A Closer look at Cortisol – Hormonal Obesity XXXX

I can make you fat. Actually, I can make anybody fat. How? It is very simple. I prescribe prednisone, a synthetic version of the human hormone cortisol. Prednisone is used to treat many different types of inflammatory diseases, including asthma, rheumatoid arthritis, lupus, psoriasis, inflammatory bowel disease, cancer, glomerulonephritis and myasthenia gravis.  Cortisol makes you fat. Not coincidentally, both insulin and cortisol play a key role in carbohydrate metabolism.

Cortisol

Cortisol is the so-called stress hormone.   It mediates the ‘flight or fight response’ with help from the sympathetic nervous system. Cortisol is part of a class of steroid hormones called glucocorticoids (glucose + cortex + steroid) produced in the adrenal cortex. Cortisol is produced in response to stress. In Paleolithic times, this was often a physical stress, such a being chased by a predator. The release of cortisol was essential in preparing our bodies for action – to fight or flee. Cortisol increases alertness and decreases the need for sleep.

Glucose availability is substantially enhanced. This provides energy for muscles that are needed to avoid being eaten. Non-essential metabolic activities are curtailed. All available energy is directed towards surviving the coming stressful period. Growth, digestion and other long-term issues are temporarily restricted. Proteins are broken down and converted to glucose (gluconeogenesis). In the fasted state, cortisol has several mechanisms to increase glucose in the body.

The blood glucose raising effect of synthetic cortisol prednisone has been known for at least 40 years. These include:

  1. Stimulation of hepatic gluconeogenesis
  2. Inhibition of glucose uptake in peripheral tissues
  3. Stimulation of fat and amino acid breakdown (helps provide substrate for hepatic gluconeogenesis)

Vigorous physical exertion (fight or flight) soon followed using up these newly available stores of glucose. Shortly thereafter, we were either dead, or the danger was past. In either case, the cortisol levels decreased again back to low levels. The body is well adapted to the short-term increase in cortisol and glucose.

Cortisol raises insulin

At first glance cortisol and insulin appear have opposite effects. Insulin is a storage hormone. Under high insulin levels, the body stores energy in the form of glycogen and fat. Cortisol, on the other hand prepares the body for action. This moves energy out of stores and into readily available forms such as glucose. That they would have similar weight gain effects seems remarkable. With short-term physical stress, insulin and cortisol play opposite roles. This situation is quite different for long-term psychological stress.

In modern times, chronic, non-physical stressors increase cortisol. For example, marital issues, problems at work, arguments with children, and sleep deprivation are all serious stressors, but do not result in vigorous physical exertion afterwards to lower blood glucose. Under conditions of chronic stress, glucose levels remain high. There is no vigorous physical exertion to burn off the glucose, and there is no resolution to the stressor. The blood glucose can remain elevated for months.   This chronic elevation in glucose can trigger the release of insulin. Chronically elevated cortisol leads to increased insulin. This has been demonstrated in several studies.

One study measured people repeatedly during a random working day. Cortisol increases with self-perceived stress levels. This stress-related increase in cortisol showed consistent strong relationship to both increased glucose and increased insulin levels (16). Since insulin is the major driver of obesity, it should be no surprise that it was also related to both BMI and abdominal obesity.

Using synthetic cortisol, we can also increase insulin experimentally. Healthy volunteers were given 50mg cortisol four times daily over 5 days. Insulin levels rose 36% from baseline. Another study showed that the use of prednisone increases glucose levels by 6.5% and insulin levels by 20%. Over time, insulin resistance also develops mainly at the hepatic level. There is a direct dose-response relationship between cortisol and insulin. For every unit of free cortisol increase, insulin increased by 9.7 mU/I.

Long-term use of prednisone may lead to an insulin resistant state or full-blown diabetes. The increased insulin resistance seen in type 2 diabetes leads to elevated insulin levels. Even five years after the cure of Cushing’s disease, the elevated insulin levels persist. This is likely related to the insulin resistance syndrome that has developed. This is another mechanism where excess cortisol leads to increased insulin.

Glucocorticoids produce insulin resistance in skeletal muscle by interfering with numerous steps in the insulin-signaling network. The molecular mechanisms have been mapped out including decreased IRS-1, and increased levels of proteins PTP1B and p38MAPK. These interfere with insulin action after it binds the insulin receptor. In addition, muscles release amino acids for gluconeogenesis, increasing insulin resistance. Adiponectin, secreted by fat cells, which normally increase insulin sensitivity, are suppressed by glucocorticoids.

In a way, insulin resistance should be expected, since cortisol generally opposes insulin. Cortisol raises blood sugar where insulin lowers it. This insulin resistance, as we will see in later chapters is crucial in the development of obesity. Insulin resistance will lead directly to increased insulin levels. Increased insulin is a major driver of obesity. Multiple studies show that increasing cortisol confirms this insulin resistance.

