title: Circadian phenotyping of obese and diabetic db/db mice.
abstract: Growing evidence links metabolic disorders to circadian alterations. Genetically obese db/db mice, lacking the long isoform of leptin receptor, are a recognized model of type 2 diabetes. In this study, we aimed at characterizing the potential circadian alterations of db/db mice in comparison to db/+ control mice. By using telemetry devices, we first reported arrhythmicity in general activity of most db/db mice under both light-dark cycle and constant darkness, while their rhythm of body temperature is less dramatically disrupted. Water access restricted to nighttime restores significant rhythmicity in behaviorally arrhythmic db/db mice, indicating a masking effect of polydipsia when water is available ad libitum. Endogenous period of temperature rhythm under constant dark conditions is significantly increased (+30 min) in db/db compared with db/+ mice. Next, we studied the oscillations of clock proteins (PER1, PER2 and BMAL1) in the suprachiasmatic nuclei (SCN), the site of the master clock, and detected no difference according to the genotype. Furthermore, c-FOS and P-ERK1/2 expression in response to a light pulse in late night was significantly increased (+80 and +55%, respectively) in the SCN of these diabetic mice. We previously showed that, in addition to altered activity rhythms, db/db mice exhibit altered feeding rhythm. Therefore, we investigated daily patterns of clock protein expression in medial hypothalamic oscillators involved in feeding behavior (arcuate nucleus, ventro- and dorso-medial hypothalamic nuclei). Compared with db/+ mice, very subtle or no difference in oscillations of PER1 and BMAL1 is found in the medial hypothalamus. Although we did not find a clear link between altered hypothalamic clockwork and behavioral rhythms in db/db mice, our results highlight a lengthened endogenous period and altered photic integration in these genetically obese and diabetic mice.
authors.affiliation: Regulation of Circadian Clocks Team, Institute of Cellular and Integrative Neurosciences, UPR3212, CNRS, University of Strasbourg, France; Evolutionary Ecophysiology Team, Dept Ecology, Physiology and Ethology, Institut Pluridisciplinaire Hubert Curien, UMR7178, CNRS, University of Strasbourg, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Grosbellet
authors.affiliation: Regulation of Circadian Clocks Team, Institute of Cellular and Integrative Neurosciences, UPR3212, CNRS, University of Strasbourg, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dumont
authors.affiliation: ADIR - SERVIER Research Group, Suresnes, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Schuster-Klein
authors.affiliation: ADIR - SERVIER Research Group, Suresnes, France.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Guardiola-Lemaitre
authors.affiliation: Regulation of Circadian Clocks Team, Institute of Cellular and Integrative Neurosciences, UPR3212, CNRS, University of Strasbourg, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Pevet
authors.affiliation: Evolutionary Ecophysiology Team, Dept Ecology, Physiology and Ethology, Institut Pluridisciplinaire Hubert Curien, UMR7178, CNRS, University of Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Criscuolo
authors.affiliation: Regulation of Circadian Clocks Team, Institute of Cellular and Integrative Neurosciences, UPR3212, CNRS, University of Strasbourg, France. Electronic address: challet@inci-cnrs.unistra.fr.
authors.forename: Etienne
authors.initials: E
authors.lastname: Challet
mesh_terms: D000818:Animals; D001831:Body Temperature; D002940:Circadian Rhythm; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis; D056950:Period Circadian Proteins / Q000096:biosynthesis*; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D013045:Species Specificity
chemical_list: D056950:Period Circadian Proteins; D016760:Proto-Oncogene Proteins c-fos; D048052:Mitogen-Activated Protein Kinase 3
keywords: Circadian rhythm; Diabetes; Hypothalamus; Obesity