Insulin sensitivity : modulation by the brain

The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated glucose uptake by muscle and insulin-stimulated FA uptake by WAT is in part dependent on insulin action in the brain. These effects of circulating insulin on peripheral organs via the brain are abrogated by high-fat diet. These brain-dependent effects of insulin could reflect a similar situation for other hormones, for instance thyroid hormones. Furthermore, we demonstrate that topiramate improves insulin resistance by restoring insulin sensitivity in the brain, suggesting that therapeutical targets in the brain may offer challenging new approaches to treat insulin resistance of peripheral organs in T2DM.UBL - phd migration 201

Group housing and social dominance hierarchy affect circadian activity patterns in mice

In this study, we investigated the effect of social environment on circadian patterns in activity by group housing either six male or six female mice together in a cage, under regular light-dark cycles. Based on the interactions among the animals, the social dominance rank of individual mice was quantitatively established by calculating Elo ratings. Our results indicated that, during our experiment, the social dominance hierarchy was rapidly established, stable yet complex, often showing more than one dominant mouse and several subordinate mice. Moreover, we found that especially dominant male mice, but not female mice, displayed a significantly higher fraction of their activity during daytime. This resulted in reduced rhythm amplitude in dominant males. After division into separate cages, male mice showed an enhancement of their 24 h rhythm, due to lower daytime activity. Recordings of several physiological parameters showed no evidence for reduced health as a potential consequence of reduced rhythm amplitude. For female mice, transfer to individual housing did not affect their daily activity pattern. We conclude that 24 h rhythms under light-dark cycles are influenced by the social environment in males but not in females, and lead to a decrement in behavioural rhythm amplitude that is larger in dominant mice.Circadian clocks in health and diseas

Insulin sensitivity : modulation by the brain

The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated glucose uptake by muscle and insulin-stimulated FA uptake by WAT is in part dependent on insulin action in the brain. These effects of circulating insulin on peripheral organs via the brain are abrogated by high-fat diet. These brain-dependent effects of insulin could reflect a similar situation for other hormones, for instance thyroid hormones. Furthermore, we demonstrate that topiramate improves insulin resistance by restoring insulin sensitivity in the brain, suggesting that therapeutical targets in the brain may offer challenging new approaches to treat insulin resistance of peripheral organs in T2DM

The suprachiasmatic nuclei as a seasonal clock

Circadian clocks in health and diseas

Regulation of Circadian and Acute Activity Levels by the Murine Suprachiasmatic Nuclei

Circadian clocks in health and diseas

Role of brain insulin signalling on tissue-specific glucose disposal

Diabetes mellitus: pathophysiological changes and therap

Lack of exercise leads to significant and reversible loss of scale invariance in both aged and young mice

Circadian clocks in health and diseas

The Brain Modulates Insulin Sensitivity in Multiple Tissues

Diabetes mellitus: pathophysiological changes and therap

Stimulatory Effect of Insulin on Glucose Uptake by Muscle Involves the Central Nervous System in Insulin-Sensitive Mice

OBJECTIVE - Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated tissue-specific glucose uptake. RESEARCH DESIGN AND METHODS - Tolbutamide, an inhibitor of ATP-sensitive K+ channels (KATP channels), or vehicle was infused into the lateral ventricle in the basal state and during hyperinsulinemic-euglycemic conditions in postabsorptive, chow-fed C57Bl/6J mice and in postabsorptive C57Bl/6J mice with dietinduced obesity. Whole-body glucose uptake was measured by D-[14C]glucose kinetics and tissue-specific glucose uptake by 2-deoxy-D-[3H]glucose uptake. RESULTS - During clamp conditions, intracerebroventricular administration of tolbutamide impaired the ability of insulin to inhibit EGP by ~20%. In addition, intracerebroventricular tolbutamide diminished insulin-stimulated glucose uptake in muscle (by ~59%) but not in heart or adipose tissue. In contrast, in insulin-resistant mice with diet-induced obesity, intracerebroventricular tolbutamide did not alter the effects of insulin during clamp conditions on EGP or glucose uptake by muscle. CONCLUSIONS - Insulin stimulates glucose uptake in muscle in part through effects via KATP channels in the central nervous system, in analogy with the inhibitory effects of insulin on EGP. Highfat diet-induced obesity abolished the central effects of insulin on liver and muscle. These observations stress the role of central insulin resistance in the pathophysiology of diet-induced insulin resistance. © 2011 by the American Diabetes Association