If cortisol raises insulin, then reducing cortisol should reduce insulin. We find this situation in transplant patients who are maintained on synthetic cortisol for years or decades as part of their anti-rejection medications. Weaning off the prednisone resulted 25% drop in plasma insulin. This translated to a 6.0% weight loss and a 7.7% decrease in waist girth.

The cardiovascular consequences of excess cortisol sound suspiciously like those of insulin excess. This is also known as the metabolic syndrome and includes high blood sugar, blood pressure, cholesterol and abdominal obesity. Cushing’s syndrome also includes high insulin, blood sugars, blood pressure, cholesterol and truncal obesity.

Cortisol and obesity

Does excess cortisol, from long-term psychological stress lead to weight gain? Certainly anecdotal evidence seems to suggest that stress leads to obesity. But there are certain disease states characterized by excessive cortisol production.  This is called Cushing’s disease or Cushing’s syndrome.  Harvey Cushing originally described a 23-year-old woman in 1912 that suffered from weight gain, excessive hair growth and loss of menstruation. High blood sugars and overt diabetes is present in up to 1/3 of cases. Patients taking long term prednisone often appear similar to these patients and develop what is termed Cushinoid syndrome. There is a particular redistribution of the fat from the limbs to the trunk and face called truncal obesity. The term ‘moon face’ is used to describe the peculiar gain of weight in the face. A ‘buffalo hump’ describes the deposition of fat in the back.

But the hallmark of this disease is weight gain. In case series, 97% of patients show a central weight gain, and 94% show increased body weight. Insulin resistance is another key characteristic of Cushing’s syndrome. Both cortisol and prednisone cause weight gain. Many patients complain that they gain weight no matter how little they eat and no matter how much they exercise. Any disease that results in excess cortisol secretion results in weight gain. Cortisol causes weight gain.

Subclinical Cushing’s syndrome is associated with obesity. These patients can be found by blood testing, but do not yet have symptoms of the disease. Fasting glucose and insulin were similarly elevated in these patients. Cortisol causes weight gain.

However, this effect is seen even within the normal population, without evidence of Cushing’s syndrome. In a random sample from North Glasgow, Scotland, cortisol excretion rates were strongly correlated to Body Mass Index (BMI) and waist measurements. Higher cortisol levels were seen in heavier people. Cortisol related weight gain particularly deposits fat in the abdomen, which results in an increased waist/hip ratio (WHR). This weight distribution of fat in the abdomen is more dangerous to the health than generalized fat.

Other measures of cortisol confirm the association with abdominal obesity. People with higher urinary cortisol excretion have higher waist to hip ratios. People with higher cortisol in the saliva have increased BMI and waist/hip ratio. In other words, there is substantial evidence that chronic cortisol stimulation increases both insulin and obesity. Long-term exposure to cortisol in the body may be measured by scalp hair analysis. In a study comparing obese patients to normal weight, researchers found elevated levels of scalp hair cortisol.

The ultimate test is this. Can I make somebody fat with prednisone? If I can, this proves a causal relationship, rather than a mere association. Does prednisone cause obesity? Absolutely! Weight gain is one of the most common and well-known side effects of the medication. This is a causal relationship. Giving high doses of prednisone causes weight gain. We raised cortisol. People gained weight. Cortisol causes weight gain.

What about the opposite?  If high cortisol causes weight gain, then low cortisol levels should cause weight loss. This exact situation exists in the case of Addison’s disease. Also known as adrenal insufficiency, Thomas Addison described this classic condition in 1885. Cortisol is produced in the adrenal gland. When it is damaged, cortisol levels can drop very low. The major cause of Addison’s disease is autoimmune destruction. Previously, tuberculosis had been a major cause of the syndrome.

The hallmark of Addison’s disease is weight loss. In large case series, 97% of patients exhibit weight loss. Cortisol levels went down. People lost weight. Cortisol causes weight gain.

Cortisol may act through high insulin levels and insulin resistance. There may be other pathways of obesity yet to be discovered. However, the fact that is undeniable is that excess cortisol causes weight gain. By extension, stress causes weight gain. This is something that many people have intuitively understood despite the lack of rigorous evidence. It certainly makes sense. Much more sense than calories causing weight gain.

NewHOT3 Cortisol

Reducing stress is difficult, but vitally important. Contrary to popular belief, sitting in front of the television or computer is a poor way to relieve stress. Instead, stress relief is an active process. There are many time-tested methods of stress relief. These include mindfulness meditation, yoga, massage therapy, and exercise. Studies on mindfulness intervention were able to use yoga, guided meditations, and group discussion to successfully reduce cortisol and abdominal fat.

