Leptin and estrogen signaling crosstalk in the brain modulates energy metabolism

Abstract

Leptin and estrogen are key hormones in regulating feeding, metabolic health, and body weight. In this review, we explore how the interaction between leptin and estrogen may modulate body weight through changes in metabolism and feeding behaviour. A significant proportion of arcuate neurons co-express receptors for leptin and estrogen, providing ample opportunity for signal crosstalk to occur in the brain. We conducted a narrative literature review and identified the major mechanisms through which leptin and estrogen interact, with a focus on signal transduction pathways. G-protein coupled receptor 30 (GPR30) is a good candidate for an inter-pathway connection because it interacts with estrogen receptors and affects the activation of signal transducer and activator of transcription (STAT3), an important downstream factor in both estrogen and leptin signaling pathways in the hypothalamus. Evidence suggests that estrogen and leptin receptors both utilize hypothalamic STAT3-activating pathways to modulate appetite and lipid storage, and that these pathways may depend on one another for adequate activation. While there are some physiological results to support this point of connection, the cellular and biochemical details remain unclear. Better understanding how leptin and estrogen interact will better inform the treatment of metabolic disorders, including type 2 diabetes, obesity, and post-menopausal weight gain.