title: 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.
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.forename: Kirk
authors.initials: K
authors.lastname: Habegger
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Schriever
authors.forename: Cristina
authors.initials: C
authors.lastname: García-Cáceres
authors.forename: Dhiraj G
authors.initials: DG
authors.lastname: Kabra
authors.forename: Jazzminn
authors.initials: J
authors.lastname: Hembree
authors.forename: Jenna
authors.initials: J
authors.lastname: Holland
authors.forename: Christine
authors.initials: C
authors.lastname: Raver
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Tiano
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Paul
authors.initials: P
authors.lastname: Pfluger
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
authors.forename: Vasily
authors.initials: V
authors.lastname: Gelfanov
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D001823:Body Composition / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D004338:Drug Combinations; D055808:Drug Discovery; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D006801:Humans; D061986:MCF-7 Cells; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D004338:Drug Combinations; D004967:Estrogens; D011960:Receptors, Estrogen; D052216:Glucagon-Like Peptide 1