin levels had a trend toward a decrease in HFD-fed LCN2−/− mice. After adjustment to body weight, the serum levels of glucose, insulin, and adiponectin were consistently different at the statistically significant level, indicating that the changes in glucose tolerance and insulin sensitivity after HFD in LCN2−/− mice is not simply due to body weight effects. To further confirm that LCN2−/− mice have decreased insulin sensitivity, in vivo insulin-stimulated Akt phosphorylation was evaluated. Wild-type and LCN2−/− mice on RCD were injected intraperitoneally with insulin, killed after 10 min, and tissues were collected for evaluation of Akt phosohorylation. Consistently, insulin-stimulated Akt phosphorylation in liver, muscle, and adipose cells was significantly reduced in LCN2−/− mice as compared with wild-type mice (Fig. 4). The examination of LCN2 effect on upstream signaling components of insulin signaling pathway demonstrated that the expression levels of insulin receptor substrate-1 protein were markedly reduced in WAT of LCN2−/− mice on an HFD compared with wild-type mice (Fig. S2). This data further support that LCN2−/− mice developed more insulin resistance and LCN2 regulates insulin signaling activity likely at the upstream level.


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)

Assessment of insulin sensitivity. GTTs (A) and ITTs (C) conducted in LCN2−/− mice on an HFD (n = 10–12, age 14–15 weeks). GTTs (B) and ITTs (D) conducted in LCN2−/− mice on an RCD (n = 10–12, age 28–29 weeks). Data are represented as means ± SE. Experiments were repeated on two independent sets of mice, yielding similar results. *P < 0.05; **P < 0.01.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874698&req=5

Figure 3: Assessment of insulin sensitivity. GTTs (A) and ITTs (C) conducted in LCN2−/− mice on an HFD (n = 10–12, age 14–15 weeks). GTTs (B) and ITTs (D) conducted in LCN2−/− mice on an RCD (n = 10–12, age 28–29 weeks). Data are represented as means ± SE. Experiments were repeated on two independent sets of mice, yielding similar results. *P < 0.05; **P < 0.01.
Mentions: To assess the effects of LCN2 deficiency on systemic insulin sensitivity, GTTs and ITTs were performed. Glucose clearance curves in response to glucose administration were significantly increased in HFD-fed (Fig. 3A) but not RCD-fed LCN2−/− mice (Fig. 3B), indicating that LCN2−/− mice are more glucose intolerant upon HFD feeding. In the ITT, increased insulin-stimulated glucose disposal curve was observed in LCN2−/− mice, indicating that LCN2−/− mice are more insulin resistant than wild-type controls when fed an HFD (Fig. 3C) or aged (Fig. 3D). Analysis of serum metabolic parameters, as shown in Table 1, demonstrated that levels of fasting serum glucose and insulin were significantly elevated, while adiponectin levels were reduced in HFD-fed LCN2−/− mice when compared with wild-type controls. Serum levels of leptin and plasminogen activator inhibitor-1 were not significantly changed in LCN2−/− mice on an RCD, although serum leptin levels had a trend toward a decrease in HFD-fed LCN2−/− mice. After adjustment to body weight, the serum levels of glucose, insulin, and adiponectin were consistently different at the statistically significant level, indicating that the changes in glucose tolerance and insulin sensitivity after HFD in LCN2−/− mice is not simply due to body weight effects. To further confirm that LCN2−/− mice have decreased insulin sensitivity, in vivo insulin-stimulated Akt phosphorylation was evaluated. Wild-type and LCN2−/− mice on RCD were injected intraperitoneally with insulin, killed after 10 min, and tissues were collected for evaluation of Akt phosohorylation. Consistently, insulin-stimulated Akt phosphorylation in liver, muscle, and adipose cells was significantly reduced in LCN2−/− mice as compared with wild-type mice (Fig. 4). The examination of LCN2 effect on upstream signaling components of insulin signaling pathway demonstrated that the expression levels of insulin receptor substrate-1 protein were markedly reduced in WAT of LCN2−/− mice on an HFD compared with wild-type mice (Fig. S2). This data further support that LCN2−/− mice developed more insulin resistance and LCN2 regulates insulin signaling activity likely at the upstream level.

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