An intrinsic circadian clock of the pancreas is required for normal insulin release and glucose homeostasis in mice

AIMS/HYPOTHESIS: Loss of circadian clocks from all tissues causes defective glucose homeostasis as well as loss of feeding and activity rhythms. Little is known about peripheral tissue clocks, so we tested the hypothesis that an intrinsic circadian clock of the pancreas is important for glucose homeostasis. METHODS: We monitored real-time bioluminescence of pancreas explants from circadian reporter mice and examined clock gene expression in beta cells by immunohistochemistry and in situ hybridisation. We generated mice selectively lacking the essential clock gene Bmal1 (also known as Arntl) in the pancreas and tested mutant mice and littermate controls for glucose and insulin tolerance, insulin production and behaviour. We examined islets isolated from mutants and littermate controls for glucose-stimulated insulin secretion and total insulin content. RESULTS: Pancreas explants exhibited robust circadian rhythms. Clock genes Bmal1 and Per1 were expressed in beta cells. Despite normal activity and feeding behaviour, mutant mice lacking clock function in the pancreas had severe glucose intolerance and defective insulin production; their isolated pancreatic islets had defective glucose-stimulated insulin secretion, but normal total insulin content. CONCLUSIONS/INTERPRETATION: The mouse pancreas has an autonomous clock function and beta cells are very likely to be one of the pancreatic cell types possessing an intrinsic clock. The Bmal1 circadian clock gene is required in the pancreas, probably in beta cells, for normal insulin secretion and glucose homeostasis. Our results provide evidence for a previously unrecognised molecular regulator of pancreatic glucose-sensing and/or insulin secretion

Periprandial changes of the sympathetic–parasympathetic balance related to perceived satiety in humans

Food intake regulation involves various central and peripheral mechanisms. In this study the relevance of physiological responses reflecting the autonomic nervous system were evaluated in relation to perceived satiety. Subjects were exposed to a lunch-induced hunger-satiety shift, while profiling diverse sensory, physiological, and biochemical characteristics at 15 min intervals. Sensory ratings comprised questionnaires with visual analogues scales about their feeling of satiety, desire to eat, fullness, and hunger. Physiological characteristics included heart rate, heart rate variability, and blood pressure, while biochemical markers such as cortisol levels and α-amylase activity were monitored in saliva. The four sensory ratings correlated with heart rate and salivary α-amylase suggesting a higher sympathetic tone during satiety. Furthermore, heart rate variability was associated with age and waist-to-hip ratio and cortisol levels negatively correlated with body mass index. Finally, neither chewing nor swallowing contributed to a heart rate increase at food consumption, but orosensory stimulation, as tested with modified sham feeding, caused a partial increase of heart rate. In conclusion, after meal ingestion critical physiological alterations reveal a elevated sympathetic tone, which is a potential measure of satiety

Hedonic and incentive signals for body weight control

Here we review the emerging neurobiological understanding of the role of the brain’s reward system in the regulation of body weight in health and in disease. Common obesity is characterized by the over-consumption of palatable/rewarding foods, reflecting an imbalance in the relative importance of hedonic versus homeostatic signals. The popular ‘incentive salience theory’ of food reward recognises not only a hedonic/pleasure component (‘liking’) but also an incentive motivation component (‘wanting’ or ‘reward-seeking’). Central to the neurobiology of the reward mechanism is the mesoaccumbal dopamine system that confers incentive motivation not only for natural rewards such as food but also by artificial rewards (eg. addictive drugs). Indeed, this mesoaccumbal dopamine system receives and integrates information about the incentive (rewarding) value of foods with information about metabolic status. Problematic over-eating likely reflects a changing balance in the control exerted by hypothalamic versus reward circuits and/or it could reflect an allostatic shift in the hedonic set point for food reward. Certainly, for obesity to prevail, metabolic satiety signals such as leptin and insulin fail to regain control of appetitive brain networks, including those involved in food reward. On the other hand, metabolic control could reflect increased signalling by the stomach-derived orexigenic hormone, ghrelin. We have shown that ghrelin activates the mesoaccumbal dopamine system and that central ghrelin signalling is required for reward from both chemical drugs (eg alcohol) and also from palatable food. Future therapies for problematic over-eating and obesity may include drugs that interfere with incentive motivation, such as ghrelin antagonists

Global loss of Bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism

Extent: 11p.The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood. Here we investigated adipocyte function and the metabolic status of mice with a global loss of the core clock gene Bmal1 fed either a normal or a high fat diet (22% by weight). Bmal1 null mice aged 2 months were killed across 24 hours and plasma adiponectin and leptin, and adipose tissue expression of Adipoq, Lep, Retn and Nampt mRNA measured. Glucose, insulin and pyruvate tolerance tests were conducted and the expression of liver glycolytic and gluconeogenic enzyme mRNA determined. Bmal1 null mice displayed a pattern of increased plasma adiponectin and plasma leptin concentrations on both control and high fat diets. Bmal1 null male and female mice displayed increased adiposity (1.8 fold and 2.3 fold respectively) on the normal diet, but the high fat diet did not exaggerate these differences. Despite normal glucose and insulin tolerance, Bmal1 null mice had increased production of glucose from pyruvate, implying increased liver gluconeogenesis. The Bmal1 null mice had arrhythmic clock gene expression in epigonadal fat and liver, and loss of rhythmic transcription of a range of metabolic genes. Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated. These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism.David John Kennaway, Tamara Jayne Varcoe, Athena Voultsios, Michael James Bode