(Image caption:
Mouse Central Amygdala containing Prepronociceptin (green) and PKC delta (magenta) neurons)

The Neurobiology of Noshing: Why is it so easy to overeat calorie-rich tasty foods?

When you eat something super tasty, ever wonder why you really don’t
want to stop even though you know you’ve eaten enough? Scientists at the
UNC School of Medicine may have found the reason.

In lab experiments, Thomas Kash,
PhD, the John R. Andrews Distinguished Professor in the Department of
Pharmacology, and colleagues discovered a specific network of cellular
communication emanating from the emotion-processing region of the brain,
motivating mice to keep eating tasty food even though their basic
energy needs had been met.

The existence of this mammalian brain circuit, described in a paper in Neuron,
might help explain why humans so often overeat in our modern
environment of abundant and delicious fare. The circuit is a byproduct
of evolution, when large calorie-rich meals were scarce, and so our
brains were wired to devour as many calories as humanly possible because
no one knew when the next super meal would come.

“This circuit seems to be the brain’s way of telling you that if
something tastes really good, then it’s worth whatever price you’re
paying to get to it, so don’t stop,” Kash said.

Scientists in search of anti-obesity remedies have spent decades
researching and targeting brain cells and circuits involved in ordinary,
“homeostatic” feeding, which is triggered by hunger and keeps our
energy level up. But this approach has had limited success. More
recently, some scientists have been studying “hedonic” feeding – the
pleasure-driven eating of calorie-rich food that tends to go way beyond
our strict energy needs.

Hedonic feeding is thought to reflect modern humans’ lingering
adaptation for ancient environments where famines were frequent.
Perceiving calorie-rich food as particularly tasty and pleasurable, and
bingeing on it whenever it was available, would have conferred a crucial
survival advantage by storing up extra energy. Following that instinct
now, in a time of plenty, can lead to obesity – a condition affecting
about 40 percent of adults in the United States – and related conditions
such as diabetes, heart disease, and cancers.

“There’s just so much calorically dense food available all the time
now, and we haven’t yet lost this wiring that influences us to eat as
much food as possible,” Kash said.

Experiments in the past few years have suggested that our wiring for
hedonic feeding involves nociceptin, a small protein that works as a
signaling molecule in the mammalian nervous system. Kash’s laboratory
and other groups have found
that compounds blocking nociceptin activity – called nociceptin
receptor antagonists – have little or no effect on homeostatic feeding
by lab rats and mice, but these compounds do curb hedonic bingeing on
tasty, calorie-rich foods. Thus, drug developers have eyed these
antagonists as potential anti-obesity, anti-binge-eating drugs, and
researchers have been eager to identify the specific brain circuits
through which they work. The goal would be to develop a more targeted
treatment.

Identifying this circuit is largely what Kash and colleagues
accomplished in their new study. They engineered mice to produce a
fluorescent molecule along with nociceptin, literally illuminating the
cells that drive nociceptin circuits. There are multiple nociceptin
circuits in the brain, but Kash and colleagues observed that one in
particular became active when the mice got a chance to binge on
calorie-rich food. The circuit projects to different parts of the brain,
including those known to regulate feeding. It starts in an
emotion-processing region of the brain called the central amygdala.

Deleting about half of the nociceptin-making neurons in this circuit
reduced the mice’s bingeing and kept their weight down when they had
access to rich food, without affecting their intake of ordinary chow.

“Scientists have studied the amygdala for a long time, and they’ve
linked it to pain and anxiety and fear, but our findings here highlight
that it does other things too, like regulate pathological eating,” Kash
said.

He and his team are now studying in more detail how this circuit
works, the timing of its activity in relation to feeding and other
factors, and how nociceptin antagonists alter its functions.

First author J. Andrew Hardaway, PhD, research assistant professor of
pharmacology at the UNC School of Medicine, said, “Our study is one of
the first to describe how the brain’s emotional center contributes to
eating for pleasure. It adds support to the idea that everything mammals
eat is being dynamically categorized along a spectrum of good/tasty to
bad/disgusting, and this may be physically represented in subsets of
neurons in the amygdala. The next major step and challenge is to tap
into these subsets to derive new therapeutics for obesity and binge
eating.”

Other scientists are studying nociceptin antagonists as possible
treatments not only for obesity and binge-eating but also for
depression, pain, and substance abuse.

“The behavioral effects of blocking nociceptin activity probably
involve multiple mechanisms in the brain,” Kash said. “But on the whole,
blocking nociceptin seems to stabilize behavior, bringing it closer to
normal.”



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