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:

Stimulation of hepatic gluconeogenesis Inhibition of glucose uptake in peripheral tissues 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.

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

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