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.

The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake

Abstract

Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1−/− mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of α-melanocyte–stimulating hormone (α-Msh) and carboxy-cleaved β-endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1−/− mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc-Foxo1−/− mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Body weight and composition.
Figure 2: Food intake and leptin sensitivity.
Figure 3: Evidence of altered Cpe activity in Pomc-Foxo1−/− mice.
Figure 4: Regulation of Cpe by diet and calorie restriction.
Figure 5: Regulation of Pc-1 and Cpe expression.

References

  1. Yach, D., Stuckler, D. & Brownell, K.D. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat. Med. 12, 62–66 (2006).

    Article  CAS  Google Scholar 

  2. Bray, G.A. Lifestyle and pharmacological approaches to weight loss: efficacy and safety. J. Clin. Endocrinol. Metab. 93, S81–88 (2008).

    Article  CAS  Google Scholar 

  3. Schwartz, M.W., Woods, S.C., Porte, D. Jr., Seeley, R.J. & Baskin, D.G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    Article  CAS  Google Scholar 

  4. Plum, L., Belgardt, B.F. & Bruning, J.C. Central insulin action in energy and glucose homeostasis. J. Clin. Invest. 116, 1761–1766 (2006).

    Article  CAS  Google Scholar 

  5. Woods, S.C., Lotter, E.C., McKay, L.D. & Porte, D. Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).

    Article  CAS  Google Scholar 

  6. McGowan, M.K., Andrews, K.M., Fenner, D. & Grossman, S.P. Chronic intrahypothalamic insulin infusion in the rat: behavioral specificity. Physiol. Behav. 54, 1031–1034 (1993).

    Article  CAS  Google Scholar 

  7. Benoit, S.C. et al. The catabolic action of insulin in the brain is mediated by melanocortins. J. Neurosci. 22, 9048–9052 (2002).

    Article  CAS  Google Scholar 

  8. Accili, D. & Arden, K.C. FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and Transformation. Cell 117, 421–426 (2004).

    Article  CAS  Google Scholar 

  9. Kitamura, T. et al. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat. Med. 12, 534–540 (2006).

    Article  CAS  Google Scholar 

  10. Kim, M.S. et al. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat. Neurosci. 9, 901–906 (2006).

    Article  CAS  Google Scholar 

  11. Fukuda, M. et al. Monitoring FoxO1 localization in chemically identified neurons. J. Neurosci. 28, 13640–13648 (2008).

    Article  CAS  Google Scholar 

  12. Creemers, J.W. et al. Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3. Endocrinology 147, 1621–1631 (2006).

    Article  CAS  Google Scholar 

  13. Nillni, E.A. Regulation of prohormone convertases in hypothalamic neurons: implications for prothyrotropin-releasing hormone and proopiomelanocortin. Endocrinology 148, 4191–4200 (2007).

    Article  CAS  Google Scholar 

  14. Pritchard, L.E. & White, A. Neuropeptide processing and its impact on melanocortin pathways. Endocrinology 148, 4201–4207 (2007).

    Article  CAS  Google Scholar 

  15. Fox, D.L. & Good, D.J. Nescient helix-loop-helix 2 interacts with signal transducer and activator of transcription 3 to regulate transcription of prohormone convertase 1/3. Mol. Endocrinol. 22, 1438–1448 (2008).

    Article  CAS  Google Scholar 

  16. Sanchez, V.C. et al. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J. Clin. Invest. 114, 357–369 (2004).

    Article  CAS  Google Scholar 

  17. Benjannet, S., Rondeau, N., Day, R., Chretien, M. & Seidah, N.G. PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues. Proc. Natl. Acad. Sci. USA 88, 3564–3568 (1991).

    Article  CAS  Google Scholar 

  18. Perone, M.J., Ahmed, I., Linton, E.A. & Castro, M.G. Procorticotrophin releasing hormone is endoproteolytically processed by the prohormone convertase PC2 but not by PC1 within stably transfected CHO-K1 cells. Biochem. Soc. Trans. 24, 497S (1996).

    Article  CAS  Google Scholar 

  19. Brakch, N. et al. Role of prohormone convertases in pro-neuropeptide Y processing: coexpression and in vitro kinetic investigations. Biochemistry 36, 16309–16320 (1997).

