Nov 12, 2012 by NATASHA LONGO
It's Not Just About What You Eat, But Also When You Eat It
There is a link between our fat cells and molecules within our biological clock. That clock tells the body when to sleep and metabolize food and fat cells store excess energy and signal these levels to the brain. Eat at the wrong times and gaining weight is that much easier.
In a new study this week in Nature Medicine, 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, shows that deletion of a clock gene known as Bmal1, in fat cells, causes obesity in mice, with a shift in the timing of when this nocturnal species normally eats. These findings shed light on the complex causes of weight gain in humans.
The Penn studies are surprising in two respects. "The first is that a relatively modest shift in food consumption into what is normally the rest period for mice can favor energy storage," says Paschos. "Our mice became obese without consuming more calories." Indeed, the Penn researchers could also cause obesity in normal mice by replicating the altered pattern of food consumption observed in mice with a broken clock in their fat cells.
Earlier this year in Nature, a study described a powerful link between circadian rhythms and metabolism suggesting a new avenue for understanding disorders of both systems, including jet lag, sleep disorders, obesity and diabetes.
“This fundamentally changes our knowledge about the workings of the circadian clock and how it orchestrates our sleep-wake cycles, when we eat and even the times our bodies metabolize nutrients,” said Ronald M. Evans, a professor in Salk's Gene Expression Laboratory.
This behavioral change in the mice is somewhat akin to night-eating syndrome in humans, also associated with obesity and originally described by Penn's Albert Stunkard in 1955.
The second surprising observation relates to the molecular clock itself. Traditionally, clocks in peripheral tissues are thought to follow the lead of the "master clock" in the SCN of the brain, a bit like members of an orchestra following a 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," explains FitzGerald.
Daily intake of food is driven by oscillating expression of genes that drive and suppress appetite in the hypothalamus. When the clock was broken in fat cells, the Penn investigators found that this hypothalamic rhythm was disrupted to favor food consumption at the time of inappropriate intake -- daytime in mice, nighttime in humans.
When a species' typical daily rhythm is thrown off, changes in metabolism also happen. For example, in people, night shift workers have an increased prevalence of obesity and metabolic syndrome, and patients with sleep disorders have a higher risk for developing obesity. Also, less sleep means more weight gain in healthy men and women.
Dr. Steven McKnight of the University of Texas Southwest Medical Center in Dallas and his team discovered details on how food can influence circadian rhythms. Food contributes a certain amount of fuel for the body processes, which gets stored in the form of a substance known as NADPH, a major energy pathway.
While many experts argue that light has the strongest influence on how that clock is oriented, some evidence suggests that what and when we eat might play an equally, if not more important, role.
Balancing energy levels in the body requires integrating multiple signals between the central nervous system and outlying tissues, such as the liver and heart. Fat cells not only store and release energy but also communicate with the brain about the amount of stored energy via the hormone leptin. When leptin is secreted, it causes more energy to be used and less eating via pathways in the hypothalamus.
Mice typically fed a fatty diet quickly develop changes in their normal activity patterns. The animals begin eating more during the day, when mice--being nocturnal--are supposed to be asleep. They also exhibit changes in the molecular components of the circadian clock and in important aspects of metabolic chemistry.
The Penn team found that only a handful of genes were altered when the clock was broken in fat cells and these governed how unsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were released into the blood stream. Interestingly, these are the same fatty acids that are typically associated with fish oils. Sure enough, levels of EPA and DHA were low in both plasma and in the hypothalamus at the time of inappropriate feeding. "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," notes Paschos.
The findings point to a role for the fat cell clock molecules in organizing energy regulation and the timing of eating by communicating with the hypothalamus, which ultimately affects stored energy and body weight.
Taken together, these studies emphasize the importance of the molecular clock as an orchestrator of metabolism and reflect 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."
In addition, researchers have found that mice on the high-fat diet displayed altered activity of key genes that control the roughly 24-hour circadian rhythm. These clock-controlled metabolic genes are expressed in parts of the brain, as well as in the liver and fat tissue. The high-fat diet suppressed the activity of the core clock genes.
It's not only activity and feeding that shifts, but also the molecular processes involved in metabolism. The changes appear to be global. The clock is an ancient mechanism for matching behavior to changes in the external environment that vary in accordance with the rotation of the earth, and the cycle of light and darkness. The clock is also clearly influenced by the composition of the diet.
Natasha Longo has a master's degree in nutrition and is a certified fitness and nutritional counselor. She has consulted on public health policy and procurement in Canada, Australia, Spain, Ireland, England and Germany.