Article

Diabetologia

, Volume 52, Issue 11, pp 2416-2424

First online:

Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity

  • A. M. HennigeAffiliated withDepartment of Internal Medicine 4, University of Tuebingen
  • , T. SartoriusAffiliated withDepartment of Internal Medicine 4, University of TuebingenInstitute of Pharmacy, Department of Pharmacology and Toxicology, University of Tuebingen
  • , S. Z. LutzAffiliated withDepartment of Internal Medicine 4, University of Tuebingen
  • , O. TschritterAffiliated withDepartment of Internal Medicine 4, University of Tuebingen
  • , H. PreisslAffiliated withInstitute of Medical Psychology and Behavioural Neurobiology, University of TuebingenDepartment of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences
  • , S. HoppAffiliated withDepartment of Internal Medicine 4, University of Tuebingen
  • , A. FritscheAffiliated withDepartment of Internal Medicine 4, University of Tuebingen
  • , H.-G. RammenseeAffiliated withDepartment of Immunology, Institute for Cell Biology, University of Tuebingen
  • , P. RuthAffiliated withInstitute of Pharmacy, Department of Pharmacology and Toxicology, University of Tuebingen

Abstract

Aims/hypothesis

There is evidence from mouse models and humans that alterations in insulin action in the brain are accompanied by an obese phenotype; however, the impact of insulin with regard to behavioural aspects such as locomotion is unknown.

Methods

To address insulin action in the brain with regard to cortical activity in distinct frequency bands and the behavioural consequences, the insulin signalling pathway was followed from the receptor to electrical activity and locomotion. Western blot analysis, electrocorticograms with intracerebroventricular (i.c.v.) application of insulin, and measurements of locomotor activity were performed in lean and obese, as well as Toll-like receptor (TLR) 2/4-deficient, mice.

Results

We show that insulin application i.c.v. into lean mice was accompanied by a profound increase in cortical activity in the slow frequency range, while diet-induced obese mice displayed insulin resistance. In parallel, insulin administered i.c.v. increased locomotor activity in lean mice, whereas a phosphatidylinositol-3 (PI3) kinase inhibitor or obesity abolished insulin-mediated locomotion. A potential candidate that links insulin signalling to locomotion is the Kv1.3 channel that is activated by PI3-kinase. Pharmacological inhibition of Kv1.3 channels that bypassed insulin receptor activation promoted activity. Moreover, mice deficient in TLR2/4-dependent signalling displayed an increase in cortical activity in the slow frequency range that was correlated with improved spontaneous and insulin-mediated locomotor activity.

Conclusions/interpretation

Our data provide functional evidence for a direct effect of insulin on brain activation patterns in the slow frequency bands and locomotor activity in lean mice, while in obese mice, insulin-mediated locomotion is blunted and further aggravates physical inactivity.

Keywords

Brain Electrocorticogram Insulin resistance Locomotor activity Obesity Toll-like receptor