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Chronic HO-1 induction with cobalt protoporphyrin (CoPP) treatment increases oxygen consumption, activity, heat production and lowers body weight in obese melanocortin-4 receptor-deficient mice.

Csongradi E, Docarmo JM, Dubinion JH, Vera T, Stec DE - Int J Obes (Lond) (2011)

Bottom Line: Despite these findings, the mechanism by which HO-1 induction reduces body weight is unclear.Chronic HO-1 induction does not alter food intake, suggesting other mechanisms such as increases in metabolism and activity may be responsible for the observed reduction of body weight.Our results suggest that chronic HO-1 induction with CoPP induction elicits weight loss by increasing metabolism and activity by an MC4R-independent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, USA.

ABSTRACT

Objective: Heme oxygenase-1 induction (HO-1) elicits chronic weight loss in several rodent models of obesity. Despite these findings, the mechanism by which HO-1 induction reduces body weight is unclear. Chronic HO-1 induction does not alter food intake, suggesting other mechanisms such as increases in metabolism and activity may be responsible for the observed reduction of body weight. In this study, we investigated the mechanism of weight loss elicited by chronic HO-1 induction in a model of genetic obesity due to melanocortin-4 receptor (MC4R) deficiency.

Design: Experiments were performed on loxTB MC4R-deficient mice as well as lean controls. Mice were administered cobalt protoporphyrin (CoPP, 5 mg kg(-1)), an inducer of HO-1, once weekly, from 4 to 23 weeks of age. Body weights were measured weekly and fasted blood glucose and insulin, as well as food intake were determined at 18 weeks of age. Oxygen consumption (VO(2)), CO(2) production (VCO(2)), activity and body heat production were measured at 20 weeks of age.

Results: Chronic CoPP treatment resulted in a significant decrease in body weight from 5 weeks on in loxTB mice. Chronic CoPP treatment resulted in a significant decrease in fasted blood glucose levels, plasma insulin and a significant increase in plasma adiponectin levels in MC4R-deficient mice. Chronic CoPP treatment increased VO(2) (47 ± 4 vs 38 ± 3 ml kg(-1) per min, P<0.05) and VCO(2) (44 ± 7 vs 34 ± 4 ml kg(-1) per min, P<0.05) in treated vs non-treated, MC4R-deficient mice (n=4). Heat production (10%) and activity (18%) were also significantly (P<0.05) increased in CoPP-treated MC4R-deficient mice.

Conclusion: Our results suggest that chronic HO-1 induction with CoPP induction elicits weight loss by increasing metabolism and activity by an MC4R-independent pathway.

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A) Representative Western blots from adipose tissue of control and CoPP treated loxTB mice. B) Levels of HO-1 protein. C) Levels of pAKT. D) Levels of pAMPK. E) Levels of pMTOR. F) Levels of glucose transporter 4 (Glut 4). * =P< 0.05 as compared to corresponding value in non-CoPP treated mice, n=6/group.
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Figure 6: A) Representative Western blots from adipose tissue of control and CoPP treated loxTB mice. B) Levels of HO-1 protein. C) Levels of pAKT. D) Levels of pAMPK. E) Levels of pMTOR. F) Levels of glucose transporter 4 (Glut 4). * =P< 0.05 as compared to corresponding value in non-CoPP treated mice, n=6/group.

Mentions: Chronic CoPP treatment induced HO-1 protein in the adipose tissue of loxTB mice (Figure 6A & B). The induction of HO-1 in the adipose tissue was also associated with increases in pAKT (Figure 6A &C), pAMPK (Figure 6A & D), pMTOR (Figure 6A & E), and Glut 4 (Figure 6A &F). Chronic CoPP treatment induced HO-1 protein in the liver of loxTB mice (Figure 7A &B). However, induction of HO-1 in the liver was not associated with changes in the levels of pAKT (Figure 7A &C), pAMPK (Figure 7A & D), or Glut 4 (Figure 7A & F). Hepatic induction of HO-1 was associated with a decrease in the levels of pMTOR (Figure 7A &E) in loxTB treated mice. Chronic CoPP treatment resulted in significant HO-1 induction in gastrocnemius muscle of loxTB mice (Figures 8A & B). Induction of HO-1 in the muscle was associated with no changes in the levels of pAMPK (Figures 8A & C) but resulted in a significant decrease in the levels of Glut 4 (Figures 8A & D).


