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

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.

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

“…The mean intakes of carbohydrate, saturated fatty acids and fat were adjusted for baseline, sex and age especially in the theta band, may interfere with physical activity during a lifestyle intervention that causes increased energy expenditure and subsequent loss of body fat. This is well in line with a recent study in mice showing an increase in locomotor activity after intracerebroventricular injection of insulin accompanied by increases in cortical theta and delta activity [12]. High insulin sensitivity of the brain at baseline was associated with lower intake of fat, especially saturated fat, during the lifestyle intervention.…”

“…At that time, we speculated that fatty acids derived from visceral fat depots may cause insulin resistance of the brain and therefore lead to further weight gain. Indeed, recent studies confirmed that intracerebroventricular palmitic acid infusion and high-fat diet induce insulin resistance in different brain regions in mice and rats [12,14,15]. These observations, together with the present finding of high insulin sensitivity in the brain associated with lower intake of saturated fat, may suggest that insulin resistance in the brain elevates serum concentrations of saturated fatty acids not only by increasing visceral fat mass, but also more directly by decreasing physical activity and increasing intake of saturated fat.…”

“…In animal studies, knock-out of the insulin receptor [10] and diet-induced deterioration of insulin signalling [11] led to obesity. Although most animal studies showing a direct link between insulin and control of body weight focused on hypothalamic insulin receptors, there is also evidence that cerebrocortical activity is modulated by insulin in parallel to changes in spontaneous locomotion [12]. In addition, induction of cerebral insulin resistance by a high-fat diet abolished these insulin effects on cortical activity and locomotion in these animals.…”

Brown adipose tissue transplantation improves whole-body energy metabolism

“…However, similar changes were not observed in epididymal or subcutaneous fat (Supplementary information, Figure S1F-S1G). A previous research has suggested that a reduction in physical activity occurs in mouse models of obesity [7]. Remarkably, BAT transplantation significantly reversed the reduction in physical activity in HFD-fed mice (Supplementary information, Figure S1C).…”

Translational Science: How experimental research has contributed to the understanding of spontaneous Physical Activity and Energy Homeostasis

“…In relation to hormones, insulin and leptin emerge as potential modulators of SPA. Hennige et al 53 showed that insulin i.c.v. injection promotes SPA in lean but not in diet-induced obese mice, which develop hypothalamic resistance to insulin 53 .…”