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Targeted estrogen delivery reverses the metabolic syndrome

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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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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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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Supplementary Figures 1–7 and Supplementary Tables 1 and 2 (PDF 3314 kb)

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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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