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Targeted estrogen delivery reverses the metabolic syndrome

Nature Medicine volume 18, pages 1847–1856 (2012)Cite this article

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Abstract

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.

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Figure 1: Two-week treatment of DIO male mice with GLP-1–estrogen conjugates.
Figure 2: Uterotrophic and mitogenic effects of GLP-1–estrogen conjugates.
Figure 3: Metabolic effects of estrogen conjugates to a low-potency GLP-1 analog and the CNS-specific effects of the GLP-1–estrogen conjugates.
Figure 4: In vitro and in vivo assessment of estrogen-specific signaling readouts.
Figure 5: In vitro and in vivo pharmacokinetic profile of the stable GLP-1–estrogen conjugate and comparative efficacy to alternative combinations of peptides and nuclear hormones.

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References

  1. Grundy, S.M. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat. Rev. Drug Discov. 5, 295–309 (2006).

    Article  CAS  Google Scholar 

  2. Roth, J.D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl. Acad. Sci. USA 105, 7257–7262 (2008).

    Article  CAS  Google Scholar 

  3. Müller, T.D. et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci. 18, 383–393 (2012).

    Article  Google Scholar 

  4. Drucker, D.J. The biology of incretin hormones. Cell Metab. 3, 153–165 (2006).

    Article  CAS  Google Scholar 

  5. Barrera, J.G., Sandoval, D.A., D'Alessio, D.A. & Seeley, R.J. GLP-1 and energy balance: an integrated model of short-term and long-term control. Nature reviews. Endocrinology 7, 507–516 (2011).

    Article  CAS  Google Scholar 

  6. Cvetković, R.S. & Plosker, G.L. Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea). Drugs 67, 935–954 (2007).

    Article  Google Scholar 

  7. Davies, M.J., Kela, R. & Khunti, K. Liraglutide—overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes. Diabetes Obes. Metab. 13, 207–220 (2011).

    Article  CAS  Google Scholar 

  8. Amori, R.E., Lau, J. & Pittas, A.G. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. J. Am. Med. Assoc. 298, 194–206 (2007).

    Article  CAS  Google Scholar 

  9. Talsania, T., Anini, Y., Siu, S., Drucker, D.J. & Brubaker, P.L. Peripheral exendin-4 and peptide YY3–36 synergistically reduce food intake through different mechanisms in mice. Endocrinology 146, 3748–3756 (2005).

    Article  CAS  Google Scholar 

  10. Williams, D.L., Baskin, D.G. & Schwartz, M.W. Leptin regulation of the anorexic response to glucagon-like peptide-1 receptor stimulation. Diabetes 55, 3387–3393 (2006).

    Article  CAS  Google Scholar 

  11. Day, J.W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).

    Article  CAS  Google Scholar 

  12. Mauvais-Jarvis, F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol. Metab. 22, 24–33 (2011).

    Article  CAS  Google Scholar 

  13. Musatov, S. et al. Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc. Natl. Acad. Sci. USA 104, 2501–2506 (2007).

    Article  CAS  Google Scholar 

  14. Gao, Q. et al. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat. Med. 13, 89–94 (2007).

    Article  CAS  Google Scholar 

  15. Gao, Q. & Horvath, T.L. Cross-talk between estrogen and leptin signaling in the hypothalamus. Am. J. Physiol. Endocrinol. Metab. 294, E817–E826 (2008).

    Article  CAS  Google Scholar 

  16. Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14, 453–465 (2011).

    Article  CAS  Google Scholar 

  17. Nilsson, S., Koehler, K.F. & Gustafsson, J.A. Development of subtype-selective oestrogen receptor-based therapeutics. Nat. Rev. Drug Discov. 10, 778–792 (2011).

    Article  CAS  Google Scholar 

  18. Patterson, J.T. et al. A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1. ACS Chem. Biol. 6, 135–145 (2011).

    Article  CAS  Google Scholar 

  19. Adelhorst, K., Hedegaard, B.B., Knudsen, L.B. & Kirk, O. Structure-activity studies of glucagon-like peptide-1. J. Biol. Chem. 269, 6275–6278 (1994).

    CAS  PubMed  Google Scholar 

  20. Bryzgalova, G. et al. Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet–fed mice. Am. J. Physiol. Endocrinol. Metab. 295, E904–E912 (2008).

    Article  CAS  Google Scholar 

  21. Inoue, S. et al. Genomic binding-site cloning reveals an estrogen-responsive gene that encodes a RING finger protein. Proc. Natl. Acad. Sci. USA 90, 11117–11121 (1993).

    Article  CAS  Google Scholar 

  22. Papageorgiou, A. & Denef, C. Estradiol induces expression of 5-hydroxytryptamine (5-HT) 4, 5–HT5, and 5–HT6 receptor messenger ribonucleic acid in rat anterior pituitary cell aggregates and allows prolactin release via the 5–HT4 receptor. Endocrinology 148, 1384–1395 (2007).

    Article  CAS  Google Scholar 

  23. Jankowski, M., Rachelska, G., Donghao, W., McCann, S.M. & Gutkowska, J. Estrogen receptors activate atrial natriuretic peptide in the rat heart. Proc. Natl. Acad. Sci. USA 98, 11765–11770 (2001).

    Article  CAS  Google Scholar 

  24. Lee, K. et al. Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer. BMC Cancer 8, 158 (2008).

    Article  Google Scholar 

  25. Bjerre Knudsen, L. et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 151, 1473–1486 (2010).

    Article  Google Scholar 

  26. Cho, M.A. et al. Expression and role of estrogen receptor α and β in medullary thyroid carcinoma: different roles in cancer growth and apoptosis. J. Endocrinol. 195, 255–263 (2007).

