Weight Struggles? Blame New Neurons in Your Hypothalamus

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05/21/2012
Neurogenesis spurred by a high-fat diet encourages more eating and fat
storage, animal study suggests

New nerve cells formed in a select part of the brain could hold
considerable sway over how much you eat and consequently weigh, new
animal research by Johns Hopkins scientists suggests in a study
published in the May issue of Nature Neuroscience.

The idea that the brain is still forming new nerve cells, or neurons,
into adulthood has become well-established over the past several
decades, says study leader Seth Blackshaw, Ph.D., an associate professor
in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins
University School of Medicine. However, he adds, researchers had
previously thought that this process, called neurogenesis, only occurs
in two brain areas: the hippocampus, involved in memory, and the
olfactory bulb, involved in smell.

More recent research suggests that a third area, the hypothalamus —
associated with a variety of bodily functions, including sleep, body
temperature, hunger and thirst — also produces new neurons. However, the
precise source of this neurogenesis and the function of these newborn
neurons remained a mystery.

To answer these questions, Blackshaw and his colleagues used mice as a
model system. The researchers started by investigating whether any
particular part of the hypothalamus had a high level of cell growth,
suggesting that neurogenesis was occurring. They injected the animals
with a compound called bromodeoxyuridine (BrdU), which selectively
incorporates itself into newly replicating DNA of dividing cells, where
it’s readily detectable. Within a few days, the researchers found high
levels of BrdU in an area of the hypothalamus called the median
eminence, which lies on the base of the brain’s fluid-filled third
ventricle.

Further tests showed that these rapidly proliferating cells were
tanycytes, a good candidate for producing new neurons since they have
many characteristics in common with cells involved in neurogenesis
during early development. To confirm that tanycytes were indeed
producing new neurons and not other types of cells, Blackshaw and his
colleagues selectively bred mice that produced a fluorescent protein
only in their tanycytes. Within a few weeks, they found neurons that
also fluoresced, proof that these cells came from tanycyte progenitors.

With the source of hypothalamic neurogenesis settled, the researchers
turned to the question of function. Knowing that many previous studies
have suggested that animals raised on a high-fat diet are at
significantly greater risk of obesity and metabolic syndrome as adults,
Blackshaw’s team wondered whether hypothalamic neurogenesis might play a
role in this phenomenon.

The researchers fed mice a diet of high-fat chow starting at weaning and
looked for evidence of neurogenesis at several different time points.
While very young animals showed no difference compared with mice fed
normal chow, neurogenesis quadrupled in adults that had consistently
eaten the high-fat chow since weaning. These animals gained more weight
and had higher fat mass than animals raised on normal chow.

When Blackshaw and his colleagues killed off new neurons in the high-fat
eaters by irradiating just their median eminences with precise X-ray
beams, the mice gained significantly less weight and fat than animals
who had eaten the same diet and were considerably more active,
suggesting that these new neurons play a critical role in regulating
weight, fat storage and energy expenditure.

“People typically think growing new neurons in the brain is a good thing
— but it’s really just another way for the brain to modify behavior,”
Blackshaw explains. He adds that hypothalamic neurogenesis is probably a
mechanism that evolved to help wild animals survive and helped our
ancestors do the same in the past. Wild animals that encounter a rich
and abundant food source would be well-served to eat as much as
possible, since such a resource is typically scarce in nature.

Being exposed to such a resource during youth, and consequently
encouraging the growth of neurons that would promote more food intake
and energy storage in the future, would be advantageous. However,
Blackshaw explains, for lab animals as well as people in developed
countries, who have nearly unlimited access to abundant food, such
neurogenesis isn’t necessarily beneficial — it could encourage excessive
weight gain and fat storage when they’re not necessary.

If the team’s work is confirmed in future studies, he adds, researchers
might eventually use these findings as a basis to treat obesity by
inhibiting hypothalamic neurogenesis, either by irradiating the median
eminence or developing drugs that inhibit this process.

Other Hopkins researchers involved in this study include Daniel A. Lee,
Joseph L. Bedong, Thomas Pak, Hong Wang, Juan Song, Ana Miranda-Angulo,
Vani Takiar, Vanessa Charubhumi, Susan Aja and Eric Ford.

This research was supported by the National Institutes of Health, the
National Science Foundation, a Basil O’Connor Starter Scholar Award, the
Klingenstein Fund and NARSAD. Seth Blackshaw is a W.M. Keck
Distinguished Young Scholar in Medical Research.


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