I CAN MAKE YOU fat. Actually, I can make anybody fat. How? I prescribe prednisone, a synthetic version of the human hormone cortisol. Prednisone is used to treat many diseases, including asthma, rheumatoid arthritis, lupus, psoriasis, inflammatory bowel disease, cancer, glomerulonephritis and myasthenia gravis.
And what is one of the most consistent effects of prednisone? Like insulin, it makes you fat. Not coincidentally, both insulin and cortisol play a key role in carbohydrate metabolism. Prolonged cortisol stimulation will raise glucose levels and, subsequently, insulin. This increase in insulin plays a substantial role in the resulting weight gain.
THE STRESS HORMONE
CORTISOL IS THE so-called stress hormone, which mediates the flight-or-fight response, a set of physiological responses to perceived threats. Cortisol, part of a class of steroid hormones called glucocorticoids (glucose + cortex + steroid), is produced in the adrenal cortex. In Paleolithic times, the stress that led to a release of cortisol was often physical: for instance, being chased by a predator. Cortisol is essential in preparing our bodies for action—to fight or flee.
Once released, cortisol substantially enhances glucose availability,1 which provides energy for muscles—very necessary in helping us to run and avoid being eaten. All available energy is directed toward surviving the stressful event. Growth, digestion and other long-term metabolic activities are temporarily restricted. Proteins are broken down and converted to glucose (gluconeogenesis).
Vigorous physical exertion (fight or flight) soon often followed, burning up these newly available stores of glucose. Shortly thereafter, we were either dead, or the danger was past and our cortisol decreased back to its normal low levels.
And that’s the point: the body is well adapted to a short-term increase in cortisol and glucose levels. Over the long term, however, a problem arises.
CORTISOL RAISES INSULIN
AT FIRST GLANCE, cortisol and insulin appear have opposite effects. Insulin is a storage hormone. Under high insulin levels (mealtimes), the body stores energy in the form of glycogen and fat. Cortisol, however, prepares the body for action, moving energy out of stores and into readily available forms, such as glucose. That cortisol and insulin would have similar weight-gain effects seems remarkable—but they do. With short-term physical stress, insulin and cortisol play opposite roles. Something quite different happens, though, when we’re under long-term psychological stress.
In our modern-day lives, we have many chronic, nonphysical stressors that increase our cortisol levels. For example, marital issues, problems at work, arguments with children and sleep deprivation are all serious stressors, but they do not result in the vigorous physical exertion needed to burn off the blood glucose. Under conditions of chronic stress, glucose levels remain high and there is no resolution to the stressor. Our blood glucose can remain elevated for months, triggering the release of insulin. Chronically elevated cortisol leads to increased insulin levels—as demonstrated by several studies.
One 1998 study showed that cortisol levels increased with self-perceived stress levels, strongly linked to increased levels of both glucose and insulin.2 Since insulin is the major driver of obesity, it should be no surprise that both body mass index and abdominal obesity increased.
Using synthetic cortisol, we can increase insulin experimentally. Healthy volunteers given high-dose cortisol increased their insulin levels 36 percent above their baseline.3 Prednisone increases glucose levels by 6.5 percent and insulin levels by 20 percent.4
Over time, insulin resistance (that is, impairment of the body’s ability to process insulin) also develops, mainly in the liver 5 and skeletal muscle.6 There is a direct dose/response relationship between cortisol and insulin.7 Long-term use of prednisone leads to an insulin-resistant state in a patient or even to full-blown diabetes.8 This increased insulin resistance leads back to elevated insulin levels. Glucorticoids cause muscle breakdown, releasing amino acids for gluconeogenesis, increasing blood sugars. Adiponectin, secreted by fat cells, which normally increase insulin sensitivity, are suppressed by glucocorticoids.
In a sense, insulin resistance should be expected, since cortisol generally opposes insulin. Cortisol raises blood sugar, while insulin lowers it. Insulin resistance (discussed in depth in chapter 10) is crucial to the development of obesity. Insulin resistance leads directly to higher insulin levels, and increased insulin levels are a major driver of obesity. Multiple studies confirm that increasing cortisol increases insulin resistance.9, 10, 11
If increasing cortisol raises insulin, then reducing cortisol should lower it.
We find this effect in transplant patients who take prednisone (the synthetic cortisol) for years or decades as part of their anti-rejection medication.
According to one study, weaning them off prednisone resulted in a 25 percent drop in plasma insulin, which translated to a 6.0 percent weight loss and a 7.7 percent decrease in waist girth.12
CORTISOL AND OBESITY
HERE’S THE REAL question we are interested in: Does excess cortisol lead to weight gain? The ultimate test is this: Can I make somebody fat with prednisone? If so, that can prove a causal relationship, rather than a mere association. So does prednisone cause obesity? Absolutely! Weight gain is one of prednisone’s most common, well-known and dreaded side effects.
This relationship is causal.
It is helpful to look at what happens to people with certain diseases, particularly Cushing’s disease or Cushing’s syndrome, which is characterized by long-term excessive cortisol production. Cushing’s disease is named for Harvey Cushing, who in 1912 described a twenty-three-year- old woman suffering from weight gain, excessive hair growth and loss of menstruation. In up to one-third of Cushing’s cases, high blood sugars and overt diabetes are also present.
But the hallmark of Cushing’s syndrome, even in people with mild forms, is weight gain. In one case series, 97 percent of patients show abdominal weight gain and 94 percent show increased body weight.13, 14 Patients gain weight no matter how little they eat and no matter how much they exercise. Any disease that causes excess cortisol secretion results in weight gain.
Cortisol causes weight gain.
However, there’s evidence of the association between cortisol and weight gain even in people who don’t have Cushing’s syndrome. In a random sample from north Glasgow, Scotland,15 cortisol-excretion rates were strongly correlated to body mass index and waist measurements. Higher cortisol levels were seen in heavier people. Cortisol-related weight gain, particularly abdominal fat deposits, results in an increased waist-to-hip ratio. (This effect is significant because abdominal fat deposits are more dangerous to health than all-over weight gain.)
Other measures of cortisol confirm its association with abdominal obesity.
People with higher urinary cortisol excretion have higher waist-to-hip ratios. 16 People with higher cortisol in their saliva have increased body mass index and waist-to-hip ratio.17 Long-term exposure to cortisol in the body may also be measured by scalp-hair analysis. In a study18 comparing obese patients to those of normal weight, researchers found elevated levels of cortisol in scalp hair of the obese patients. In other words, substantial evidence indicates that chronic cortisol stimulation increases both insulin secretion and obesity. Therefore, the hormonal theory of obesity takes shape: chronically high cortisol raises insulin levels, which in turn leads to obesity.
What about the opposite? If high cortisol levels cause weight gain, then low cortisol levels should cause weight loss. This exact situation exists in the case of Addison’s disease. Thomas Addison described this classic condition, also known as adrenal insufficiency, in 1855. Cortisol is produced in the adrenal gland. When the adrenal gland is damaged, cortisol levels in the body can drop very low. The hallmark of Addison’s disease is weight loss. Up to 97 percent of patients exhibited weight loss.19 (Cortisol levels went down. People lost weight.)
Cortisol may act through high insulin levels and insulin resistance, but there may also be other pathways of obesity yet to be discovered. However, the undeniable fact remains that excess cortisol causes weight gain.
And so, by extension, stress causes weight gain—something that many people have intuitively understood, despite the lack of rigorous evidence. Stress contains neither calories nor carbohydrates, but can still lead to obesity. Long-term stress leads to long-term elevated cortisol levels, which leads to extra pounds.
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, including mindfulness meditation, yoga, massage therapy and exercise. Studies on mindfulness intervention found that participants were able to use yoga, guided meditations and group discussion to successfully reduce cortisol and abdominal fat.20
For practical information on reducing stress through mindfulness meditation and improved sleep hygiene, see appendix C.
SLEEP
SLEEP DEPRIVATION IS a major cause of chronic stress today. Sleep duration has been steadily declining.21 In 1910, people slept nine hours on average. However, recently, more than 30 percent of adults between thirty and sixty- four years of age report getting fewer than six hours of sleep per night.22 Shift workers are especially prone to sleep deprivation and often report fewer than five hours of sleep per night.23
Population studies consistently link short sleep duration and excess weight,24, 25 generally with seven hours being the point where weight gain starts. Sleeping five to six hours was associated with a more than 50 percent increased risk of weight gain.26 The more sleep deprivation, the more weight gained.
MECHANISMS
SLEEP DEPRIVATION IS a potent psychological stressor and thus stimulates cortisol. This, in turn, results in both high insulin levels and insulin resistance. A single night of sleep deprivation increases cortisol levels by more than 100 percent.27 By the next evening, cortisol is still 37 percent to 45 percent higher.28
Restriction of sleep to four hours in healthy volunteers resulted in a 40 percent decrease in insulin sensitivity,29 even after a single sleep-deprived night.30 After five days of sleep restriction, insulin secretion increased 20 percent and insulin sensitivity decreased by 25 percent. Cortisol increased by 20 percent.