    Article  CAS  Google Scholar 

  27. Le May, C. et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc. Natl. Acad. Sci. USA 103, 9232–9237 (2006).

    Article  CAS  Google Scholar 

  28. Liu, S. et al. Importance of extranuclear estrogen receptor-α and membrane G protein–coupled estrogen receptor in pancreatic islet survival. Diabetes 58, 2292–2302 (2009).

    Article  CAS  Google Scholar 

  29. Tiano, J.P. et al. Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes. J. Clin. Invest. 121, 3331–3342 (2011).

    Article  CAS  Google Scholar 

  30. Wong, W.P. et al. Extranuclear estrogen receptor-α stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis. Proc. Natl. Acad. Sci. USA 107, 13057–13062 (2010).

    Article  CAS  Google Scholar 

  31. Shughrue, P.J., Askew, G.R., Dellovade, T.L. & Merchenthaler, I. Estrogen-binding sites and their functional capacity in estrogen receptor double knockout mouse brain. Endocrinology 143, 1643–1650 (2002).

    Article  CAS  Google Scholar 

  32. Park, C.J. et al. Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice. J. Clin. Invest. 121, 604–612 (2011).

    Article  CAS  Google Scholar 

  33. Revankar, C.M., Cimino, D.F., Sklar, L.A., Arterburn, J.B. & Prossnitz, E.R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307, 1625–1630 (2005).

    Article  CAS  Google Scholar 

  34. Mårtensson, U.E. et al. Deletion of the G protein–coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinology 150, 687–698 (2009).

    Article  Google Scholar 

  35. Son, S. et al. Preparation and structural, biochemical, and pharmaceutical characterizations of bile acid–modified long-acting exendin-4 derivatives. J. Med. Chem. 52, 6889–6896 (2009).

    Article  CAS  Google Scholar 

  36. Harrington, W.R. et al. Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action. Mol. Endocrinol. 20, 491–502 (2006).

    Article  CAS  Google Scholar 

  37. Krop, I.E. et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J. Clin. Oncol. 28, 2698–2704 (2010).

    Article  CAS  Google Scholar 

  38. Erickson, H.K. et al. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 66, 4426–4433 (2006).

    Article  CAS  Google Scholar 

  39. López, M. et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat. Med. 16, 1001–1008 (2010).

    Article  Google Scholar 

  40. Thaler, J.P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Smiley and J. Levy for assistance in peptide synthesis, purification and characterization; J. Patterson and J. Day for their contribution to optimizing the peptide sequences; J. Ford for cell culture maintenance; J. Gidda and S. Vignati for their expert advice on pharmacology studies; and Y.-X. Li (Medpace Bioanalytical Labs) for assistance with in vivo pharmacokinetic studies. Partial research funding was provided by Marcadia Biotech, which has been acquired by Roche Pharma.

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Authors and Affiliations

  1. Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany

    Brian Finan, Kerstin Stemmer, Timo D Müller, Chun-Xia Yi, Sonja C Schriever, Cristina García-Cáceres, Dhiraj G Kabra, Paul Pfluger & Matthias H Tschöp

  2. Department of Medicine, Division of Metabolic Diseases, Technische Universität München, Munich, Germany

    Brian Finan, Kerstin Stemmer, Timo D Müller, Chun-Xia Yi, Sonja C Schriever, Cristina García-Cáceres, Dhiraj G Kabra, Paul Pfluger & Matthias H Tschöp

  3. Department of Chemistry, Indiana University, Bloomington, Indiana, USA

    Brian Finan, Bin Yang, Vasily Gelfanov & Richard D DiMarchi

  4. Department of Internal Medicine, Division of Endocrinology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Nickki Ottaway, Kirk Habegger, Jazzminn Hembree, Jenna Holland, Christine Raver, Randy J Seeley, Diego Perez-Tilve, Paul Pfluger & Matthias H Tschöp

  5. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, GmbH, Neuherberg, Germany

    Wolfgang Hans, Martin Irmler, Johannes Beckers & Martin Hrabě de Angelis

  6. Chair of Experimental Genetics, Technische Universität München, Freising-Weihenstephan, Germany

    Johannes Beckers & Martin Hrabě de Angelis

  7. Department of Medicine, Division of Endocrinology, Comprehensive Center on Obesity, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

    Joseph P Tiano & Franck Mauvais-Jarvis

  8. Jiangsu Hengrui Medicine Co., Ltd, Jiangsu Province, China

    Lianshan Zhang

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Contributions

B.F. designed, synthesized and characterized compounds, designed and performed in vitro, ex vivo and in vivo experiments, analyzed and interpreted data and wrote the manuscript. B.Y. helped design and synthesize compounds and interpreted data. N.O. designed and led all in vivo pharmacology and metabolism studies and interpreted data. K.S. planned and led in vivo xenograft studies and interpreted data. K.H., T.D.M., C.-X.Y., D.P.-T. and P.P. designed, supervised and performed in vivo experiments and interpreted data. S.C.S., C.G.-C., D.G.K., J. Holland, J. Hembree and C.R. performed in vivo pharmacology and metabolism experiments and analyzed data. W.H. planned and led the bone density analysis. M.I., J.B., M.H.d.A., J.P.T., F.M.-J., R.J.S. and L.Z. gave advice on experimental design and interpreted data. V.G. developed in vitro receptor assays and interpreted in vitro data. R.D.D. and M.H.T. conceptualized, designed and interpreted all studies and wrote the manuscript.

Corresponding authors

Correspondence to Richard D DiMarchi or Matthias H Tschöp.

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The authors declare no competing financial interests.

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Finan, B., Yang, B., Ottaway, N. et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med 18, 1847–1856 (2012). https://doi.org/10.1038/nm.3009

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