Abstract
Sleep is greatly affected by changes in metabolic state. A possible mechanism where energy-sensing and sleep-regulatory functions overlap is related to lipid metabolism. Fatty acid synthase (FAS) plays a central role in lipid metabolism as a key enzyme in the formation of long-chain fatty acids. We studied the effects of systemic administration of C75, an inhibitor of FAS, on sleep, behavioral activity and metabolic parameters in mice. Since the effects of C75 on feeding and metabolism are the opposite of ghrelin's and C75 suppresses ghrelin production, we also tested the role of ghrelin signaling in the actions of C75 by using ghrelin receptor knockout (KO) mice. After a transient increase in wakefulness, C75 elicited dose-dependent and long lasting inhibition of REMS, motor activity and feeding. Simultaneously, C75 significantly attenuated slow-wave activity of the electroencephalogram. Energy expenditure, body temperature and respiratory exchange ratio were suppressed. The diurnal rhythm of feeding was completely abolished by C75. There was significant correlation between the anorectic effects, the decrease in motor activity and the diminished energy expenditure after C75 injection. We found no significant difference between wild-type and ghrelin receptor KO mice in their sleep and metabolic responses to C75. The effects of C75 resemble to what was previously reported in association with visceral illness. Our findings suggest that sleep and metabolic effects of C75 in mice are independent of the ghrelin system and may be due to its aversive actions in mice.
Highlights
There is a known relationship among feeding, metabolism and sleep
Increased adiposity induced by cafeteria diet or [6] high-fat diet [7] and obesity due to leptin [8] or leptin receptor [9] deficiency leads to increases in sleep
Our major finding is that systemic injection of C75 suppresses motor activity, rapid-eye-movement sleep (REMS), and slow-wave activity of the electroencephalogram (SWA) of the EEG in both normal and ghrelin receptor KO mice
Summary
There is a known relationship among feeding, metabolism and sleep. Metabolic states characterized by positive energy balance are typically associated with increased sleep while food deprivation stimulates wakefulness and motor activity. Increased feeding induced by prior food deprivation elicits postprandial sleep [2,3,4]. Ventromedial hypothalamic (VMH) lesion [5] is associated with increased sleep time in rats. Satiety and adiposity signals are likely to mediate the effects of positive energy states on sleep. Satiety hormones, such as cholecystokinin (CCK) [10,11,12] and insulin [13,14] are released postprandially and stimulate sleep. Postprandial sleep is prevented by CCK1 receptor antagonists [3]
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