The Suprachiasmatic Nucleus Controls Circadian Energy Metabolism and Hepatic Insulin Sensitivity
- Claudia P. Coomans1,3⇑,
- Sjoerd A.A. van den Berg2,
- Eliane A. Lucassen1,
- Thijs Houben1,
- Amanda C.M. Pronk2,
- Rianne D. van der Spek4,
- Andries Kalsbeek4,5,
- Nienke R. Biermasz3,
- Ko Willems van Dijk2,
- Johannes A. Romijn3,4 and
- Johanna H. Meijer1
- 1Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
- 2Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
- 3Department of Endocrinology and Metabolic Disorders; Leiden University Medical Center, Leiden, the Netherlands
- 4Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, the Netherlands
- 5Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands
- Corresponding author: Claudia P. Coomans,
C.P.C. and S.A.A.v.d.B. contributed equally to this study.
J.A.R. and J.H.M. contributed equally to this study.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0507/-/DC1
See accompanying commentary, p. 1017.
- Received April 19, 2012.
- Accepted October 17, 2012.
- © 2013 by the American Diabetes Association.
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