    Article  CAS  Google Scholar 

  20. Viale, A. et al. Cellular localization and role of prohormone convertases in the processing of pro-melanin concentrating hormone in mammals. J. Biol. Chem. 274, 6536–6545 (1999).

    Article  CAS  Google Scholar 

  21. Allen, R.G. et al. Altered processing of pro-orphanin FQ/nociceptin and pro-opiomelanocortin-derived peptides in the brains of mice expressing defective prohormone convertase 2. J. Neurosci. 21, 5864–5870 (2001).

    Article  CAS  Google Scholar 

  22. Furuta, M. et al. Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J. Biol. Chem. 276, 27197–27202 (2001).

    Article  CAS  Google Scholar 

  23. Zhu, X. et al. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl. Acad. Sci. USA 99, 10293–10298 (2002).

    Article  CAS  Google Scholar 

  24. Lloyd, D.J., Bohan, S. & Gekakis, N. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum. Mol. Genet. 15, 1884–1893 (2006).

    Article  CAS  Google Scholar 

  25. Jackson, R.S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16, 303–306 (1997).

    Article  CAS  Google Scholar 

  26. Naggert, J.K. et al. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat. Genet. 10, 135–142 (1995).

    Article  CAS  Google Scholar 

  27. Chen, H. et al. Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. Hum. Mutat. 18, 120–131 (2001).

    Article  Google Scholar 

  28. Che, F.Y. et al. Identification of peptides from brain and pituitary of Cpe(fat)/Cpe(fat) mice. Proc. Natl. Acad. Sci. USA 98, 9971–9976 (2001).

    Article  CAS  Google Scholar 

  29. Cawley, N.X. et al. The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits. Endocrinology 145, 5807–5819 (2004).

    Article  CAS  Google Scholar 

  30. Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 42, 983–991 (2004).

    Article  CAS  Google Scholar 

  31. Belgardt, B.F. et al. PDK1 Deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell. Metab. 7, 291–301 (2008).

    Article  CAS  Google Scholar 

  32. Buettner, C. et al. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat. Med. 14, 667–675 (2008).

    Article  CAS  Google Scholar 

  33. Leibel, R.L., Rosenbaum, M. & Hirsch, J. Changes in energy expenditure resulting from altered body weight. N. Engl. J. Med. 332, 621–628 (1995).

    Article  CAS  Google Scholar 

  34. Berman, Y., Mzhavia, N., Polonskaia, A. & Devi, L.A. Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice. J. Biol. Chem. 276, 1466–1473 (2001).

    Article  CAS  Google Scholar 

  35. Miller, R. et al. Obliteration of alpha-melanocyte-stimulating hormone derived from POMC in pituitary and brains of PC2-deficient mice. J. Neurochem. 86, 556–563 (2003).

    Article  CAS  Google Scholar 

  36. Zhu, X., Rouille, Y., Lamango, N.S., Steiner, D.F. & Lindberg, I. Internal cleavage of the inhibitory 7B2 carboxyl-terminal peptide by PC2: a potential mechanism for its inactivation. Proc. Natl. Acad. Sci. USA 93, 4919–4924 (1996).

    Article  CAS  Google Scholar 

  37. Overton, J.M. & Williams, T.D. Behavioral and physiologic responses to caloric restriction in mice. Physiol. Behav. 81, 749–754 (2004).

    Article  CAS  Google Scholar 

  38. Wertz-Lutz, A.E., Daniel, J.A., Clapper, J.A., Trenkle, A. & Beitz, D.C. Prolonged, moderate nutrient restriction in beef cattle results in persistently elevated circulating ghrelin concentrations. J. Anim. Sci. 86, 564–575 (2008).

    Article  CAS  Google Scholar 

  39. Nakae, J. et al. The forkhead transcription factor foxo1 regulates adipocyte differentiation. Dev. Cell 4, 119–129 (2003).

    Article  CAS  Google Scholar 

  40. Kitamura, T. et al. A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J. Clin. Invest. 117, 2477–2485 (2007).

    Article  CAS  Google Scholar 

  41. Nicolas, P. & Li, C.H. Beta-endorphin-(1-27) is a naturally occurring antagonist to etorphine-induced analgesia. Proc. Natl. Acad. Sci. USA 82, 3178–3181 (1985).

