Targeted Estrogen Delivery Reverses the Metabolic Syndrome

Nat Med. 2012 Dec;18(12):1847-56. doi: 10.1038/nm.3009. Epub 2012 Nov 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Binding, Competitive
  • Body Composition / physiology
  • Chromatography, High Pressure Liquid
  • Drug Combinations
  • Drug Discovery
  • Estrogens / metabolism
  • Estrogens / pharmacology*
  • Estrogens / therapeutic use
  • Female
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glucose Tolerance Test
  • Humans
  • MCF-7 Cells
  • Magnetic Resonance Imaging
  • Male
  • Mass Spectrometry
  • Metabolic Syndrome / drug therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Xenograft Model Antitumor Assays

Substances

  • Drug Combinations
  • Estrogens
  • Receptors, Estrogen
  • Glucagon-Like Peptide 1