Continue to Sleep Deprivation – Hormonal Obesity XXXXI

Start here with Calories I – How Do We Gain Weight?

20 Responses

  1. Im coming to laymens assumptions. we know that insulin causes weight gain and cortisol raises insulin levels would u not say that cortisol causes weight gain because it raises isulin levels?

  2. […] Continue to A Closer Look at Cortisol – Hormonal Obesity XXXX […]

  3. Gudmundur Johannsson

    Great post!
    Some of the things you talk about here about are discussed in Malcolm Kendrick’s book “The Great Cholesterol Con” where he argues that chronic stress/cortisol is the main culprit in CVD, citing the research of the late Per Björntorp.
    Maybe you have discussed this elsewhere, but have you seen any data on whether the insulin/cortisol relationship goes both ways, ie does insulin resistance/hyperinsulinemia cause HPA dysfunction?

  4. Michelle

    HI
    MY daughter is Hypopituitaric due to a tumour which grew out of her pituitary and effectively “squashed” it. had neurosurgery almost a year ago but no clear indication of any pituitary function yet except some growth hormone. She has gained tremendous weight (esp on stomach) & incr BMI since the surgery and being on hormone replacement for everything – including cortisol. She takes 3 doses a day – morning, mid afternoon and evening. We are trying out reducing the afternoon dose to try reduce & reverse weight gain. Hopefully will be able to reduce other doses as well once we see how that goes. Do you have any other comments or suggestions regarding how to reduce her weight. (Before we discovered the issue she looked like a skeleton all over except for her tummy which still had fatty deposit – but obviously nowhere near size it is now.) She is in high school so a difficult time to be overweight

  5. The main chronic stressor that should be emphasized in this article is CAFFEINE! The stresses mentioned above are accute…caffeine’s daily persistent, multiple-times-per-day use is CHRONIC! Caffeine increases cortisol and cortisol causes weight gain! http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2249754/

    • Actually it’s not caffeine, it’s sleep deprivation, or lack of sleep (or poor quality sleep). The test for this is easy, take a chronic coffee drinker and get them to stop coffee for 2-3 days. Then give them back their coffee, but force them to have only 1-3 hours sleep. The difference between the 2 are night and day. Sleep deprivation slows the entire metabolic process down and forces the adrenals and cortisol to work at quadruple overtime pace just to keep your eyes open.

      There is a direct correlation between sleep deprivation, obesity and diabetes. You can literally pole everyone who was ever been diagnosed with Type 2 diabetes, and you’ll find they have either had sleeping issues or have been forced to get up early, dating back as far as they can remember, even when they were kids. Of course, sleep deprivation mixed with caffeine to try and keep one awake has even more of an astronomical effect.

      • Brian, I’ve been researching academic sources on this topic and have found increased levels of Cortisol cause sleep deprivation. It seems like you’re right that sleep deprivation would also trigger Cortisol levels to go up. Caffeine increases cortisol levels, as if jolting our body to answer a stressor, even if there isn’t a stressful task or situation at hand.

  6. I know this is an old post, but I was hoping Dr. Flung could comment on fasting raising cortisol levels. I have read that one of the reasons people (particularly women) should not fast is that it strains their adrenals by causing a surge in cortisol. Have you found this to be at all counterproductive to your fasting protocols?

    Also, it seems that another manner by which diet and weight gain are associated in that inflammatory foods (like seed oils, processed carbs and sugar) cause systemic body inflammation. The body then tries to counteract this inflammation by releasing cortisol, which causes the insulin cascade you describe.

    Thank you so much for your very insightful work!

    • I’d be very interested in reading what Dr. Fung has to say about this, but we do know that in certain individuals anyway, cortisol levels can rise by a significant amount from dietary restriction. Often you need to find the right balance here, but what we don’t want to think is that if cortisol is one of our big enemies, we should avoid all things that raise it. This can be managed and we don’t want to cast off the real benefits of a good dietary strategy simply because it’s not all plusses. While this needs to all be taken into account, there are strategies that can be used to manage cortisol levels, including things like stress management and certain nutraceuticals.

      We also need to be aware that when cortisol is higher, there may be some good reasons behind this, and this is actually the body’s natural anti inflammatory. So if you lower that, you run the risk of increasing inflammation, so it is then wise to look to manage inflammation by other means.

      Dietary restriction in itself can represent a stressful condition, the body perceives a lack and looks to compensate, and one of the means by which it does so is by way of conservation, and adrenal hormones play a central role in this. Over time though the body will adjust and the effects of this will be lessened accordingly, and this is why it can take a while to adjust to a new dietary regimen.

  7. The odd thing. I’m on Prednisone and I’ve lost weight. In fact, I was steadily gaining weight until I started on Prednisone. I have low AM Cortisol levels, and have since 2012.

