Obesity Linked To Obsessive-Compulsive Behavior Via Brain Circuit

Date: Jun-11-2013An investigation of the brain circuits behind compulsive behavior has surprisingly revealed they may be intimately linked
to circuits that control obesity. The US researchers say the discovery offers new insights into the development and treatment of
both compulsive behavior and eating disorders.

Study leaders and neuro-psychiatrists Michael Lutter and Andrew Pieper of the University of Iowa (UI), and colleagues, write
about their work in this week's online early edition of the Proceedings of the National Academy of Sciences (PNAS)
.

They describe how they bred mice missing a gene known to cause obesity, and suspected of being involved in compulsive behavior, and mated them with mice bred to have compulsive
grooming and were surprised to see offspring that were neither obese nor compulsive groomers.

They say this shows the brain circuits that control obsessive-compulsive behavior are meshed with circuits that control food intake
and body weight: a finding that will have implications for treating the compulsive behavior in many psychiatric
diseases like obsessive-compulsive disorder (OCD), Tourette syndrome, and eating disorders.
Obese Mice and Compulsive Groomers
The researchers worked with two types of mice engineered for studying human disorders: one bred to study compulsive behavior
(Pieper's field of interest), and the other bred to study an inherited form of obesity (Lutter's specialism).

The compulsive behavior mice are missing a brain protein called SAPAP3, the lack of which causes them to groom themselves
excessively. The behavior can be effectively controlled with fluoxetine, a drug commonly used to treat OCD in people.

The inherited obesity mice lack a brain protein called MC4R. Mutations in the MC4R gene are the biggest single-gene cause of
over-eating and morbid obesity in people.

Lutter, an assistant professor of psychiatry at the UI Carver College of Medicine, is interested in MC4R signaling pathways and
how they affect the development of obesity.

"I'm also interested in how these same molecules affect mood and anxiety and reward, because it's known that there is a
connection between depression and anxiety and development of obesity," he explains in a statement.
What Happened When the Two Strains Interbred
Lutter and Pieper, who is an associate professor of psychiatry and neurology at Carver, were aware of an old study that suggested
MC4R might play a role not only in food intake and obesity, but also in compulsive behavior, so they decided to test the idea, as
Lutter explains:

"We knew in one mouse you could stimulate excessive grooming through this MC4R pathway and in another mouse a different
pathway (SAPAP3) caused compulsive grooming."

"So, we decided to breed the two mice together to see if it would have an effect on compulsive grooming," he adds.

The breeding experiment bore out their hypothesis: knocking out the MC4R protein in OCD mice lacking SAPAP3 normalized their
grooming behavior. And they also found chemically blocking the protein had the same effect, which was mirrored by normal
patterns in brain cell communication linked to compulsive behavior.
Unexpected Finding: Deleting Both SAPAP3 and MC4R Led to Normal Weight Mice
But they were surprised by another totally unexpected finding. Deleting SAPAP3, lack of which causes compulsive grooming,
restored normal weight in mice without MC4R, lack of which would normally make them obese.

"We had this other, completely shocking finding -- we completely rescued body weight and food intake in the double null mouse,"
Lutter exclaims.

Thus it appeared that they were influencing two, until now unknown to be related, brain regions simultaneously: one involved in
grooming and behavior, the other with food intake and body mass.
Explanation May Lie In Evolution
Lutter suggests that while a connection between obesity and obsessive-compulsive behavior might not be obvious at first, there
could be an evolutionary explanation. Survival depends on eating clean, safe food, so when this is abundant, the drive increases,
and when it is scarce, it decreases.

"Obsessive behavior, or fear of contamination, may be an evolutionary protection against eating rotten food," he
explains.

Oils and fats are calorie- and nutrient-rich but also spoil more quickly than foods that are less dense in nutrients and calories like
onions, apples and potatoes.

(Refrigeration, which reduces risk of contamination, has not been around long enough to have made an impact on the evolution of
these brain circuits.)

Lutter wonders if the circuits they have found help determine whether or not to eat calorie-dense foods.

Perhaps a disturbance in the circuits may on the one hand result in obesity because people are less anxious and obsessive and
consume energy-dense foods, and on the other hand they are excessively anxious and obsessive and limit their food selection or
intake, leading to disorders like anorexia nervosa, Tourette syndrome, or OCD.

Pieper says they now want to find out if the two pathways talk to each other. Whatever the answer, it is likely to increase
understanding toward new drugs for treating some of these disorders.

Funds from The Hartwell Foundation, the Brain and Behavior Foundation, the National Institutes of Health and a NARSAD
Young Investigator Award helped finance the study.

In another study published in January 2013, researchers at MIT describe how they used optogenetic brain stimulation to block compulsive behavior
in mice lacking SAPAP3.

Written by Catharine Paddock PhD

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