title: Leptin normalizes photic synchronization in male ob/ob mice, via indirect effects on the suprachiasmatic nucleus.
abstract: Mounting evidence indicates a strong link between metabolic diseases and circadian dysfunctions. The metabolic hormone leptin, substantially increased in dietary obesity, displays chronobiotic properties. Here we investigated whether leptin is involved in the alteration of timing associated with obesity, via direct or indirect effects on the suprachiasmatic nucleus (SCN), the site of the master clock. Photic synchronization was studied in obese ob/ob mice (deficient in leptin), either injected or not with high doses of recombinant murine leptin (5 mg/kg). This was performed first at a behavioral level, by shifting the light-dark cycle and inducing phase shifts by 30-minute light pulses and then at molecular levels (c-FOS and P-ERK1/2). Moreover, to characterize the targets mediating the chronomodulatory effects of leptin, we studied the induction of phosphorylated signal transducer and activator of transcription 3 (P-STAT3) in the SCN and in different structures projecting to the SCN, including the medial hypothalamus. Ob/ob mice showed altered photic synchronization, including augmented light-induced phase delays. Acute leptin treatment normalized the photic responses of the SCN at both the behavioral and molecular levels (decrease of light-induced c-FOS). Leptin-induced P-STAT3 was modulated by light in the arcuate nucleus and both the ventromedial and dorsomedial hypothalamic nuclei, whereas its expression was independent of the presence of leptin in the SCN. These results suggest an indirect action of leptin on the SCN, possibly mediated by the medial hypothalamus. Taken together, these results highlight a central role of leptin in the relationship between metabolic disturbances and circadian disruptions.
authors.affiliation: Regulation of Circadian Clocks Team (E.G., S.G., P.P., E.C.), Institute of Cellular and Integrative Neurosciences, Centre National de la Recherche Scientifique UPR3212, and Evolutionary Ecophysiology Team (E.G., F.C.), Department of Ecology, Physiology, and Ethology, Hubert Curien Pluridisciplinary Institute, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7178, University of Strasbourg, 67000 Strasbourg, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Grosbellet
authors.forename: Sylviane
authors.initials: S
authors.lastname: Gourmelen
authors.forename: Paul
authors.initials: P
authors.lastname: Pévet
authors.forename: François
authors.initials: F
authors.lastname: Criscuolo
authors.forename: Etienne
authors.initials: E
authors.lastname: Challet
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics / Q000502:physiology; D020738:Leptin / Q000494:pharmacology*; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000502:physiology*
chemical_list: D020738:Leptin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases