Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

International Journal of Obesity volume 36, pages 244–253 (2012)Cite this article

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 (VO2), CO2 production (VCO2), 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 VO2 (47±4 vs 38±3 ml kg−1 per min, P<0.05) and VCO2 (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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Galbraith RA, Kappas A . Regulation of food intake and body weight by cobalt porphyrins in animals. Proc Natl Acad Sci USA 1989; 86: 7653–7657.

    Article  CAS  Google Scholar 

  2. 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: 1658–1669.

    Article  CAS  Google Scholar 

  3. 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: 1293–1304.

    Article  CAS  Google Scholar 

  4. Galbraith RA, Kappas A . Intracerebroventricular administration of cobalt protoporphyrin elicits prolonged weight reduction in rats. Am J Physiol 1991; 261 (Part 2): R1395–R1401.

    CAS  PubMed  Google Scholar 

  5. 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 (Part 2): R805–R812.

    CAS  PubMed  Google Scholar 

  6. Galbraith RA, Chua Jr SC, Kappas A . Hypothalamic mechanism for cobalt protoporphyrin-induced hypophagia and weight loss: inhibition of the feeding response to NPY. Brain Res Mol Brain Res 1992; 15: 298–302.

    Article  CAS  Google Scholar 

  7. Turner MB, Corp ES, Galbraith RA . Lack of NPY-induced feeding in cobalt protoporphyrin-treated rats is a postreceptor defect. Physiol Behav 1994; 56: 1009–1014.

    Article  CAS  Google Scholar 

  8. Li M, Vizzard MA, Jaworski DM, Galbraith RA . The weight loss elicited by cobalt protoporphyrin is related to decreased activity of nitric oxide synthase in the hypothalamus. J Appl Physiol 2006; 100: 1983–1991.

    Article  CAS  Google Scholar 

  9. Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza S, Munusamy S et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J Biol Chem 2010; 285: 17271–17276.

    Article  CAS  Google Scholar 

  10. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–141.

    Article  CAS  Google Scholar 

  11. Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005; 123: 493–505.

    Article  CAS  Google Scholar 

  12. Ste ML, Miura GI, Marsh DJ, Yagaloff K, Palmiter RD . A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci USA 2000; 97: 12339–12344.

    Article  Google Scholar 

  13. Vaisse C, Clement K, Guy-Grand B, Froguel P . A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 1998; 20: 113–114.

    Article  CAS  Google Scholar 

  14. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O′Rahilly S . A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet 1998; 20: 111–112.

    Article  CAS  Google Scholar 

  15. Ma L, Tataranni PA, Bogardus C, Baier LJ . Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians. Diabetes 2004; 53: 2696–2699.

    Article  CAS  Google Scholar 

  16. Butler AA, Kozak LP . A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes 2010; 59: 323–329.

    Article  CAS  Google Scholar 

  17. Converso DP, Taille C, Carreras MC, Jaitovich A, Poderoso JJ, Boczkowski J . HO-1 is located in liver mitochondria and modulates mitochondrial heme content and metabolism. FASEB J 2006; 20: 1236–1238.

    Article  CAS  Google Scholar 

  18. Slebos DJ, Ryter SW, van der Toorn M, Liu F, Guo F, Baty CJ et al. Mitochondrial localization and function of heme oxygenase-1 in cigarette smoke-induced cell death. Am J Respir Cell Mol Biol 2007; 36: 409–417.

    Article  CAS  Google Scholar 

  19. Di Noia MA, Van Driesche S, Palmieri F, Yang LM, Quan S, Goodman AI et al. Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes. J Biol Chem 2006; 281: 15687–15693.

    Article  CAS  Google Scholar 

  20. Suliman HB, Carraway MS, Ali AS, Reynolds CM, Welty-Wolf KE, Piantadosi CA . The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest 2007; 117: 3730–3741.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Piantadosi CA, Carraway MS, Babiker A, Suliman HB . Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 2008; 103: 1232–1240.

    Article  CAS  Google Scholar 

  22. Rhodes MA, Carraway MS, Piantadosi CA, Reynolds CM, Cherry AD, Wester TE et al. Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans. Am J Physiol Heart Circ Physiol 2009; 297: H392–H399.

    Article  CAS  Google Scholar 

  23. Li M, Kim DH, Tsenovoy PL, Peterson SJ, Rezzani R, Rodella LF et al. Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes 2008; 57: 1526–1535.

    Article  CAS  Google Scholar 

  24. Ignarro LJ, Degnan JN, Baricos WH, Kadowitz PJ, Wolin MS . Activation of purified guanylate cyclase by nitric oxide requires heme. Comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung. Biochim Biophys Acta 1982; 718: 49–59.