  8. Thanks for pointing out this very important connection Jason. Diet alone is sometimes not sufficient to bring insulin down to healthy levels, so we turn to blood sugar lowering medications, when we should be first looking at cortisol levels. Most of the excess blood glucose with type 2 diabetics actually comes from the liver, which we’ve shown to be the case, mostly from excess gluconeogenesis. Cortisol is a major driver of this, directly, and it also increases insulin as you point out, which worsens this over time.

    You don’t have to wait to get affected by high cortisol though. There’s so little emphasis on this in the treatment of type 2 diabetes, but if you look to conventional authorities, well they aren’t interested in managing the disease anyway so that should be no surprise. The science is there though for those who care to look. Thankfully, people like yourself do care about trying to make us better, and thanks for all of your significant contributions on this subject!

  9. After a lifetime of great health, I’m currently experiencing high pre-diabetic fasting glucose levels, probably as a combined result of 1) several years of severe sleep deprivation following the birth of my child, 2) some yo-yo-ing on and off of low-carb diets during the same period, and possibly 3) the beginning of perimenopause (I’m almost 45). My big question is: Is it too late to reverse this? I am sleeping better, I am getting back into yoga and exercise, I’ve quit caffeine and alcohol and sugar and I am trying to create a diet that incorporates whole grains and “slow carbs” as well as fat and protein. But I am so close to diabetic numbers right now and I’m worried I won’t be able to reverse my current state of insulin resistance. Is there a specific turning point where it’s too late to undo the harm and return to normal insulin response and glucose levels? Is there something else I should be doing? Huge thanks for any responses.

  10. A few days into every water fast I start getting what I like to describe as a “cortisol rush.” my whole body almost hurts from stress, my chest feels tight from anxiety, it gets harder to breathe. have any patients ever mentioned it to you? Every time I have done a water fast longer than 4 days, it’s this stress and anxiety that has forced me to break the fast. (I have never fasted longer than 9 days because of it). I am female, late twenties, 5’2 and weight fluctuates from about 110 to 125 pounds. What can be done to deal with it?

  11. I understand the science, but the article was not clear, will fasting help with obesity that is related to elevated cortisol? Or does it make any difference?or make it worse?

  12. I am on a 5 day dose of prednisone for bronchitis. I want to start a short water fast1-3days tomorrow because its my day off so I think it will be easiest to start/do, but i am on my 4th day of prednisone today- My question is should i take the last dose tomorrow or could it maybe be skipped/ended a day earlier?
    Thanks

  13. Can you please tell what tests I should undergo and if there are increased cortisol levels, what drug specifically cures it?

  14. In my case, insomnia issues have probably caught up with me.
    63 years old, 114 lbs…….
    one year ago fbs was 83, insulin 6.3. hba1c, 5.5. Last 8 months I have been hflc, fasting from 5 pm until 1pm. walk 2 miles/day, weight lifting 2-3 x week. I went down 2 clothes sizes!

    so, 8 months later, fbs 98, fasting insulin 8, hga1c 5.7. I cried all day when I got my results. SIGH! REALLY??????????

    I am now on a journey to reduce my years of insomnia issues. I wake up between 2-4 am and stay awake for hours….. Sometimes I can fall back asleep, sometimes, not . Using l-glutamin, gaba (helping) and soon to start the ” back to the old formula, seriphos. I need to reduce my cortisol. I have great sleep hygiene.
    I also am slightly anemic and will correct this as this too can affect my hga1c.
    the book, “the mood cure” discusses cortisol and sleep.

    A naturapath encouraged me to stop the fasting for now as this can, in some people, increase bs.
    Also Chris Kessler discusses this. Dr Mercola recommends cycling low carb with days of high carb as this also can cause increase fbs/insulin..
    I just keep on trying…………

    Maybe this can help someone else.

    • Carole, I’ve experienced the same insomnia problem. I was eating once a day at noon, and would wake up between 2-4am. The next day I felt sleep deprived, even if my total hours slept was around 7 hours. However I just fixed it. I shifted my meal to between 5 to 7pm. Sleep almost immediately improved, with no 2am wake-ups. Seems that feeding and fasting times can affect circadian rhythm. In fact, some travellers adjust their circadian rhythms by fasting around 12-16 hours before their breakfast in the next time zone. Late day feeding worked for me… Please let me know if it had the same benefit for you.

    • Kiril…thanks for the info. I will try ANYTHING!!!
      Woulddn’t that be something if that helped me. I’m going to try it.

  15. Lavender

    Ditto for me…I feed once per day & try to fit in schedule 5-8, earlier the better. Bed 10:30-11 ; arise 6:30-7. Only wake/need to get up if I consume too many fluids late in the evening. I also have PMR & on 13 mg prednisolone. Even adding that, insulin/cortisol increasers, the timing was the deal for me as well.

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