Insulin-mediated cortical activity in the slow frequency range is diminished in obese mice and promotes physical inactivity.
OBJECTIVE
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
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.
Hennige
A M
AM
Department of Internal Medicine 4, University of Tuebingen, 72076, Tuebingen, Germany.
Sartorius
T
T
Department of Internal Medicine 4, University of Tuebingen, 72076, Tuebingen, Germany.|Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Tuebingen, Tuebingen, Germany.
Lutz
S Z
SZ
Department of Internal Medicine 4, University of Tuebingen, 72076, Tuebingen, Germany.
Tschritter
O
O
Department of Internal Medicine 4, University of Tuebingen, 72076, Tuebingen, Germany.
Preissl
H
H
Institute of Medical Psychology and Behavioural Neurobiology, University of Tuebingen, Tuebingen, Germany.|Department of Obstetrics and Gynecology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Hopp
S
S
Department of Internal Medicine 4, University of Tuebingen, 72076, Tuebingen, Germany.
Fritsche
A
A
Department of Internal Medicine 4, University of Tuebingen, 72076, Tuebingen, Germany.
Rammensee
H-G
HG
Department of Immunology, Institute for Cell Biology, University of Tuebingen, Tuebingen, Germany.
Ruth
P
P
Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Tuebingen, Tuebingen, Germany.
Häring
H-U
HU
Department of Internal Medicine 4, University of Tuebingen, 72076, Tuebingen, Germany. Hans-Ulrich.Haering@med.uni-tuebingen.de.
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D002552:Cerebral Ventricles / Q000187:drug effects / Q000503:physiopathology; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D053609:Lethargy / Q000503:physiopathology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese / Q000502:physiology*; D009765:Obesity / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013686:Telemetry / Q000379:methods; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology
D007328:Insulin; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin