ScienceDaily (Nov. 11, 2012) — Fat cells store excess energy and signal these levels to the brain. 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 the clock gene Arntl, also known as
Bmal1, in fat cells, causes mice to become obese, with a shift in the
timing of when this nocturnal species normally eats. These findings shed
light on the complex causes of obesity 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.
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.
Balancing Act Balancing energy levels in the body requires
integrating mul¬tiple 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.
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 cen¬tral
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."
This work was supported by the National Heart Lung and Blood
Institute (RO1 HL097800) and the Medical Research Council (grant
UD99999906).
Co-authors include Salam Ibrahim, Wen-Liang Song, Takeshige Kunieda,
Gregory Grant, Teresa M Reyes, Fenfen Wang, and John A Lawson, all from
Penn.
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Story Source:
The above story is reprinted from materials provided by Perelman School of Medicine at the University of Pennsylvania, via Newswise.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Journal Reference:
- Georgios K Paschos, Salam Ibrahim, Wen-Liang Song, Takeshige
Kunieda, Gregory Grant, Teresa M Reyes, Christopher A Bradfield, Cheryl H
Vaughan, Michael Eiden, Mojgan Masoodi, Julian L Griffin, Fenfen Wang,
John A Lawson, Garret A FitzGerald. Obesity in mice with adipocyte-specific deletion of clock component Arntl. Nature Medicine, 2012; DOI: 10.1038/nm.2979
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