If the circadian clock is important for health, then it follows that certain mutations and genes that control the clock should lead to some form of illness. The first indication for this came from the clock mutant mouse. The observation was that these were obese, rolly polly, large and soft. In retrospect, this should have been no surprise because a careful analysis of their behavior showed that they're hyperphagic, meaning that they eat too much, hyperlipidemic, hyperleptinemic, they have hepatic steatosis and hyperglycemic hypoinsulinemia. We talked about glucose metabolism as being a clock regulated process, and in these mice, the glucose homeostasis is disrupted, including poor insulin secretion. Their condition is similar to metabolic syndrome. Do other clock mutant mice suffer from metabolic disorders? The BMAL1 mice have abnormal adipogenesis. The Cryptochrome mutant mice show glucose intolerance and changes in lipid metabolism. the casein kinase 1 mutant animals show increases in metabolic rate, and mutants in some of the components of the complimentary feedback loop, Rev Erb alpha and RORa also show changes in metabolic rate. How might this be working? Logically there are at least a couple of ways. Just for clock-controlled gene processes, some of the clock gene transcription factors might be regulating expression of components of metabolism via transcription, and by disrupting the clock transcription factors the metabolic state is also disrupted. Another possibility is more consistent with a jet lag or a shift work model. That disruption of the clock gene results in a sub-optimal entrainment, entrainment to a phase that leads to disorganization of expression of clock-controlled processes or even to their suppression. A molecular internal desynchronization may occur. If you think about it, the extensive clock control is like a finely-tuned choreography. Everything is organized to happen at the right time, just like a Rube Goldberg machine. If something falls out of its correct place and time then the entire system collapses. Still another concept stems not from mis-entrainment either by genes or by an alarm clock, but from mis- entrainment by eating at the wrong time. As you heard earlier in this lecture the clock and the liver is entrained by feeding time. In an optimal entrainment condition this would be at a phase that is consistent with other internal entrained phases, but in a jet lag or shift work situation, or in a clock mutant animal, there may be a new and suboptimal set of phase relationships leading to metabolic malfunction. From what you learned about social jetlag and overweight, and shift work and metabolic disease, you get the idea of how working against the clock can lead to metabolic disorders. Coming at this from another angle, polymorphisms in human clock genes have been associated with many metabolic phenotypes having to do with glucose and lipid metabolism. In fact, these associations seem to be much more common than those that have been described for sleep timing itself. In the lecture on clock-controlled processes we showed you many diverse functions that are clock-regulated, not just metabolism. It follows that the mutant mice may be abnormal in any number of these phenotypes. Another commonly reported pathology in clock mutant mice concerns blood pressure and heart rate. Perhaps this is not so surprising since these are both clock-regulated processes but the mechanism for this is still not known. As of metabolism, there are reports of increased incidents of cardiac disease in shift workers and also there's a strident time of day incidence of heart attacks. They occur most often in the morning. Mice are generally difficult to use to study affective disorders. That said, the CLK mice show mania: they sleep less than a wild type mouse, they explore new spaces more than a wild type mouse, and they have less anxiety usually measured by how much time they spend in an open space. It's entirely unclear why this might be, but perhaps a clue lies in the misregulation of monoamine oxidase a, as discussed in the clock control gene lecture or for that manner, misregulation of any number of neurotransmitters. Monoamine oxidaseER is also regulating the breakdown of serotonin, one of the most effective molecules that's targeted in the treatment of depression. Coming from the side of human genetics, several polymorphisms and clock genes have been associated with seasonal depression and bipolar disorder. Depression in circadian clock is a good example of the hen and egg problem again. Disruptive sleep is one of the common symptoms of depression, and it could be that a fundamental clock problem leads to this behavior which then progresses to depression, or the fragmented sleep could derive from the depression itself. One of the first findings that come from epidemiological studies of shift workers was an increased incidence of breast cancer. This association is so well-established that in Denmark long-term shift workers that developed breast cancer can get compensation from the state. This work pathology observation hasn't been precisely repeated in animal models, however, there are reports concerning increased incidences of cancer in mutant animals. The PER2 mutant mice suffer more skin cancer when exposed to UV light. Both the timing of the cell cycle as well as the DNA damage repair mechanism are regulated by the circadian clock. In cancer, often the cell cycle gating by the clock is lost and obviously, there's been a problem with damage to the integrity of the DNA. It took a surprisingly long time to work these phenotypes out in the mouse models because most of the mice raised for experiments are used at a relatively young age, and the most severe symptoms appear as the animals become mature adults. This suggests that the diseases of the circadian clock are diseases that derive from the accumulation of small effects, a lifetime of an internal clock that's phased suboptimally relative to the zeitgeber cycle. This is consistent with the observations in, for instance long-term shift workers where pathologies occur usually only after many years, if they're going to appear at all. [SOUND]
