UCSF. US: Unexpected Findings Have Implications for Anti-Obesity Therapies. Using techniques developed only over the past few years, UC San
Francisco researchers have completed experiments that overturn the
scientific consensus on how the brain’s “hunger circuit” governs eating.
Because of this circuit’s potential role in obesity, it has been
extensively studied by neuroscientists and has attracted intense
interest among pharmaceutical companies. According to the UCSF
scientists, their unexpected new findings could reshape basic research
on feeding behavior as well as strategies for the development of new
anti-obesity drugs.
Scientists have generally believed that the hunger circuit, made up
of two groups of cells known as AgRP and POMC neurons, senses long-term
changes in the body’s hormone and nutrient levels, and that the
activation of AgRP neurons directly drives eating. But the new work
shows that the AgRP-POMC circuit responds within seconds to the mere
presence of food, and that AgRP neurons motivate animals to seek and
obtain food, rather than directly prompting them to consume it.
“No one would have predicted this. It’s one of the most surprising results in the field in a long time,” said Zachary Knight,
PhD, assistant professor of physiology at UCSF. “These findings really
change our view of what this region of the brain is doing.”
It has been known for 75 years that a region at the base of the brain
called the hypothalamus exerts profound control over eating behavior.
As neuroscientists refined this observation over the ensuing decades,
they zeroed in first on a small area of the hypothalamus known as the
arcuate nucleus, and more recently on AgRP and POMC neurons, two small
populations of cells within that nucleus.
These two groups of cells, which collectively occupy an area smaller
than a millimeter in the mouse brain, are functionally organized in a
seesaw-like fashion: when AgRP neurons are active, POMC neurons are not,
and vice versa.
Hundreds of experiments in which scientists added hormones or
nutrients to brain slices while recording the activity of AgRP and POMC
neurons have laid the foundation of the dominant model of how the hunger
circuit works. As we grow hungry, this view holds, gradual changes in
hormone levels send signals that begin to trigger AgRP neurons, the
activity of which eventually drives us to eat. As we become sated,
circulating nutrients such as glucose activate POMC neurons, which
suppresses the desire to eat more food.
Yiming Chen, a graduate student in Knight’s lab, was expecting to
build on the prevailing model of the hunger circuit when he began
experiments using newly developed fiber optic devices that allowed him
to record AgRP-POMC activity in real time as mice were given food after a
period of fasting. “No one had actually recorded the activity of these
neurons in a behaving mouse, because the cells in this region are
incredibly heterogeneous and located deep within the brain,” said Chen.
“The technology to do this experiment has only existed for a few years.”
But as reported in the February 19, 2015 online issue of Cell,
just seconds after food was given to the mice, and before they had
begun to eat, Chen saw AgRP activity begin to plummet, and POMC activity
correspondingly begin to rise.
“Our prediction was that if we gave a hungry mouse some food, then
slowly, over many minutes, it would become satiated and we would see
these neurons slowly change their activity,” Knight said. “What we found
instead was very surprising. If you simply give food to the mouse,
almost immediately the neurons reversed their activation state. This
happens when the mouse first sees and smells the food, before they even
take a bite.”
The researchers found that the AgRP-POMC circuit could be quickly
“reset,” with POMC cell activity dampened and AgRP neurons again
beginning to fire, if the food were taken away. The magnitude of the
transition from AgRP to POMC activity was also directly correlated with
the palatability of the food offered: peanut butter and chocolate, both
of which are much preferred by mice over standard lab chow, caused a
stronger and more rapid reversal of AgRP-POMC activity. The AgRP-POMC
responses also depended on the accessibility of the food. A slower and
weaker transition was seen if the mice were able detect the presence of
peanut butter through smell, but couldn’t see the food.
These results show that, while slow, hunger-induced changes in
hormones and nutrients activate AgRP neurons over the long term, these
neurons are rapidly inactivated by the sight and smell of food alone. A
major implication of this discovery, Knight and Chen said, is that the
function of AgRP neurons is to motivate hungry animals to seek and find
food, not to directly control eating behavior itself.
The fact that more accessible and more palatable, energy-rich foods
engage POMC neurons and shut down AgRP activity more strongly suggests
that the circuit also has “anticipatory” aspects, by which these neurons
predict the nutritional value of a forthcoming meal and adjust their
activity accordingly.
Both of these roles of the AgRP-POMC circuit make sense, said the
researchers: if an animal has successfully obtained food, the most
adaptive brain mechanism would suppress the motivation to continue
searching; likewise, since energy-dense foods alleviate hunger for
longer periods, discovery of these foods should more strongly tamp down
the hunger circuit and the desire to seek additional nutrition.
“Evolution has made these neurons a key control point in the hunger
circuit, but it’s primarily to control the discovery of food,” said
Knight. “It’s controlling the motivation to go out and find food, not
the intake of food itself.”
So far, clinical trials of drugs that target AgRP-related pathways
have been disappointing, Knight said, and he believes the new research
may provide a new perspective on these efforts. “What probably drives
obesity is the rewarding aspect of food. When you want dessert after
you’ve finished dinner, it’s because it tastes good, and that doesn’t
require hunger at all,” Knight said. “Finding that this circuitry
primarily controls food discovery rather than eating changes our view of
what we might be manipulating with drugs targeting AgRP pathways. We
might be manipulating the decision to go to the grocery store, not
necessarily the decision to take the next bite of food.”
Other members of the Knight laboratory participating in the research
were Yen-Chu Lin, research specialist, and graduate student Tzu-Wei Kuo.
The research was supported by the New York Stem Cell Foundation, the
Rita Allen Foundation, the McKnight Foundation, the Alfred P. Sloan
Foundation, a NARSAD Young Investigator Grant from the Brain and
Behavior Research Foundation, the Esther A. and Joseph Klingenstein
Foundation, the Program for Breakthrough Biomedical Research, the UCSF
Diabetes Center Obesity Pilot Program, and the National Institutes of
Health.