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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) Effect of chronic CoPP treatment on 24 hour O2 consumption in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. B) Effect of chornic CoPP treatment on 24 hour CO2 production in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. * =P< 0.05 as compared to corresponding value in non-CoPP treated mice. † = P<0.05 as compared to corresponding value in non-CoPP treated control mice, n=4/group.
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Figure 4: A) Effect of chronic CoPP treatment on 24 hour O2 consumption in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. B) Effect of chornic CoPP treatment on 24 hour CO2 production in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. * =P< 0.05 as compared to corresponding value in non-CoPP treated mice. † = P<0.05 as compared to corresponding value in non-CoPP treated control mice, n=4/group.

Mentions: Basal O2 consumption was significantly decreased in MC4R deficient loxTB mice as compared to control mice when normalized for total body mass (Figure 4A, left panel). However, Basal O2 consumption when not normalized to body weight was not different in MC4R deficient loxTB mice as compared to control mice (Figure 4A, right panel). Chronic CoPP treatment significantly increased O2 consumption by 20% in control mice and 28% in loxTB mice irrespective normalization (Figure 4A). Basal CO2 production was significantly decreases in loxTB mice as compared to control mice when normalized for total body mass (Figure 4B, left panel). Basal CO2 production when not normalized to body weight was significantly increased in loxTB mice as compared to control mice (Figure 4B, right panel). Chronic CoPP treatment significantly increased CO2 production by 17% in control mice and 28% in loxTB mice and this effect was even more dramatic in loxTB mice when not normalized to body mass (Figure 4B). Chronic CoPP treatment had no effect on 24 hour RQ in loxTB which averaged 0.9 + .02 vs. 0.88 + .04 VO2/VCO2 in loxTB vs. CoPP treated loxTB mice. There was a trend for a decrease in RQ during the day time in CoPP treated loxTB mice with RQ averaging .87 + .01 vs. .82 + .02 VO2/VCO2 in each group respectively. CoPP treatment had no effect on 24 hour RQ in control mice with RQ values averaging 0.83 + .01 VO2/VCO2 in both each group.


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) Effect of chronic CoPP treatment on 24 hour O2 consumption in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. B) Effect of chornic CoPP treatment on 24 hour CO2 production in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. * =P< 0.05 as compared to corresponding value in non-CoPP treated mice. † = P<0.05 as compared to corresponding value in non-CoPP treated control mice, n=4/group.
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Figure 4: A) Effect of chronic CoPP treatment on 24 hour O2 consumption in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. B) Effect of chornic CoPP treatment on 24 hour CO2 production in control C57 and loxTB mice normalized to body mass in the left panel and not normalized in the right panel. * =P< 0.05 as compared to corresponding value in non-CoPP treated mice. † = P<0.05 as compared to corresponding value in non-CoPP treated control mice, n=4/group.
Mentions: Basal O2 consumption was significantly decreased in MC4R deficient loxTB mice as compared to control mice when normalized for total body mass (Figure 4A, left panel). However, Basal O2 consumption when not normalized to body weight was not different in MC4R deficient loxTB mice as compared to control mice (Figure 4A, right panel). Chronic CoPP treatment significantly increased O2 consumption by 20% in control mice and 28% in loxTB mice irrespective normalization (Figure 4A). Basal CO2 production was significantly decreases in loxTB mice as compared to control mice when normalized for total body mass (Figure 4B, left panel). Basal CO2 production when not normalized to body weight was significantly increased in loxTB mice as compared to control mice (Figure 4B, right panel). Chronic CoPP treatment significantly increased CO2 production by 17% in control mice and 28% in loxTB mice and this effect was even more dramatic in loxTB mice when not normalized to body mass (Figure 4B). Chronic CoPP treatment had no effect on 24 hour RQ in loxTB which averaged 0.9 + .02 vs. 0.88 + .04 VO2/VCO2 in loxTB vs. CoPP treated loxTB mice. There was a trend for a decrease in RQ during the day time in CoPP treated loxTB mice with RQ averaging .87 + .01 vs. .82 + .02 VO2/VCO2 in each group respectively. CoPP treatment had no effect on 24 hour RQ in control mice with RQ values averaging 0.83 + .01 VO2/VCO2 in both each group.

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