    Article  CAS  Google Scholar 

  25. Makino R, Matsuda H, Obayashi E, Shiro Y, Iizuka T, Hori H . EPR characterization of axial bond in metal center of native and cobalt-substituted guanylate cyclase. J Biol Chem 1999; 274: 7714–7723.

    Article  CAS  Google Scholar 

  26. Ndisang JF, Jadhav A . Heme arginate therapy enhanced adiponectin and atrial natriuretic peptide, but abated endothelin-1 with attenuation of kidney histopathological lesions in mineralocorticoid-induced hypertension. J Pharmacol Exp Ther 2010; 334: 87–98.

    Article  CAS  Google Scholar 

  27. Nicolai A, Li M, Kim DH, Peterson SJ, Vanella L, Positano V et al. Heme oxygenase-1 induction remodels adipose tissue and improves insulin sensitivity in obesity-induced diabetic rats. Hypertension 2009; 53: 508–515.

    Article  CAS  Google Scholar 

  28. Ewing JF, Haber SN, Maines MD . Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: hyperthermia causes rapid induction of mRNA and protein. J Neurochem 1992; 58: 1140–1149.

    Article  CAS  Google Scholar 

  29. Rodella L, Lamon BD, Rezzani R, Sangras B, Goodman AI, Falck JR et al. Carbon monoxide and biliverdin prevent endothelial cell sloughing in rats with type I diabetes. Free Radic Biol Med 2006; 40: 2198–2205.

    Article  CAS  Google Scholar 

  30. Turkseven S, Kruger A, Mingone CJ, Kaminski P, Inaba M, Rodella LF et al. Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes. Am J Physiol Heart Circ Physiol 2005; 289: H701–H707.

    Article  CAS  Google Scholar 

  31. Ndisang JF, Jadhav A . Up-regulating the hemeoxygenase system enhances insulin sensitivity and improves glucose metabolism in insulin-resistant diabetes in Goto-Kakizaki rats. Endocrinology 2009; 150: 2627–2636.

    Article  CAS  Google Scholar 

  32. Ndisang JF, Lane N, Jadhav A . The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways. Endocrinology 2009; 150: 2098–2108.

    Article  CAS  Google Scholar 

  33. Tallam LS, da Silva AA, Hall JE . Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin. Hypertension 2006; 48: 58–64.

    Article  CAS  Google Scholar 

  34. Zhou L, Williams T, Lachey JL, Kishi T, Cowley MA, Heisler LK . Serotonergic pathways converge upon central melanocortin systems to regulate energy balance. Peptides 2005; 26: 1728–1732.

    Article  CAS  Google Scholar 

  35. Lam DD, Przydzial MJ, Ridley SH, Yeo GS, Rochford JJ, O’Rahilly S et al. Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 2008; 149: 1323–1328.

    Article  CAS  Google Scholar 

  36. Chen AS, Metzger JM, Trumbauer ME, Guan XM, Yu H, Frazier EG et al. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res 2000; 9: 145–154.

    Article  CAS  Google Scholar 

  37. Cepoi D, Phillips T, Cismowski M, Goodfellow VS, Ling N, Cone RD et al. Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis. Brain Res 2004; 1000: 64–71.

    Article  CAS  Google Scholar 

  38. Markison S, Foster AC, Chen C, Brookhart GB, Hesse A, Hoare SR et al. The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology 2005; 146: 2766–2773.

    Article  CAS  Google Scholar 

  39. Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000; 141: 3518–3521.

    Article  CAS  Google Scholar 

  40. Butler AA, Cone RD . Knockout studies defining different roles for melanocortin receptors in energy homeostasis. Ann NY Acad Sci 2003; 994: 240–245.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the technical support of Megan V Storm. We also thank Dr Roger D Cone and Dr Bradford B Lowell for providing initial breeding pairs of the melanocortin-4 receptor-deficient mice. This work was supported by a grant from the National Institutes of Health, PO1HL-51971.

Author information

Authors and Affiliations

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

    E Csongradi, J M doCarmo, J H Dubinion, T Vera & D E Stec

  2. 1st Department of Internal Medicine, Medical and Health Sciences Center, University of Debrecen, Debrecen, Hungary

    E Csongradi

Authors
  1. E Csongradi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M doCarmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J H Dubinion
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Vera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D E Stec
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D E Stec.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Csongradi, E., doCarmo, J., Dubinion, J. et al. 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. Int J Obes 36, 244–253 (2012). https://doi.org/10.1038/ijo.2011.78

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2011.78

Keywords

This article is cited by

Search

Advanced search

Quick links