Monthly Archives: June 2011

To begin to understand how sleep interacts with metabolism, we need to understand a bit about neuroanatomy. In sleep, the cerebral cortex is in a state of cortical synchronization. In wakefulness, several subcortical regions of the brain stimulate the cortex to remove this synchronization. When we undergo slow wave Non REM sleep (drowsiness) there are a small group of neurons in the hypothalamus called VLPO neurons that are GABAergic (inhibitory) and they fire on the subcortical areas that are stimulating the cortex. In doing so, these VLPO neurons bring about cortical synchronization. After sleep begins, NREM sleep gives way to REM sleep. During REM sleep there is a coordination of cross talk between the grey matter brainstem nuclei while cortical synchronization is maintained. This is quite complex coordination of events that occurs in the brain while we sleep. A common disease of dis-coordination of sleep is Narcolepsy. In other words, the tracts that normally control the stages of sleep occur out of sequence and cause people to fall asleep and lose muscle control in wakefulness. Narcolepsy occurs because we lose a specific set of neurons in the hypothalamus that effects this coordination of signals. These neurons are called the hypocretin neurons (HC). These neurons are found in the ventral lateral hypothalamus in a small area that also control appetite and feeding. These neurons also effect loops that effect feeding. There is no set point. When we lose HC neurons we set up the neurochemistry that becomes resistant obesity. The dopamine tracts are the direct targets of the HC neurons. We don't see obesity as a common phenotype when we see tumors of surgical ablation of these dopamine outflow tracts. This is the main reason many do not believe there is a set point for obesity. The hypocretin neurons sit scattered through many MSH cells (also involved in obesity). The HC neurons make two peptides called (hypocretin 1 and 2)HCrT1 and HCrT2. In the literature, these peptide hormones are also known as the orexins so you do not get confused. These peptides are remarkably similar to gut incretin hormones that help tell the brain what type of foods are present in the gut. Another remarkable trait of the hypocretin neurons is that in the human brain there is only 50,000 total HC neurons in an organ with over one trillion cells. And they appear to be very new in mammalian phylogeny. It appears mammals handle sleep and energy metabolism very differently than the rest of the living. The small amount of HC neurons, however, project widely all over the brain. We now know that the hypocretin neurons control the stability of wakefulness or our arousal. It appears they may also control energy metabolism via leptin function.

Okay, now that we established that mitochondria leakiness determines our lifespan, what can we say about disease generation? Does leakiness determine disease progression? Well, it appears it does. We know that lower life forms like yeast accumulate mitochondrial mutations one hundred thousand times more frequently than in their nuclear DNA. Most of those occur in the control region of the mitochondrial DNA (mtDNA). The new theory of mitochondrial aging is that leakiness of free radicals at the first cytochrome also helps weed out those mitochondrial mutations as we age. Why? Mitochondria that are sluggish to the signal to divide because of the mutation would be taken out by apoptosis very quickly. Moreover, if the mitochondria were in perfect order, it would divide immediately and through clonal expansion lay waste to its inefficient brethren. This is intracellular natural selection at work. So the more mutations in the mtDNA coding region the more leakiness occurs. That leakiness is the signal to the nuclear DNA to make new mitochondria. This pathway is called the retrograde response. This is how a defective mitochondria signals the nucleus that something is amiss. In theories past, we always believed it was the nuclear DNA that set the tempo for such decisions but now we know that power rests with the mitochondria. This retrograde pathway is found in yeast all the way up to humans phylogenetically.