Professor Onno C. Meijer, PhD, Einthoven Laboratory, Leiden University Medical Center, Leiden, The Netherlands

Cushing’s Syndrome is what happens when we are exposed to (way) too much cortisol, or its synthetic variants. Out of the many unwanted aspects of Cushing’s, fat accumulation is the most visible one, and also one of the biggest risks for additional health problems. The medical jargon talks – perhaps rather callously – about ‘truncal obesity’, ‘moon face’, and ‘buffalo hump’. The latter refers to the accumulation of fat in between the shoulders. This is such a typical feature of cortisol excess that, when scientists were able to generate an animal model for Cushing’s Disease, they prominently displayed a picture of a mouse-with-buffalo hump in the article that described their work(1). Why does cortisol lead to the appearance of all this fat?

The answer is related to the normal role of cortisol as a stress hormone. When we encounter a stressful situation, we need to somehow cope with that situation – we get ‘stressed’. Being stressed means being in a particular ‘state’, not only mentally, but also physically. Although stress has a bad reputation, the stress response is essential for survival, as all organisms will meet challenges in their lives that require this state of being stressed.

The body has very effective ways of bringing about physical states: hormones. Hormones are messenger molecules that come from one source – glands, such as the adrenal gland. The power of hormones lies in the fact that they are transported via the blood to reach each and every cell in the body. They are ‘public announcements’, and as such a perfect way to bring about a coordinated change in the activity of many organs. They can cause a different state.

Immediately at the start of the stress response, the hormone adrenaline (a.k.a. epinephrine) is released to support the ‘fight or flight’ response. In other words: adrenaline prepares the body for active coping with the stressful situation. Adrenaline for example ‘tells’ the liver to release sugar and fat into the blood, which can be burned by muscles, to actually make us able to fight or flight. But this effect of adrenaline is relatively short lasting. Enter: cortisol. Cortisol is our second major stress hormone, slower, but ever so powerful. Its levels in the blood typically will start to increase after a couple of minutes. Cortisol levels can remain elevated for

days or weeks when stress is chronic. One of the functions of cortisol is to support a sustained stress response.

Cortisol acts slower than adrenaline but in a more profound manner. Like adrenaline, cortisol tells the liver to spit out its stored sugar and fat as food for muscles, but it also tells the liver to make new sugar and fat. While both hormones tell the liver to make energy available, cortisol is the one to replenish the liver energy stores. What happens under the influence of cortisol is that the liver actually uses all the resources it can find and converts these into sugar and fat for the other organs to use. In parallel, cortisol causes breakdown of muscles that are not being used, in order to generate building blocks for fat and sugar production in the liver(2).

Effective coordination by cortisol…(3)

These cortisol effects can be really useful for different stress situations. For actual fight-flight we need the sugar and fat. If the stressor would be starvation, it is even useful to break down muscles to ensure activity of the vital organs. However, in case of Cushing’s syndrome, the patient is normally at rest and does not need all this extra energy. Yet: it is there in the blood. What happens next?

The body cannot do many things with sugar and fat circulating in the blood. In fact, with fat it can do only two things. It can burn it (normally into calories, that is: fuel for our muscles and other organs). Or it can store it: in our fat depots. With sugar there is one more option: the body can turn it into fat. To burn, or to store. And so, what cortisol does here is to ensure that more than plenty of fat is present in the blood, even by breaking down muscles. That fat has nowhere to go other than into its depots: and here we arrive at obesity. And, for that matter, at thinning of arms and legs, as muscles are actively being told to shrink and return their building blocks to generate ‘fuel’. A nasty consequence of what normally is a healthy response to adapt to stressors.

What we do not know is why fat accumulates in the face and in between the shoulders. It may be that the latter involves a sort of reactivation of a special fat organ: the brown fat (also known as Brown Adipose Tissue, or BAT). This is a special type of tissue that takes up fat, but does not store it. BAT rather burns fat

into heat. BAT is present in large amounts in babies: they have a relatively large surface and therefore lose heat more than adults. The major location of BAT in babies is right in between the shoulders. The bad thing is that the buffalo hump may represent ‘awakened’ BAT tissue, but that this BAT tissue only stores the fat and does not burn it (otherwise there would be no accumulation)(4).

And so, the unpleasant effect of cortisol on fat accumulation does make sense. The increase in glucose in parallel increases the risk to develop diabetes. The friend that cortisol normally is, turns into a foe: it is really too much of a good thing.

1 Sahut-Barnola I, de Joussineau C, Val P, Lambert-Langlais S, Damon C, Lefrançois-Martinez A-M, Pointud J-C, Marceau G, Sapin V, Tissier F, Ragazzon B, Bertherat J, Kirschner LS, Stratakis CA, Martinez A. Cushing’s syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. PLoS Genet 2010;6(6):e1000980. doi:10.1371/journal.pgen.1000980.

2 This breaking down of muscles is called a ‘catabolic’ action. Androgens, the male sex hormones, do the opposite and support muscle growth – these are then the anabolic steroids.

3 One of the other organs that is part is this same coordination is the brain, that start to generate hunger signals under the influence of cortisol. Although in case of acute threats this effect is counteracted by other stress factors in the brain. This is why stressed people may either eat more or less than normally.

4 Adults do have some active brown fat tissue, located more inside the body. Activating this BAT is presently a popular subject in research on obesity. Activated BAT will simply take up fat from the blood and make it disappear as heat (and some CO2 and water). A sure (but limited) way to lose calories.

Editor’s Note: Dr. Meijer was a featured speaker at the 2017 Annual Summit of WAPO, the World Alliance of Pituitary Organizations, of which CSRF is a founding member.  This article originally appeared in the December 2017 Global Pituitary Voice, the WAPO newsletter.

Winter/Spring, 2018