Limits...
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.

Show MeSH

Related in: MedlinePlus

Adaptive thermogenesis in LCN2−/− mice. A: Basal rectal body temperature of 8-week-old male and female wild-type and LCN2−/− mice on an RCD (n = 7–10) measured during the daytime in an ambient temperature of 22°C. B: Body temperature curve of LCN2−/− mice (n = 8) and wild-type mice (n = 7) exposed to 4°C. C: Gene expression of LCN2 in WAT of wild-type mice exposed to 4°C for 5 h. D: Gene expression of UCP-1 and PGC-1α in BAT and PPARδ, CPT-1, Tfam, and Nrf1 in skeletal muscle of HFD-fed mice (n = 6). E: Gene expression of UCP-1 and PGC-1α in BAT. F: ATGL protein expression in WAT under the HFD and cold conditions. G: Gene expression of HSL in BAT and WAT of mice exposed to 4°C for 5 h. H: Gene expression of mitochondrial genes in BAT of LCN2−/− mice under the HFD condition. The data are represented as means ± SE. *P < 0.05; **P < 0.01.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2874698&req=5

Figure 2: Adaptive thermogenesis in LCN2−/− mice. A: Basal rectal body temperature of 8-week-old male and female wild-type and LCN2−/− mice on an RCD (n = 7–10) measured during the daytime in an ambient temperature of 22°C. B: Body temperature curve of LCN2−/− mice (n = 8) and wild-type mice (n = 7) exposed to 4°C. C: Gene expression of LCN2 in WAT of wild-type mice exposed to 4°C for 5 h. D: Gene expression of UCP-1 and PGC-1α in BAT and PPARδ, CPT-1, Tfam, and Nrf1 in skeletal muscle of HFD-fed mice (n = 6). E: Gene expression of UCP-1 and PGC-1α in BAT. F: ATGL protein expression in WAT under the HFD and cold conditions. G: Gene expression of HSL in BAT and WAT of mice exposed to 4°C for 5 h. H: Gene expression of mitochondrial genes in BAT of LCN2−/− mice under the HFD condition. The data are represented as means ± SE. *P < 0.05; **P < 0.01.

Mentions: Because LCN2-deficient mice gained more body weight and increased adiposity, particularly when mice were fed an HFD or aged, we examined food intake and energy expenditure in LCN2−/− mice. An analysis of indirect calorimetry measurements showed that food intake, ambulatory activity, Vo2, and RQ were not significantly different between RCD-fed wild-type and LCN2−/− mice at 18 weeks of age (Fig. S1 in the online appendix, available at http://diabetes.diabetesjournals.org/cgi/content/full/db09–1735/DC1). We then assessed thermogenic activity of brown adipose tissue (BAT) under thermoneutral and thermal stress conditions. Body temperature was measured in an ambient temperature of 28°C and 22°C as well as during acute exposure to 4°C. Wild-type and LCN2−/− mice at 12 weeks of age exhibited a similar body temperature in an ambient temperature of 28°C (wild type, 38.34 ± 0.34; LCN2−/−, 38.2 ± 0.30). However, female LCN2−/− mice had a significantly lower rectal temperature than wild-type mice (Fig. 2A), while male LCN2−/− mice had a trend toward decrease in rectal temperature when kept in an ambient temperature of 22°C. More strikingly, LCN2−/− mice displayed cold sensitivity and could not survive when exposed to 4°C for >10 h. LCN2−/− mice (seven of seven) died after being exposed to 4°C for 12 h, while all of the wild-type mice (n = 7) in the experiment survived. When acutely exposed to 4°C, rectal temperature of LCN2−/− mice dropped significantly within 3 h compared with wild-type mice (Fig. 2B). Five-hour cold exposure caused a 10-fold increase in LCN2 gene expression in adipose tissue in wild-type mice (Fig. 2C), suggesting that LCN2 is a critical regulator of energy metabolism.


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)

Adaptive thermogenesis in LCN2−/− mice. A: Basal rectal body temperature of 8-week-old male and female wild-type and LCN2−/− mice on an RCD (n = 7–10) measured during the daytime in an ambient temperature of 22°C. B: Body temperature curve of LCN2−/− mice (n = 8) and wild-type mice (n = 7) exposed to 4°C. C: Gene expression of LCN2 in WAT of wild-type mice exposed to 4°C for 5 h. D: Gene expression of UCP-1 and PGC-1α in BAT and PPARδ, CPT-1, Tfam, and Nrf1 in skeletal muscle of HFD-fed mice (n = 6). E: Gene expression of UCP-1 and PGC-1α in BAT. F: ATGL protein expression in WAT under the HFD and cold conditions. G: Gene expression of HSL in BAT and WAT of mice exposed to 4°C for 5 h. H: Gene expression of mitochondrial genes in BAT of LCN2−/− mice under the HFD condition. The data are represented as means ± SE. *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 2: Adaptive thermogenesis in LCN2−/− mice. A: Basal rectal body temperature of 8-week-old male and female wild-type and LCN2−/− mice on an RCD (n = 7–10) measured during the daytime in an ambient temperature of 22°C. B: Body temperature curve of LCN2−/− mice (n = 8) and wild-type mice (n = 7) exposed to 4°C. C: Gene expression of LCN2 in WAT of wild-type mice exposed to 4°C for 5 h. D: Gene expression of UCP-1 and PGC-1α in BAT and PPARδ, CPT-1, Tfam, and Nrf1 in skeletal muscle of HFD-fed mice (n = 6). E: Gene expression of UCP-1 and PGC-1α in BAT. F: ATGL protein expression in WAT under the HFD and cold conditions. G: Gene expression of HSL in BAT and WAT of mice exposed to 4°C for 5 h. H: Gene expression of mitochondrial genes in BAT of LCN2−/− mice under the HFD condition. The data are represented as means ± SE. *P < 0.05; **P < 0.01.
Mentions: Because LCN2-deficient mice gained more body weight and increased adiposity, particularly when mice were fed an HFD or aged, we examined food intake and energy expenditure in LCN2−/− mice. An analysis of indirect calorimetry measurements showed that food intake, ambulatory activity, Vo2, and RQ were not significantly different between RCD-fed wild-type and LCN2−/− mice at 18 weeks of age (Fig. S1 in the online appendix, available at http://diabetes.diabetesjournals.org/cgi/content/full/db09–1735/DC1). We then assessed thermogenic activity of brown adipose tissue (BAT) under thermoneutral and thermal stress conditions. Body temperature was measured in an ambient temperature of 28°C and 22°C as well as during acute exposure to 4°C. Wild-type and LCN2−/− mice at 12 weeks of age exhibited a similar body temperature in an ambient temperature of 28°C (wild type, 38.34 ± 0.34; LCN2−/−, 38.2 ± 0.30). However, female LCN2−/− mice had a significantly lower rectal temperature than wild-type mice (Fig. 2A), while male LCN2−/− mice had a trend toward decrease in rectal temperature when kept in an ambient temperature of 22°C. More strikingly, LCN2−/− mice displayed cold sensitivity and could not survive when exposed to 4°C for >10 h. LCN2−/− mice (seven of seven) died after being exposed to 4°C for 12 h, while all of the wild-type mice (n = 7) in the experiment survived. When acutely exposed to 4°C, rectal temperature of LCN2−/− mice dropped significantly within 3 h compared with wild-type mice (Fig. 2B). Five-hour cold exposure caused a 10-fold increase in LCN2 gene expression in adipose tissue in wild-type mice (Fig. 2C), suggesting that LCN2 is a critical regulator of energy metabolism.

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