    Article  CAS  Google Scholar 

  42. Yanagita, K., Shiraishi, J., Fujita, M. & Bungo, T. Effects of N-terminal fragments of beta-endorphin on feeding in chicks. Neurosci. Lett. 442, 140–142 (2008).

    Article  CAS  Google Scholar 

  43. Banks, A.S. et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 8, 333–341 (2008).

    Article  CAS  Google Scholar 

  44. Kitamura, Y.I. et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab. 2, 153–163 (2005).

    Article  CAS  Google Scholar 

  45. Bence, K.K. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12, 917–924 (2006).

    Article  CAS  Google Scholar 

  46. Nilaweera, K.N., Barrett, P., Mercer, J.G. & Morgan, P.J. Precursor-protein convertase 1 gene expression in the mouse hypothalamus: differential regulation by ob gene mutation, energy deficit and administration of leptin, and coexpression with prepro-orexin. Neuroscience 119, 713–720 (2003).

    Article  CAS  Google Scholar 

  47. Rosenbaum, M. et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J. Clin. Invest. 115, 3579–3586 (2005).

    Article  CAS  Google Scholar 

  48. Paik, J.H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309–323 (2007).

    Article  CAS  Google Scholar 

  49. Plum, L. et al. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J. Clin. Invest. 116, 1886–1901 (2006).

    Article  CAS  Google Scholar 

  50. Plum, L. et al. Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell Metab. 6, 431–445 (2007).

    Article  CAS  Google Scholar 

  51. Woronowicz, A. et al. Absence of carboxypeptidase E leads to adult hippocampal neuronal degeneration and memory deficits. Hippocampus 18, 1051–1063 (2008).

    Article  Google Scholar 

  52. Wardlaw, S.L. Regulation of β-endorphin, corticotropin-like intermediate lobe peptide, and α-melanotropin–stimulating hormone in the hypothalamus by testosterone. Endocrinology 119, 19–24 (1986).

    Article  CAS  Google Scholar 

  53. Tsigos, C., Crosby, S.R., Gibson, S., Young, R.J. & White, A. Proopiomelanocortin is the predominant adrenocorticotropin-related peptide in human cerebrospinal fluid. J. Clin. Endocrinol. Metab. 76, 620–624 (1993).

    CAS  PubMed  Google Scholar 

  54. Papadopoulos, A.D. & Wardlaw, S.L. Endogenous MSH modulates the hypothalamic-pituitary-adrenal response to the cytokine interleukin-1β. J. Neuroendocrinol. 11, 315–319 (1999).

    Article  CAS  Google Scholar 

  55. Jaffe, S.B., Sobieszczyk, S. & Wardlaw, S.L. Effect of opioid antagonism on β-endorphin processing and proopiomelanocortin-peptide release in the hypothalamus. Brain Res. 648, 24–31 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported by Deutsche Forschungsgemeinschaft PL542/1-1 (L.P.), US National Institutes of Health DK57539 and DK58282 (D.A.), DK80003 (S.L.W.) and DK63608 (Columbia Diabetes and Endocrinology Research Center). We thank R. Leibel for insightful discussions, L. Zeltser and S. Padilla for help with in situ hybridization, N. Seidah (Clinical Research Institute of Montreal) and D. Good (University of Massachusetts) for plasmids encoding pCsk1, A. White (University of Manchester) for neuropeptide antisera, and M. Low (Oregon Health Sciences University) for Pomc-Gfp transgenic mice, Y. Liu for technical assistance and members of the Accili and Wardlaw laboratories for stimulating discussions. R.A.D. is an American Cancer Society Research Professor and an Ellison Medical Foundation Senior Scholar and is supported by the Robert A. and Renee E. Belfer Family Institute for Innovative Cancer Science.

Author information

Authors and Affiliations

Authors

Contributions

L.P., H.V.L., R.D., J.T., K.S.A., M.M., A.J.K. and S.L.W. performed experiments and analyzed data. N.X.C. and J.-H.P. generated reagents used for experiments. L.P., H.V.L., Y.P.L., R.A.D., S.L.W. and D.A. designed the studies, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Domenico Accili.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Table 1 (PDF 2067 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Plum, L., Lin, H., Dutia, R. et al. The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat Med 15, 1195–1201 (2009). https://doi.org/10.1038/nm.2026

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2026

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing