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The Cellular and Molecular Substrates of Anorexia Nervosa, Part 1

The Cellular and Molecular Substrates of Anorexia Nervosa, Part 1

[Editor's Note: For Part 2, please click here]. Appetite regulation is made up of complex interlocking, incentive-driven motivational hormonal and neuronal circuitries . . . that can be pulled in many directions, especially where food is cheap and readily available.

The event that created the most indelible memories of my graduate experience recurred each morning as I trundled down to the lab. I always crossed paths with a well-disciplined jogger, heading in the opposite direction, running feverishly up a hill I was descending. It was very difficult not to stare at her, for she looked like someone freshly liberated from a concentration camp. Gaunt, pale, withered, bones protruding behind thin sheaths of skin, the jogger possessed a desperate, oddly determined look in her eyes. The look was unforgettable.

She grew paler and more emaciated as the months went by, and there came a time when we no longer crossed paths. I always wondered if she had moved away, got into a treatment program, or had simply died.

This month’s column—and the next (Part 2)—is all about the neural and molecular biology of anorexia nervosa, a disorder from which this jogger probably suffered. Starting with definitions and diagnostic criteria, then moving to the various neural circuits thought to be involved in its etiology, I will describe some recent findings from the 40,000-foot view of this most baffling disease. Here I discuss certain cellular interactions inside these circuits that may underlie the disease.

The field shows great promise, and some surprising recent research twists, in what turns out to be a very complex research story. Frustratingly, the field faces some real research challenges before consistently effective treatment strategies emerge and joggers like my morning friend become a thing of the past.

DEFINITIONS AND CONFOUNDERS

DSM-IV recognizes 2 types of restricting eating disorders whose most common feature is a deliberate alteration in caloric intake. As you know, bingeing/purging behavior is one type—classic bulimia nervosa—characterized mostly by the familiar intense restriction of food intake punctuated with temporary episodes of disinhibitory behavior. The other type, sometimes called restricting type anorexia nervosa, has few or no periods of disinhibition. Although many patients may freely transit between these behaviors, we focus our discussion on restricting anorexia, hereafter referred to as AN.

At first blush, researching the underlying neurobiological mechanisms behind AN might seem a fairly straightforward task. It has a fully known—even archetypal—set of symptoms. Its clinical course is well characterized. The disease has a surprisingly narrow age of onset (early puberty) and is mostly experienced by females, which easily makes AN one the most homogeneous of all psychiatric disorders. Would that investigating schizophrenia had such predictive luxury!

Scratching below the surface of the disorder reveals why research into AN has been such a challenge, however. Appetite regulation is made up of complex interlocking, incentive-driven motivational hormonal and neuronal circuitries. These circuits can be pulled in many directions, especially where the food supply is cheap and readily available to so many. From classic metabolic aberrations to more purely psycho-biological issues, there are many places where dysfunction could arise.

Given such variability, it is perhaps not surprising that AN has a bewildering, multifactorial etiology. There are sociocultural factors to consider; there are developmental factors to consider; and there are underlying genetic factors that may influence the psychosocial issues. (As we’ll see in Part 2, AN shows surprising heritability.) Even in healthy populations, the factors that determine appetite are many and include an individual’s homeostatic needs, his or her perceptions of those needs, the tendency to favor certain consumptive strategies over others, and food’s natural rewarding (and also punishing) properties.

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