Differential Involvement of the Suprachiasmatic Nucleus in Lipopolysaccharide-Induced Plasma Glucose and Corticosterone Responses

Abstract

The hypothalamic suprachiasmatic nucleus (SCN) is an essential component of the circadian timing system, and an important determinant of neuroendocrine and metabolic regulation. Recent data indicate a modulatory role for the immune system on the circadian timing system. The authors investigated how the circadian timing system affects the hypothalamo-pituitary-adrenal (HPA) axis and glucose regulatory responses evoked by an immune challenge induced by lipopolysaccharide (LPS). LPS-induced increases in corticosterone were minimal during the trough of the daily corticosterone rhythm; in contrast, LPS effects on glucose, glucagon, and insulin did not vary across time-of-day. Complete ablation of the SCN resulted in increased corticosterone responses but did not affect LPS-induced hyperglycemia. The paraventricular nucleus (PVN) of the hypothalamus is an important neuroendocrine and autonomic output pathway for hypothalamic information, as well as one of the main target areas of the SCN. Silencing the neuronal activity in the PVN did not affect the LPS-induced corticosterone surge and only slightly delayed the LPS-induced plasma glucose and glucagon responses. Finally, surgical interruption of the neuronal connection between hypothalamus and liver did not affect the corticosterone response but slightly delayed the LPS-induced glucose response. Together, these data support the previously proposed circadian modulation of LPS-induced neuroendocrine responses, but they are at variance with the suggested major role for the hypothalamic pacemaker on the autonomic output of the hypothalamus, as reflected by the effects of LPS on glucose homeostasis. The latter effects are more likely due to direct interactions of LPS with peripheral tissues, such as the liver. (Author correspondence: [email protected])

Keywords:

• Circadian
• Corticosterone
• Glucagon
• HPA axis
• Hypothalamus
• Immune response
• Insulin
• Leptin
• Lipopolysaccharide
• Liver
• Sympathetic

ACKNOWLEDGMENTS

We thank Wilma Verweij for correcting our English. The expert assistance of J. Timmer in animal husbandry is gratefully acknowledged. Finally, we wish to thank Anita Boelen and Susanne la Fleur for their input and discussion.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported in part by a grant from the China-Exchange Program of the Royal Netherlands Academy of Arts and Sciences.