Chronic HO-1 induction with cobalt protoporphyrin (CoPP) treatment increases oxygen consumption, activity, heat production and lowers body weight in obese melanocortin-4 receptor-deficient mice.

Csongradi E, Docarmo JM, Dubinion JH, Vera T, Stec DE - Int J Obes (Lond) (2011)

A) Representative Western blots from adipose tissue of control and CoPP treated loxTB mice. B) Levels of HO-1 protein. C) Levels of pAKT. D) Levels of pAMPK. E) Levels of pMTOR. F) Levels of glucose transporter 4 (Glut 4). * =P< 0.05 as compared to corresponding value in non-CoPP treated mice, n=6/group.
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Related In: Results  -  Collection

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Figure 6: A) Representative Western blots from adipose tissue of control and CoPP treated loxTB mice. B) Levels of HO-1 protein. C) Levels of pAKT. D) Levels of pAMPK. E) Levels of pMTOR. F) Levels of glucose transporter 4 (Glut 4). * =P< 0.05 as compared to corresponding value in non-CoPP treated mice, n=6/group.
Mentions: Chronic CoPP treatment induced HO-1 protein in the adipose tissue of loxTB mice (Figure 6A & B). The induction of HO-1 in the adipose tissue was also associated with increases in pAKT (Figure 6A &C), pAMPK (Figure 6A & D), pMTOR (Figure 6A & E), and Glut 4 (Figure 6A &F). Chronic CoPP treatment induced HO-1 protein in the liver of loxTB mice (Figure 7A &B). However, induction of HO-1 in the liver was not associated with changes in the levels of pAKT (Figure 7A &C), pAMPK (Figure 7A & D), or Glut 4 (Figure 7A & F). Hepatic induction of HO-1 was associated with a decrease in the levels of pMTOR (Figure 7A &E) in loxTB treated mice. Chronic CoPP treatment resulted in significant HO-1 induction in gastrocnemius muscle of loxTB mice (Figures 8A & B). Induction of HO-1 in the muscle was associated with no changes in the levels of pAMPK (Figures 8A & C) but resulted in a significant decrease in the levels of Glut 4 (Figures 8A & D).

Bottom Line: Despite these findings, the mechanism by which HO-1 induction reduces body weight is unclear.Chronic HO-1 induction does not alter food intake, suggesting other mechanisms such as increases in metabolism and activity may be responsible for the observed reduction of body weight.Our results suggest that chronic HO-1 induction with CoPP induction elicits weight loss by increasing metabolism and activity by an MC4R-independent pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, USA.

ABSTRACT

Objective: Heme oxygenase-1 induction (HO-1) elicits chronic weight loss in several rodent models of obesity. Despite these findings, the mechanism by which HO-1 induction reduces body weight is unclear. Chronic HO-1 induction does not alter food intake, suggesting other mechanisms such as increases in metabolism and activity may be responsible for the observed reduction of body weight. In this study, we investigated the mechanism of weight loss elicited by chronic HO-1 induction in a model of genetic obesity due to melanocortin-4 receptor (MC4R) deficiency.

Design: Experiments were performed on loxTB MC4R-deficient mice as well as lean controls. Mice were administered cobalt protoporphyrin (CoPP, 5 mg kg(-1)), an inducer of HO-1, once weekly, from 4 to 23 weeks of age. Body weights were measured weekly and fasted blood glucose and insulin, as well as food intake were determined at 18 weeks of age. Oxygen consumption (VO(2)), CO(2) production (VCO(2)), activity and body heat production were measured at 20 weeks of age.

Results: Chronic CoPP treatment resulted in a significant decrease in body weight from 5 weeks on in loxTB mice. Chronic CoPP treatment resulted in a significant decrease in fasted blood glucose levels, plasma insulin and a significant increase in plasma adiponectin levels in MC4R-deficient mice. Chronic CoPP treatment increased VO(2) (47 ± 4 vs 38 ± 3 ml kg(-1) per min, P<0.05) and VCO(2) (44 ± 7 vs 34 ± 4 ml kg(-1) per min, P<0.05) in treated vs non-treated, MC4R-deficient mice (n=4). Heat production (10%) and activity (18%) were also significantly (P<0.05) increased in CoPP-treated MC4R-deficient mice.

Conclusion: Our results suggest that chronic HO-1 induction with CoPP induction elicits weight loss by increasing metabolism and activity by an MC4R-independent pathway.

Show MeSH
Related in: MedlinePlus