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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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Plasma measurements in control, MC4R-/-, and loxTB mice. Blood samples were collected at 19 weeks of age as described in the Methods. A) Blood Glucose, B) Plasma Insulin, C) Plasma adiponectin. *=P<0.05 as compared to corresponding value in non-CoPP treated group. †=P<0.05 as compared to corresponding value in control mice. ‡ =P<0.05 as compared to corresponding value in MC4R-/- mice. n=6/group
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Figure 3: Plasma measurements in control, MC4R-/-, and loxTB mice. Blood samples were collected at 19 weeks of age as described in the Methods. A) Blood Glucose, B) Plasma Insulin, C) Plasma adiponectin. *=P<0.05 as compared to corresponding value in non-CoPP treated group. †=P<0.05 as compared to corresponding value in control mice. ‡ =P<0.05 as compared to corresponding value in MC4R-/- mice. n=6/group

Mentions: Fasting blood glucose levels were significantly increased in both loxTB and MC4R KO mice as compared to control mice. Chronic CoPP treatment equivalently lowered fasting blood glucose levels in both loxTB and MC4R KO mice but had no effect on fasting blood glucose levels in control mice (Figure 3A). Both models of MC4R deficiency exhibited increased fasting insulin levels as compared with control mice (Figure 3B). However, plasma insulin levels were significantly higher in loxTB mice as compared to MC4R KO mice. CoPP treatment significantly decreased fasting insulin levels in both models of MC4R deficiency. Plasma adiponectin levels in loxTB mice were significantly decreased as compared to control mice under basal conditions (Figure 3C). This finding was also confirmed in MC4R KO mice (Figure 3C). CoPP treatment significantly increased plasma adiponectin levels in all groups; however, the increase in the MC4R deficient mice was close to 4 fold as compared to a 70% increase exhibited in control mice (Figure 3C).


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)

Plasma measurements in control, MC4R-/-, and loxTB mice. Blood samples were collected at 19 weeks of age as described in the Methods. A) Blood Glucose, B) Plasma Insulin, C) Plasma adiponectin. *=P<0.05 as compared to corresponding value in non-CoPP treated group. †=P<0.05 as compared to corresponding value in control mice. ‡ =P<0.05 as compared to corresponding value in MC4R-/- mice. n=6/group
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3139690&req=5

Figure 3: Plasma measurements in control, MC4R-/-, and loxTB mice. Blood samples were collected at 19 weeks of age as described in the Methods. A) Blood Glucose, B) Plasma Insulin, C) Plasma adiponectin. *=P<0.05 as compared to corresponding value in non-CoPP treated group. †=P<0.05 as compared to corresponding value in control mice. ‡ =P<0.05 as compared to corresponding value in MC4R-/- mice. n=6/group
Mentions: Fasting blood glucose levels were significantly increased in both loxTB and MC4R KO mice as compared to control mice. Chronic CoPP treatment equivalently lowered fasting blood glucose levels in both loxTB and MC4R KO mice but had no effect on fasting blood glucose levels in control mice (Figure 3A). Both models of MC4R deficiency exhibited increased fasting insulin levels as compared with control mice (Figure 3B). However, plasma insulin levels were significantly higher in loxTB mice as compared to MC4R KO mice. CoPP treatment significantly decreased fasting insulin levels in both models of MC4R deficiency. Plasma adiponectin levels in loxTB mice were significantly decreased as compared to control mice under basal conditions (Figure 3C). This finding was also confirmed in MC4R KO mice (Figure 3C). CoPP treatment significantly increased plasma adiponectin levels in all groups; however, the increase in the MC4R deficient mice was close to 4 fold as compared to a 70% increase exhibited in control mice (Figure 3C).

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