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.

Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice

“…jci.org Volume 124 Number 10 October 2014 ble body weight, fat mass, and lean mass when binge-like eating behavior was assessed ( Figure 3F). No difference in plasma orexin A levels was observed among these 4 groups ( Figure 3G (31). GLP-1-estrogen has been shown to produce profound estrogen-mediated metabolic benefits in animals, while the common side effects associated with estrogen therapy (e.g., reproductive endocrine toxicity and breast cancer) are avoided (31).…”

A bi-faceted role of estrogen receptor β in breast cancer

“…The potentially profound impact of ERb1 being a target for therapy in some ER-negative breast cancers where only few options apart from aggressive chemotherapies are available, as well as emerging new concepts for selectively delivering ligands to specific tissues (Finan et al 2012), supports a continued focus on understanding the molecular mechanisms for the bi-faceted role of ERb.…”

Advances in β cell replacement and regeneration strategies for treating diabetes

“…Tethering the molecule to the ligand of a β cell-specific receptor could be an alternative approach for delivering molecules directly to the β cell. The efficacy of this approach has recently been demonstrated for GLP-1-estrogen conjugates in β cells (176).…”