title: Leptin Signaling Is Not Required for Anorexigenic Estradiol Effects in Female Mice.
abstract: 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-α (ERα) signaling is critical for estradiol's anorexigenic effects. Leprb-Cre mice were crossed with Cre-dependent Tau-green fluorescent protein (GFP) reporter, Stat3-flox or Erα-flox mice to generate female mice with GFP expression, signal transducer and activator of transcription 3 (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 whether 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 whether STAT3 is required for estrogen-induced body weight suppression. Both groups of estradiol-treated mice showed an equivalent reduction in body weight and fat content compared with vehicle controls. Finally, mice lacking ERα specifically in LepRb-expressing neurons also showed no increase in body weight or impairments in metabolic function compared with controls, indicating that estradiol acts independently of leptin-responsive cells to regulate body weight. 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.
authors.affiliation: Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048.
authors.forename: Joon S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048.
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Rizwan
authors.affiliation: Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Clegg
authors.affiliation: Centre for Neuroendocrinology and Department of Anatomy (J.S.K, M.Z.R, G.M.A.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand; and Cedars-Sinai Diabetes and Obesity Research Institute, Department of Biomedical Research (D.J.C.), Los Angeles, California 90048.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics*; D004435:Eating / Q000187:drug effects / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D047628:Estrogen Receptor alpha; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D004958:Estradiol