Recent epidemiological studies have noted a link between obesity and insufficient sleep, but the underlying mechanisms are not clear. Now, two reports provide genetic and physiological evidence of how the regulation of circadian rhythm, sleep and metabolism might be tightly coordinated.

Turek and colleagues investigated whether disruption of the circadian system could affect an animal's eating and sleeping behaviours. The circadian system, which controls the timing of almost every aspect of physiology, relies on the so-called 'clock' genes such as clock (Clk), period (Per) and timeless (Tim). The authors found that mice that lacked a functional Clk gene — the primary driver of the circadian machinery — slept less and ate more than their wild-type counterparts. Such mice are heavier and show a significant increase in body fat compared with control animals: 35% when fed a normal diet and 75% when fed a high-fat diet. In addition, they show various tissue and biochemical abnormalities that are hallmarks of metabolic disorders, such as high levels of blood glucose and cholesterol, and low levels of insulin. These phenotypes might be related to a decrease in the production of the appetite-regulating hypothalamic hormones leptin and ghrelin in the mutant mice.

In the second study, Hovath and Diano showed that the hypocretin (also called orexin) neurons in the lateral hypothalamus might be a crucial integrator of sleep and metabolism regulation. These neurons secrete hypocretin — a key regulator of both feeding and arousal — and project to many regions of the brain, including the hypothalamus, cerebral cortex, brain stem and spinal cord. Overnight food deprivation promotes the formation of excitatory synapses onto hypocretin neurons and leads to an increase in miniature excitatory postsynaptic currents in these neurons. These effects can be blocked by leptin administration during fasting and are reversed when feeding is subsequently resumed. The results point towards the intriguing possibility that obesity-associated metabolic defects, such as reduced production of leptin, and leptin dysfunction, could render hypocretin neurons more excitable and result in an increased level of arousal and insomnia.

Therefore, genes, hormones and the ability of neurons to undergo synaptic changes can all affect both sleep and metabolism. Further research on the relationships between the two processes and their molecular underpinnings should provide guidelines for the development of new therapeutic approaches to treat obesity and sleep disorders.