High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention.

AIMS/HYPOTHESIS: Loss of weight and body fat are major targets in lifestyle interventions to prevent diabetes. In the brain, insulin modulates eating behaviour and weight control, resulting in a negative energy balance. This study aimed to test whether cerebral insulin sensitivity facilitates reduction of body weight and body fat by lifestyle intervention in humans. METHODS: The study was performed as an additional arm of the TUebingen Lifestyle Intervention Program (TULIP). In 28 non-diabetic individuals (14 female/14 male; mean ± SE age 42 ± 2 years; mean ± SE BMI 29.9 ± 0.8 kg/m²), we measured cerebrocortical insulin sensitivity by using magnetoencephalography before lifestyle intervention. Total and visceral fat were measured by using MRI at baseline and after 9 months and 2 years of lifestyle intervention. RESULTS: Insulin-stimulated cerebrocortical theta activity at baseline correlated with a reduction in total adipose tissue (r = -0.59, p = 0.014) and visceral adipose tissue (r = -0.76, p = 0.001) after 9 months of lifestyle intervention, accompanied by a statistical trend for reduction in body weight change (r = -0.37, p = 0.069). Similar results were obtained after 2 years. CONCLUSIONS/INTERPRETATION: Our results suggest that high insulin sensitivity of the human brain facilitates loss of body weight and body fat during lifestyle intervention.

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

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.

Tissue selectivity of insulin detemir action in vivo.

AIMS/HYPOTHESIS: Recombinant DNA technology is a useful tool that can be used to create insulin analogues with modified absorption kinetics to improve glycaemic control in patients with type 1 and type 2 diabetes. Among conventional insulin analogues, which are usually created by amino acid exchange, insulin detemir is the first analogue to be acylated with a fatty acid to enable reversible albumin binding. In this study we determined activation of the insulin receptor (IR)-signalling cascade by insulin detemir at the level of IR and IR substrate (Irs) phosphorylation, as well as downstream signalling elements such as phosphatidylinositol 3-kinase and Akt, and performed epidural EEG in vivo. METHODS: C57Bl/6 mice were injected i.v. with either insulin detemir or human insulin and Western blot analysis was performed on liver, muscle, hypothalamic and cerebrocortical tissues. Moreover, cerebrocortical activity was detected by EEG in awake mice and cerebral insulin concentrations were measured following human insulin and insulin detemir injection. RESULTS: The time course and extent of IR phosphorylation in peripheral tissues were similar following insulin detemir treatment compared with human insulin, but insulin signalling in hypothalamic and cerebrocortical tissue determined by tyrosine-phosphorylation of the IR and Irs2 proteins occurred faster and was enhanced due to a higher insulin detemir concentration in the brain. Moreover, epidural EEG in mice displayed increased cortical activity using insulin detemir. CONCLUSIONS/INTERPRETATION: Taken together, these data suggest that insulin detemir has a tissue-selective action, with a relative preference for brain compared with peripheral tissues.