Fat cells store excess energy and signal
these levels to the brain. In a new study 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 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.
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.”
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.
For more information
Penn Medicine, Philadelphia
Obesity in mice with adipocyte-specific deletion of
clock component Arntl
(MDN) |