Joon S. Kim, Mohammed Z. Rizwan, Deborah J. Clegg, Greg M. Anderson

Estradiol and leptin are critical hormones in the regulation of body weight. The aim of this study was to determine whether this cross-talk between leptin receptor (LepRb) and estrogen receptor-alpha (ERα) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-GFP reporter, Stat3-flox or Erα-flox mice to generate female mice with GFP expression, STAT3 knockout (KO) or ERα KO, specifically in LepRb-expressing cells. The proportion of Leprb-GFP cells colocalizing ERα was high (∼80%) in the preoptic area but low (∼10%) in the mediobasal hypothalamus, suggesting that intracellular cross-talk between these receptors is minimal for metabolic regulation. To test if estradiol enhanced arcuate leptin sensitivity, ovarectomized mice received varying levels of estradiol replacement. Increasing estrogenic states did not increase the degree of leptin-induced STAT3 phosphorylation. LepRb specific STAT3 KO mice and controls were ovarectomized and given either chronic estradiol or vehicle treatment to test if STAT3 is required for estrogen-induced bodyweight suppression. Both groups of estradiol-treated mice showed an equivalent reduction in bodyweight and fat content compared to vehicle controls. Finally, mice lacking ERα specifically in LepRb-expressing neurons also showed no increase in bodyweight or impairments in metabolic function compared to controls, indicating that estradiol acts independently of leptin-responsive cells to regulate bodyweight. However, fecundity was impaired in in Leprb-ERα KO females. Contrary to the current dogma, we report that estradiol has minimal direct actions on LepRb cells in the mediodasal hypothalamus, and that its anorexigenic effects can occur entirely independently of LepRb-STAT3 signaling in female mice.