Anorexia And Metabolic Set Point

[Content warning: fat, anorexia, dieting]
[Epistemic status: crazy speculation from someone who isn’t an expert in the field. Please don’t take too seriously.]

Some anorexics I talk to describe their condition as falling into two phases.

In Phase 1, they’re a model or a ballerina or something where they’re under a lot of pressure to become thin. So they go on a diet, they have trouble just like everyone else, but they stick to it and gradually get thinner. People praise them for their thinness. They win the Ballerina Of The Year award. They’re pretty happy with how things are going, and their dieting is ego syntonic – ie they agree with it and can explain the reasons they think it’s a good decision.

In Phase 2, somebody tells them, wait, this is unhealthy. Maybe they end up in the hospital. Maybe some friends stage an intervention. They admit that they have anorexia and decide to get better and gain weight. And then they can’t. The exact way that this presents varies among people. A few say they never feel hungry – as if they’re always so stuffed they couldn’t eat another bite. More often they still feel hungry, but they feel a sense of horror at their fatness, even if they rationally understand they’re really thin. This makes it very hard to regain weight.

This reminds me of the model of obesity I talked about the other day. People start overeating for social reasons (specifically, because our society is full of tasty food). Then they find they can’t stop – their body has adjusted to its higher weight as a new set point and will defend it vigorously, producing hunger pangs and food obsessions if they try to diet.

The brain system producing these effects is called the “lipostat”, and it seems to work through a control loop. Fat cells produce a hormone called leptin. The hypothalamus measures the amount of leptin, compares to its preferred set point, and based on the result generates strong urges to eat/exercise/fidget either more or less. This in turn makes the person gain or lose weight, increasing or decreasing the amount of fat and the concentration of leptin, and completing the loop.

In (at least some cases of) obesity, constant overeating makes the hypothalamus leptin-resistant – that is, it systematically underestimates the blood level of leptin. Suppose a healthy person weighs 150 lbs, his body is on board with that, and his lipostat is set to defend a 150 lb set point. Then for some reason he becomes leptin-resistant, so that the brain is only half as good at detecting leptin as it should be. Now he will have to be 300 lbs before his brain “believes” he is the right weight and stops encouraging him to eat more. If he goes down to a “mere” 250 lbs, his brain will panic, believe he’s starving, and demand he eat more.

One point that The Hungry Brain stressed again and again is the cognitive complexity of the hunger response. For example, from Ancel Keys’ Starvation Experiment:

Over the course of their weight loss, Keys’s subjects developed a remarkable obsession with food. In addition to their inescapable, gnawing hunger, their conversations, thoughts, fantasies, and dreams revolved around food and eating – part of a phenomenon Keys called “semistarvation neurosis”. They became fascinated by recipes and cookbooks, and some even began collecting cooking utensils. Like leptin-deficient adolescents, their lives revolved around food. Also like leptin-deficient adolescents, they had very low leptin levels due to their semi-starved state.

And from studies of leptin-deficient children:

Farooqi explains that the primary reason leptin-deficient children develop obesity is that they have “an incredible drive to eat”…leptin-deficient children are nearly always hungry, and they almost always want to eat, even shortly after meals. Their appetite is so exaggerated that it’s almost impossible to put them on a diet: if their food is restricted, they find some way to eat, including retrieving stale morsels from the trash can and gnawing on fish sticks directly from the freezer. This is the desperation of starvation […] Unlike normal teenagers, those with leptin deficiency don’t have much interest in films, dating, or other teenage pursuits. They want to talk about food, about recipes. “Everything they do, think about, talk about, has to do with food” says [Dr.] Farooqi. This shows that the [leptin system] does much more than simply regulate appetite – it’s so deeply rooted in the brain that it has the ability to hijack a broad swath of brain functions, including emotions and cognition.

Once again, it’s not really clear how people’s metabolic set point drifts up, but it seems to maybe have something to do with overeating junk food.

So suppose there was an exactly opposite process. People who severely undereat find that their metabolic set point drifts down, with their hypothalamus becoming hypersensitive to leptin. Again, consider a person who would ideally weight 150 lbs. If they become twice as sensitive to leptin, their body won’t be happy unless they weigh 75 pounds. If they gain weight to be 100 pounds instead, they’ll be getting “too much” leptin, their brain will feel like they’re too fat, and their bodies will vigorously “defend against” weight gain to try to return to the distorted set point. This sounds a lot like anorexia nervosa.

