Jackson Laboratory
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| Alternative mechanisms for driving food consumption. Eating not only is a necessity, it is a learned response to hunger, too. A) In the positive-valance mechanism, hungry animals learn that eating feels good. B) In the negative-valence mechanism, hunger feels bad to animals, and they learn that eating makes these bad feelings dissipate. Credit: Image courtesy of Jackson Laboratory |
In its simplest terms, weight loss occurs when the amount of
energy consumed in the form of food is less than the amount of energy burned.
This can be accomplished by eating less or exercising more.
With either approach, the goal is to create a caloric debt that
will be resolved by burning stored carbohydrate, protein, or fat.
Challenges to losing the holiday weight (alternatively a beer
gut, Freshman Fifteen, etc.) are simple: eating feels good and being
hungry is uncomfortable.
To explain the less commonly researched "discomfort when
hungry" phenomenon, researchers at the Howard Hughes Medical Institute
(HHMI) Janelia Research Campus hypothesized that specific hypothalamic neurons
stimulate food-seeking behaviors to eliminate the negative feelings associated
with energy deficit.
The Hunger Games -- Neural
manipulation suggests AGRP signals are negative
Previously demonstrated by other groups, hypothalamic AGRP
neurons (agouti-related protein-expressing neurons) fire during energy deficit,
such as food restriction, and quickly lead to food-seeking behavior and
food-consumption.
To determine whether these neurons were associated with positive
signals (such as those associated with food reward) versus negative signals
(such as those associated with the uncomfortable feelings of hunger), mice
either with photoactivatable AGRP neurons or with virally-transduced AGRP
neurons that could be inhibited pharmacologically were subjected to flavor and
place preference tests.
In flavor preference tests, AGRP neuron activation reduced an
animal's preference for previously preferred flavored gel compared to
unstimulated controls, suggesting that a once tasty flavor was now a less
pleasant experience.
In contrast, mouse preferences for a preferred gel increased
when AGRP neurons in food-restricted mice were pharmacologically inhibited
compared to the preferences of untreated controls, suggesting that AGRP
inhibition relieved negative feelings.
In complementary place preference experiments in which mice were
offered two experimental chambers to explore, well-fed mice avoided chambers in
which they had previously received AGRP stimulation, indicating AGRP
stimulation was undesirable.
Similarly, food-restricted mice spent more time in chambers
where they had previously received AGRP inhibition, indicating that relief from
AGRP simulation was preferred. Together, these results suggest that AGRP
neurons stimulate negative signals and generate Pavlovian responses learned
through these negative experiences.
AGRP neurons anticipate
feeding and turn off
To support their behavioral studies, the HHMI Janelia group
performed deep brain imaging in freely-moving AGRP-specific calcium reporter
mice using miniature head-mounted fluorescent microscopes.
As expected, food-restricted mice showed higher fluorescent
signals than mice fed ad libitum, demonstrating that food restriction activates
AGRP neurons. Calcium signals quickly diminished when food-restricted mice were
allowed to eat. Interestingly, the calcium signals dropped before eating began,
including cases where food was visible but not accessible for consumption.
In contrast, calcium signals dropped slightly when mice were
presented a wooden pellet resembling food, but quickly returned when the mice
discovered that the wooden pellet was not food.
Together, these experiments
indicate that AGRP neuron activity is reduced when feeding cues are present.
Further, the rapidity with which the AGRP signals terminate upon
feeding or recommence upon presentation with non-food items strengthen the
hypothesis that AGRP neurons promote negative, rather than positive, signals.
Collectively, these results indicate that energy homeostasis
depends, in part, on alleviating negative signals produced during hunger.
Findings from this study corroborate the negative emotions
people experience when dieting and point to alternative avenues to regulate
food intake.
The negative-valence mechanism that AGRP neurons utilize
contrasts with the majority of hunger-associated neurons previously studied,
which stimulate reward pathways and result in positive feelings when hunger is
satisfied.
Certainly, then, fine control of energy homeostasis is
accomplished by possessing both kinds of neurons.