Friday, October 29, 2010

Depression, Anxiety, and Obesity 2

Quick review. The hypothalamus in our brains secretes CRH, a hormone that tells our pituitary gland to secrete ACTH, which then travels down through the blood to the adrenal glands (which sit on top of the kidneys). When stimulated by ACTH, the adrenal glands spit out adrenaline and cortisol. Pow! You are ready to fight, or run, or do whatever it is you need to do with your jacked-up stress hormones.

Eventually, cortisol itself can tell the hippocampus to tell the hypothalamus cool it - stop producing CRH, and the cycle shuts down. Or that's how it is supposed to work. In depression, anxiety, and obesity, the cycle is broken. Cortisol stays high. The brain and adrenal glands try to compensate by downregulating some of the receptors, but it doesn't seem to work, at least not long term. Once you have an out of whack hormonal system, all the elements of the hormonal system seem to get out of whack at the same time. I've only introduced the main characters so far - the HPA axis itself - the supporting cast is many-fold and regulates sleep, appetite, and mood. Some of the members will be familiar to you - leptin, orexin, and serotonin among others (1).

Let's discuss the supporting cast in more depth, starting with an anecdote about the hormonal system in general:

Cushing's disease results when the adrenal glands produce too much cortisol. Symptoms of Cushing's disease are weight gain, sleep disruption, hypertension, insulin resistance, depression (even psychosis) - and the depressed mood is often the first sign of the illness. Removal of an adrenal tumor producing the cortisol or adding medications that suppress the function of the adrenal gland will improve all the symptoms, including the depressed mood. Simply giving someone tons of cortisol (or glucocorticoids) will cause the same symptoms - removing the excess cortisol will resolve the symptoms.

Elevated CRH has been found in the brains of suicide victims, in the cerebrospinal fluid of living depressed people, and people with major depressive disorder seem to have an increased response (increased ACTH and cortisol production) in response to CRH stimulation in the dexamethasone suppression test compared to people without major depression. Interestingly, family members of people with major depression show similar increased hormonal activation. Depressed "comfort food" overeaters actually have lower cerebrospinal CRH levels - suggesting that the comfort food somehow soothes the savage HPA axis beast but leads to obesity.

Successful antidepressant treatment seems to resolve these hormonal abnormalities in humans (the ones that are easily tested) and the brain abnormalities in rats. In rats, administration of antidepressants seems to down regulate the expression of the CRH gene both in stressed rats AND in rats who are just hanging out and having a good old time (right up until their brains are examined microscopically, that is). This finding would suggest that antidepressants have an ability to directly affect the hormonal axis, decreasing response to stress.

Newer studies of people with different CRH receptor gene types seem to show differential response to antidepressant treatment - for some people it will work well, for others with a different CRH receptor gene, the antidepressant won't work. (In the Future Envisioned by Big Pharma and Big Medicine, once you show up at my office with symptoms of major depressive disorder or anxiety, I'll send you for genetic testing, and once the results come back, I'll be able to pick a medicine regimen fit for your genetic profile. Eventually doctors would hardly be needed - we're expensive, after all - and you'll just take a depression quiz at the insurance company website and then show up to the processing center for the genetic testing and appropriate pill. Maybe I'm being too post-industrial. Or maybe I can just see what goes on in the gleeful and industrious minds of businesspeople in health care. Heaven forbid we all eat well and take enough vacation and exercise in a guerrilla prevention campaign.)

Leptin is perhaps familiar to you. It is a hormone that regulates appetite. In general, the higher the leptin, the more your appetite should be suppressed. Obese people usually have high leptin, however, showing that this primary regulation mechanism is broken in the development of obesity. Leptin tends to have a diurnal variation - an evening rise in leptin is normal, but in obesity, this rise doesn't seem to happen (resulting in night munching?). Also, leptin has the ability to suppress cortisol production at the adrenal gland, but for some reason in obesity this suppression doesn't work well either. There are some rare leptin-deficient individuals who end up obese - they tend to be obese, anxious, and depressed, and the administration of leptin alone seems to solve all those issues.

Orexin is a brain chemical that stimulates appetite. Nom nom. It is also related to sleep disorders (most famously narcolepsy). In depression, orexin neurons seem to be less numerous (perhaps one reason why depressed individuals classically lost weight, whereas in the Land of Vegetable Oil and HCFS, when we get depressed, we generally gain weight). Orexin seems to activate catecholamines (like norepinephrine and dopamine) and our internal cannabis system (yeah, the chemicals we make in our brains that are rather like the major active ingredient in marijuana - munch munch). Serotonin seems to tell orexin to cool it. Drugs that activate system-wide serotonin (such as phentermine and the recently withdrawn meridia) are used as appetite suppressants to treat obesity. (My discussion of serotonin and heart valves and why 5-HTP skeeves me out is in this post - be sure to read the comments too.) Drugs that block serotonin cause weight gain. SSRIs (which ostensibly increase the amount of serotonin hanging out in the synapse) are used to treat emotional eating and often result in weight loss. (And yes, antidepressants often cause weight gain as well - this is likely due to the antihistamine effect of these agents rather than so much a direct serotonin effect, though I will go into this issue more fully in a subsequent post if there is interest).

And, last but not least, IL-6. IL-6 is an inflammatory cytokine that is elevated in obesity and depression. This little bugger is found in abundance in fat cells, suggesting it may have to do with metabolism itself. IL-6 is supposed to be low during the day - in depressed individuals, the levels are especially high during the day, even in depressed individuals who don't have measurable deranged HPA axis issues yet. IL-6 is an immune system activator - Inflammation - and is common to depression, anxiety, and metabolic syndrome.

All right then. Nifty! All these players do similar things in depression, anxiety and obesity, and those conditions are commonly found together. But then there is the skinny depressed person, and the happy overweight person. Rather similar to the obese person without diabetes, and the slender type II diabetic. The review papers that discuss the generalities of these conditions tend to explain these differences with; "It's complicated. More studies are being done. Genetics! Big genetics studies! Answers are at hand!"

So I'll finish today with... it's complicated. Don't get stressed! Protect your HPA axis with good food and friends and relaxation. Depression and anxiety are just as real as obesity, just not quite as visible.


  1. this study says that IL-6 induces anorexia(in rats but...)
    and this one agrees that in anorexia theyre lower

    maybe the rise and fall difference is a different type of malnutrition in both cases. i think chronic stress, depression and starvation are as interlinked as chronic stress, depression and obesity...both impaired nutrition?

    if you get a chance, my recent blog post attempts my wrap up of some conclusions i have drawn in recent studying of the mind....if you get a chance, possibly comment or correct any errors i have concluded?? would appreciate it

  2. It was a great post, malpaz - hope you saw my comment!


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