Looking for Food
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A certain level of excitement and anticipation exists when a conductor takes to the stage and taps his baton on the stand. Each member of the orchestra stiffens, ready to follow his timing, each playing their part when directed. While the conductor is clearly in control of the timing of the evening, there is nothing to stop one individual performer from stepping out on his own and causing complete chaos. One early strike by the percussionist throws the rhythm of the entire body off. This is an analogy proposed by researchers regarding how and why we might struggle with potential obesity.

Our fat cells are necessary because they store excess energy. These cells signal the brain, letting them know of their current energy storage level. It was in a study, published this week in the journal Nature Medicine that Georgios Paschos PhD, a research associate in the lab of Garret FitzGerald, MD, FRS director of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, showed that the removal of the clock gene Arntl, which also goes by the name Bmal1, in the fat cells of mice caused them to become obese. This occurred as a result of shift in the timing when this species, nocturnal in nature, would typically consume food. The researchers believe that this information could translate to the epidemic of obesity in humans, as well.

This Penn study is particularly surprising for two reasons. "The first is that a relatively modest shift in food consumption into what is normally the rest period for mice can favor energy storage," according to Paschos. "Our mice became obese without consuming more calories." Even without removing the clock gene from the fat cells, the researchers were able to replicate obesity in the normal mice simply by altering the timing of their food consumption

This research in the behavior change in mice mirrors a similar study, also conducted at Penn, in 1955 by Albert Stunkard. Stunkard's research focused on night-eating syndrome in humans and how it could lead to obesity.

The second observation utilizes the conductor/orchestra metaphor above. It has been traditionally thought that clocks in the peripheral tissues would follow the lead of the "master clock" located in the suprachiasmatic nucleus (SCN) of the brain, much like the members of the orchestra follow the lead of the conductor. "While we have long known that peripheral clocks have some capacity for autonomy - the percussionist can bang the drum without instructions from the conductor - here we see that the orchestrated behavior of the percussionist can, itself, influence the conductor," according to FitzGerald.

The SCN is a tiny region that is located on the brain's midline, right by the hypothalamus. Cone-shaped and no larger than a grain of rice, it is responsible for controlling our circadian rhythms. It conducts the overall timing, over a 24-hour cycle, for our neuronal and hormonal activities which regulate many of our body's functions.

Our primal drive for food intake is affected by an oscillating expression through genes that drive and suppress appetite. These genes are located in the hypothalamus. When researchers broke the clock in the fat cells of the mice they found that this hypothalamic rhythm was disrupted. The disruption caused the mice to seek food intake during their typical time of rest.

This disruption of your daily rhythm causes changes to your metabolism, as well. As an example, in humans, it has been noted that people who work a night shift typically have an increased likelihood of becoming obese and suffering from metabolic syndrome. It has also been found that individuals with sleep disorders have a higher risk for developing obesity, as well. Less sleep is a culprit for weight gain, even in otherwise healthy men and women.

To balance energy levels in the body, an integration of multiple signals between the central nervous system and outlying tissues are required. Our fat cells not only store and release energy to our system, but they also communicate directly with the brain regarding the amount of stored energy available. This communication is conveyed through the hormone leptin. A result of the secretion of leptin is that more energy is used. Also, the body consumes less food. This is due to information transmitted via pathways in the hypothalamus.

One of the discoveries made by the Penn research team was that only a handful of genes were altered when the clock was eliminated in the fat cells. The altered genes regulate how unsaturated fatty acids, like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were ultimately released into the blood stream. These are, not surprisingly, the same fatty acids that are typically associated with fish oils. So it came as no shock that levels of EPA and DHA were low both in the plasma and hypothalamus during inappropriate feeding times. "To our amazement, we were able to rescue the entire phenotype - inappropriate fatty acid oscillation and gene expression in the hypothalamus, feeding pattern and obesity - by supplementing EPA and DHA to the knock-out animals," states Paschos.

The Penn researchers were excited that their findings point to a specific role for the fat cell clock molecules in organizing energy regulation and the timing of eating by communicating directly with the hypothalamus. This communication ultimately directly affects stored energy and body weight.

When you consider both of their findings, these studies reflect the importance of the molecular clock as an orchestrator of metabolism and present a central role for fat cells in the integration of food intake and energy expenditure.

"Our findings show that short-term changes have an immediate effect on the rhythms of eating," says FitzGerald. "Over time, these changes lead to an increase in body weight. The conductor is indeed influenced by the percussionist."