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. 2012 Feb;36(2):244-53.
doi: 10.1038/ijo.2011.78. Epub 2011 Apr 5.

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

E Csongradi  1 , J M Docarmo, J H Dubinion, T Vera, D E Stec
Affiliations

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

E Csongradi et al. Int J Obes (Lond). 2012 Feb.

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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Conflict of interest statement

Conflict of Interest The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effect of chronic CoPP treatment on body weight in control C57 mice, melanocortin-4 receptor knockout mice (MC4R-/-), and melanocortin 4 receptor transcriptional blocker (loxTB) mice. CoPP was administered once weekly. n=6/group.
Figure 2
Figure 2
Effect of chronic CoPP treatment on distribution of fat in Control, MC4R-/-, and loxTB mice, n=6/group. Fat pads were weighted from 23 week old mice. *= p<0.05 as compared to corresponding value in non-treated.
Figure 3
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
Figure 4
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.
Figure 5
Figure 5
Effect of chronic CoPP treatment on A) 24 hour heat production and B) 24 hour locomotor activity in control C57 and loxTB mice. * =P< 0.05 as compared to corresponding value in non-CoPP treated mice, n=4/group.
Figure 6
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.
Figure 7
Figure 7
A) Representative Western blots from liver 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=4-6/group.
Figure 8
Figure 8
A) Representative Western blots from muscle of control and CoPP treated loxTB mice. B) Levels of HO-1 protein. C) Levels of pAMPK. D) 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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References

    1. Galbraith RA, Kappas A. Regulation of food intake and body weight by cobalt porphyrins in animals. Proc Natl Acad Sci U S A. 1989;86(19):7653–7657. - PMC - PubMed
    1. Peterson SJ, Drummond G, Kim DH, Li M, Kruger AL, Ikehara S, et al. L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice. J Lipid Res. 2008;49(8):1658–1669. - PMC - PubMed
    1. Peterson SJ, Kim DH, Li M, Positano V, Vanella L, Rodella LF, et al. The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice. J Lipid Res. 2009;50(7):1293–1304. - PMC - PubMed
    1. Galbraith RA, Kappas A. Intracerebroventricular administration of cobalt protoporphyrin elicits prolonged weight reduction in rats. Am J Physiol. 1991;261(6 Pt 2):R1395–R1401. - PubMed
    1. Galbraith RA, Kow LM, Pfaff D, Kappas A. Injection of cobalt protoporphyrin into the medial nuclei of the hypothalamus elicits weight loss. Am J Physiol. 1992;263(4 Pt 2):R805–R812. - PubMed

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