Three-month-old neuron-specific lipoprotein lipase (LPL)-depleted mice (NEXLP(-/-)) mice are preobese and have normal body weight before developing obesity by 4.5 months. This series of experiments investigated responses to novel environment stimuli and acute sleep deprivation in preobese NEXLPL(-/-)) mice to test the hypothesis that neuron-specific LPL deletion alters normal adaptive metabolic responses to environmental challenges.
Ghrelin receptors are expressed by key components of the arousal system. Exogenous ghrelin induces behavioral activation, promotes wakefulness and stimulates eating. We hypothesized that ghrelin-sensitive mechanisms play a role in the arousal system. To test this, we investigated the responsiveness of ghrelin receptor knockout (KO) mice to two natural wake-promoting stimuli. Additionally, we assessed the integrity of their homeostatic sleep-promoting system using sleep deprivation. There was no significant difference in the spontaneous sleep-wake activity between ghrelin receptor KO and wild-type (WT) mice. WT mice mounted robust arousal responses to a novel environment and food deprivation. Wakefulness increased for 6 h after cage change accompanied by increases in body temperature and locomotor activity. Ghrelin receptor KO mice completely lacked the wake and body temperature responses to new environment. When subjected to 48 h food deprivation, WT mice showed marked increases in their waking time during the dark periods of both days. Ghrelin receptor KO mice failed to mount an arousal response on the first night and wake increases were attenuated on the second day. The responsiveness to sleep deprivation did not differ between the two genotypes. These results indicate that the ghrelin-receptive mechanisms play an essential role in the function of the arousal system but not in homeostatic sleep-promoting mechanisms.
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 ghrelins 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.
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