title: Sexual Dimorphism in Circadian Physiology Is Altered in LXRα Deficient Mice.
abstract: The mammalian circadian timing system coordinates key molecular, cellular and physiological processes along the 24-h cycle. Accumulating evidence suggests that many clock-controlled processes display a sexual dimorphism. In mammals this is well exemplified by the difference between the male and female circadian patterns of glucocorticoid hormone secretion and clock gene expression. Here we show that the non-circadian nuclear receptor and metabolic sensor Liver X Receptor alpha (LXRα) which is known to regulate glucocorticoid production in mice modulates the sex specific circadian pattern of plasma corticosterone. Lxrα(-/-) males display a blunted corticosterone profile while females show higher amplitude as compared to wild type animals. Wild type males are significantly slower than females to resynchronize their locomotor activity rhythm after an 8 h phase advance but this difference is abrogated in Lxrα(-/-) males which display a female-like phenotype. We also show that circadian expression patterns of liver 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and Phosphoenolpyruvate carboxykinase (Pepck) differ between sexes and are differentially altered in Lxrα(-/-) animals. These changes are associated with a damped profile of plasma glucose oscillation in males but not in females. Sex specific alteration of the insulin and leptin circadian profiles were observed in Lxα(-/-) females and could be explained by the change in corticosterone profile. Together this data indicates that LXRα is a determinant of sexually dimorphic circadian patterns of key physiological parameters. The discovery of this unanticipated role for LXRα in circadian physiology underscores the importance of addressing sex differences in chronobiology studies and future LXRα targeted therapies.
authors.affiliation: University Nice Sophia Antipolis, Institute of Biology Valrose, 06108, Nice, France.|CNRS UMR 7277, 06108, Nice, France.|INSERM UMR 1091, 06108, Nice, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Feillet
authors.affiliation: University Nice Sophia Antipolis, Institute of Biology Valrose, 06108, Nice, France.|CNRS UMR 7277, 06108, Nice, France.|INSERM UMR 1091, 06108, Nice, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Guérin
authors.affiliation: Metabolic Diseases Research, Institut de Recherches Servier, 92284, Suresnes, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lonchampt
authors.affiliation: Metabolic Diseases Research, Institut de Recherches Servier, 92284, Suresnes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Dacquet
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, 77204-5056, United States of America.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: University Nice Sophia Antipolis, Institute of Biology Valrose, 06108, Nice, France.|CNRS UMR 7277, 06108, Nice, France.|INSERM UMR 1091, 06108, Nice, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Delaunay
authors.affiliation: University Nice Sophia Antipolis, Institute of Biology Valrose, 06108, Nice, France.|CNRS UMR 7277, 06108, Nice, France.|INSERM UMR 1091, 06108, Nice, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Teboul
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000627:therapeutic use; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis; D020738:Leptin / Q000096:biosynthesis; D008024:Ligands; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009068:Movement; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000502:physiology*; D010641:Phenotype; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012737:Sex Factors
chemical_list: D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D020738:Leptin; D008024:Ligands; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011965:Receptors, Glucocorticoid; D006003:Glycogen; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D019764:Phosphoenolpyruvate Carboxykinase (ATP)