TY - JOUR
T1 - Targeted estrogen delivery reverses the metabolic syndrome
AU - Finan, Brian
AU - Yang, Bin
AU - Ottaway, Nickki
AU - Stemmer, Kerstin
AU - Müller, Timo D.
AU - Yi, Chun-Xia
AU - Habegger, Kirk
AU - Schriever, Sonja C.
AU - García-Cáceres, Cristina
AU - Kabra, Dhiraj G.
AU - Hembree, Jazzminn
AU - Holland, Jenna
AU - Raver, Christine
AU - Seeley, Randy J.
AU - Hans, Wolfgang
AU - Irmler, Martin
AU - Beckers, Johannes
AU - de Angelis, Martin Hrabě
AU - Tiano, Joseph P.
AU - Mauvais-Jarvis, Franck
AU - Perez-Tilve, Diego
AU - Pfluger, Paul
AU - Zhang, Lianshan
AU - Gelfanov, Vasily
AU - DiMarchi, Richard D.
AU - Tschöp, Matthias H.
PY - 2012
Y1 - 2012
N2 - 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
AB - 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
U2 - https://doi.org/10.1038/nm.3009
DO - https://doi.org/10.1038/nm.3009
M3 - Article
C2 - 23142820
SN - 1078-8956
VL - 18
SP - 1847
EP - 1856
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -