Harvard: Researchers at Harvard Medical School and Beth Israel Deaconess Medical Center have identified previously unknown neural circuitry that plays a role in promoting satiety, the feeling of having had enough to eat. The discovery revises the current models for homeostatic control—the mechanisms by which the brain maintains the body’s status quo—of feeding behavior.
Published online in Nature Neuroscience,
the findings offer new insight into the regulation of hunger and
satiety which could help researchers find solutions to the ongoing
“Current models lack a rapidly-acting satiety mechanism analogous to the hunger-promoting neurons,” said corresponding author Bradford Lowell,
an HMS professor of medicine in the Division of Endocrinology, Diabetes
and Metabolism at Beth Israel Deaconess. “This component we identified
provides the full ‘yang’ to the hunger-promoting neurons’ ‘yin.’”
Researchers have long known that hunger is regulated by two kinds of
neurons: agouti-related protein (AgRP) neurons and pro-opiomelanocortin
(POMC) neurons. AgRP neurons drive hunger; stimulating these nerves
triggers eating within minutes. The opposing group of neurons, POMC, has
been shown to promote satiety. Lab mice engineered to lack POMC neurons
eat large quantities of food and become massively obese.
However, in recent years, new technology has allowed scientists to
selectively manipulate neurons in living animals, demonstrating specific
neurons’ direct effect on behavior. About five years ago, this type of
research revealed that POMC neurons act over the course of many
hours—not minutes like their AgRP counterparts.
“The lack of a rapid effect strongly suggested that the POMC neurons,
by themselves, are not the full counterpart to the AgRP neurons,” said
lead author Henning Fenselau
an HMS research fellow in medicine in Lowell’s laboratory at Beth
Israel Deaconess. “We hypothesized that an important but unknown neural
component of the satiety system was missing from the current models.”
What’s more, because the team was looking for neurons that would
suppress eating quickly, they narrowed their search for ones that
release the fast-acting, excitatory neurotransmitter called glutamate.
In the current paper, Lowell and colleagues investigated a third subset
of neurons, Vglut2 (vesicular glutamate transporter 2), the function of
which was previously unknown.
In a series of experiments, Lowell and colleagues used optogenetics
(the use of light to activate genetically-modified neurons) and
chemogenetics (the use of molecules to activate targeted neurons) to
manipulate specific neurons to determine their roles in feeding
behavior. First, the team demonstrated that, unlike POMC neurons, Vglut2
neurons could in fact rapidly suppress feeding behavior in mice. When
the researchers chemically stimulated the neurons in question, it
markedly decreased eating. When they inhibited the Vglut2 neurons,
They also found that all three types of neurons—the hunger-promoting
AgRP neurons and the two satiety-promoting neurons, Vglut2 neurons and
POMC neurons—interact in the same circuit. In previous research
by Lowell and colleagues, all three converge downstream in a site in
the hypothalamus known to suppress hunger. AgRP neurons inhibit activity
in this downstream site, causing hunger, while the rapidly-acting
Vglut2 neurons excite it, suppressing hunger. The third member of this
circuit, POMC neurons, indirectly decrease hunger by releasing a hormone
that bolsters Vglut2 neurons’ ability to suppress hunger.
“We think this is very important because it may be one explanation
why individuals lacking POMC genes become extremely obese, even if those
neurons by themselves do not directly promote satiety,” said Fenselau.
“Without POMC, the Vglut2 neurons are ineffective in stimulating the
downstream hypothalamic site. You need both POMC neurons and Vglut2
neurons for the satiety mechanism to work properly.”
Finally, the team sequenced the genes expressed by this subset of
neurons and found they possess receptors for the hormone oxytocin. Known
to play a role in social bonding, oxytocin is linked to feelings of
contentment and is already being investigated for its potential as a
satiety-inducing weight-loss medication. “Our findings could definitely
explain why oxytocin is effective in satiety,” said Fenselau.
To follow up, the scientists will further investigate the
interactions among the three types of neurons and the role they play in
This work was funded by the National Institutes of Health (grants R01
DK075632, R01 DK0960110, R01 DK089044, R01 DK111401, P30 DK046200, P30
DK057521 and F32 DK103387); American Heart Association Postdoctoral
Fellowship 14POST20100011; a Charles A. King Trust postdoctoral
fellowship; and an EMBO postdoctoral fellowship.