Some more evidence: people with anorexia fidget like crazy. This is the conventional wisdom among generations of psychiatrists, and has been confirmed in studies – see for example Measurement Of Fidgeting In Patients With Anorexia Nervosa Using A Novel Shoe-Based Monitor, which found anorexics fidget almost twice as much as healthy controls. This seems really damning to me. Consciously deciding to fidget is hard. If you don’t believe me, try to fidget as much as possible for the next two hours (the length of the study linked above) and see how well it goes. Most people just can’t do it. On the other hand, fidgeting (renamed to the more dignified “non-exercise activity thermogenesis”) is the classic strategy that the lipostat uses to maintain unconscious control over weight:

The research of James Levine, an endocrinologist who works with the Mayo Clinic and Arizona State University, explains this puzzling phenomenon. In a carefully controlled overfeeding study, his team showed that the primary reason some people readily burn off excess calories is that they ramp up a form of calorie-burning called “non-exercise activity thermogenesis” (NEAT). NEAT is basically a fancy term for fidgeting. When certain people overeat, their brains boost calorie expenditure by making them fidget, change posture frequently, and make other small movements throughout the day. It’s an involuntary process, and Levine’s data show that it can incinerate nearly 700 calories per day.

A purely social paradigm of anorexia can’t explain the fidgeting; a biological paradigm outright predicts it.

I’m not an expert on anorexia, so for all I know lots of people have thought of this and I’m late to the party. But a quick Google search only reveals a few small leads. Heidebrand et al have studied leptin in anorexia nervosa, but only because they think it might affect symptoms. They find circulating levels are low – which makes sense given anorexics’ low BMI, and which neither confirms nor disconfirms a leptin hypersensitivity hypothesis. They also find that leptin increases more quickly when anorexics gain weight than when healthy people gain weight, which is suggestive but doesn’t prove that much.

I also found a paper, the appropriately-named Treasure (2005) which described anorexia nervosa apparently due to brain lesions. For example:

Of the seven anorexia cases associated with primary tumours in the area of brain stem and the fourth ventricle (Table 1: cases 24–30),12,25–30 two (24 and 25) presented as typical restrictive anorexia nervosa with fear of fatness; surgical removal of the tumours led to remission and sustained weight gain in both cases.

Thirteen cases of eating disorders associated with lesions in the cerebral hemispheres were identified (Table 1: 31–43).31–38 The damage was predominantly localised in the frontal and temporal lobes (six frontal, four temporal, three frontotemporal) of the right hemisphere (nine right, three left, one bilateral)…seven cases presented as “typical” anorexia nervosa with weight and shape preoccupations.

Most of these cases weren’t typical anorexia, and almost all of them involved other obviously-neurological symptoms that ordinary anorexics lack. And most of the relevant tumors were not the hypothalamus (although a similar paper by Chipkevitch finds a disproportionately high number of hypothalamic lesions). But it does prove that excessive concern about becoming fat isn’t just caused by ballet coaches and the patriarchy. It can also be induced by purely neurological mechanisms.

(and a complicating factor – most brain tumors increase intracranial pressure, which seems to increase the ability of leptin to enter the cerebrospinal fluid in ways that might cause obesity or something. There’s actually some suggestive literature that “leptin resistance” might just be serum leptin not making it into the cerebrospinal fluid, and a bunch of studies show that anorexics have proportionally much higher – and obese people proportionally much lower – CSF:serum leptin ratios. But these studies don’t explore causality and it might just be that if you’re too fat your leptin transporters get overloaded.)

I probably shouldn’t focus on leptin so much. Everybody agrees that leptin is only one part of the biology of weight gain, that other hormones are probably more important in weight loss, and that using leptin to represent the entire biological regulation of obesity is kind of a streetlight effect.

But I feel like something like this might be true. There must be some reason why the symptoms of anorexia resemble lipostat action so closely. There must be some reason why anorexics fidget so much. And there must be some reason why brain tumors can mimic some of the most striking symptoms of anorexia, like obsessive fear of becoming fat. All of these make sense only in the context of metabolic set point theory, and I hope more people start trying to link these two ideas up.