title: The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity.
abstract: Disturbances in the circadian system are associated with the development of type 2 diabetes mellitus. Here, we studied the direct contribution of the suprachiasmatic nucleus (SCN), the central pacemaker in the circadian system, in the development of insulin resistance. Exclusive bilateral SCN lesions in male C57Bl/6J mice, as verified by immunochemistry, showed a small but significant increase in body weight (+17%), which was accounted for by an increase in fat mass. In contrast, mice with collateral damage to the ventromedial hypothalamus and paraventricular nucleus showed severe obesity and insulin resistance. Mice with exclusive SCN ablation revealed a loss of circadian rhythm in activity, oxygen consumption, and food intake. Hyperinsulinemic-euglycemic clamp analysis 8 weeks after lesioning showed that the glucose infusion rate was significantly lower in SCN lesioned mice compared with sham-operated mice (-63%). Although insulin potently inhibited endogenous glucose production (-84%), this was greatly reduced in SCN lesioned mice (-7%), indicating severe hepatic insulin resistance. Our data show that SCN malfunctioning plays an important role in the disturbance of energy balance and suggest that an absence of central clock activity, in a genetically intact animal, may lead to the development of insulin resistance.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. c.p.coomans@lumc.nl
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Coomans
authors.forename: Sjoerd A A
authors.initials: SA
authors.lastname: van den Berg
authors.forename: Eliane A
authors.initials: EA
authors.lastname: Lucassen
authors.forename: Thijs
authors.initials: T
authors.lastname: Houben
authors.forename: Amanda C M
authors.initials: AC
authors.lastname: Pronk
authors.forename: Rianne D
authors.initials: RD
authors.lastname: van der Spek
authors.forename: Andries
authors.initials: A
authors.lastname: Kalsbeek
authors.forename: Nienke R
authors.initials: NR
authors.lastname: Biermasz
authors.forename: Ko
authors.initials: K
authors.lastname: Willems van Dijk
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.forename: Johanna H
authors.initials: JH
authors.lastname: Meijer
mesh_terms: D000818:Animals; D001823:Body Composition; D001835:Body Weight; D002153:Calorimetry, Indirect; D002940:Circadian Rhythm / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013493:Suprachiasmatic Nucleus / Q000502:physiology*
chemical_list: D007328:Insulin