Targeted estrogen delivery reverses the metabolic syndrome

• Published in: Nature medicine Vol. 18; no. 12; pp. 1847 - 1856
• Main Authors: Finan, Brian, Yang, Bin, Ottaway, Nickki, Stemmer, Kerstin, Müller, Timo D, Yi, Chun-Xia, Habegger, Kirk, Schriever, Sonja C, García-Cáceres, Cristina, Kabra, Dhiraj G, Hembree, Jazzminn, Holland, Jenna, Raver, Christine, Seeley, Randy J, Hans, Wolfgang, Irmler, Martin, Beckers, Johannes, de Angelis, Martin Hrabě, Tiano, Joseph P, Mauvais-Jarvis, Franck, Perez-Tilve, Diego, Pfluger, Paul, Zhang, Lianshan, Gelfanov, Vasily, DiMarchi, Richard D, Tschöp, Matthias H
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2012; Nature Publishing Group
• Subjects: 631/92/436/1729; 692/308/575; 692/699/2743/2037; 692/700/565/1331/238; Analysis; Analysis of Variance; Animal models; Animals; Binding, Competitive; Biomedicine; Body Composition - physiology; Cancer Research; Care and treatment; Chromatography, High Pressure Liquid; Drug Combinations; Drug Discovery; Estrogen; Estrogens; Estrogens - metabolism; Estrogens - pharmacology; Estrogens - therapeutic use; Female; Females; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide 1 - therapeutic use; Glucose Tolerance Test; Health aspects; Hormones; Humans; Infectious Diseases; Lipids; Magnetic Resonance Imaging; Male; Mass Spectrometry; MCF-7 Cells; Metabolic Diseases; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - drug therapy; Metabolic syndrome X; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Medicine; Neurosciences; Obesity; Patient outcomes; Peptide hormones; Peptides; Pharmacology; Physiological aspects; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Side effects; technical-report; Tissues; Xenograft Model Antitumor Assays; United States; China; Germany
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3009

Estrogen is beneficial for obesity and type 2 diabetes, though its use is limited by important side effects. In a new study, Matthias Tschöp and colleagues avoid this issue by chemically linking estrogen to the hormone GLP-1 to selectively target metabolically relevant tissue and show that the conjugated compound corrects obesity, hyperglycemia and dyslipidemia in mice. This approach could be used for other hormone pairs to treat other diseases. 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.