The Effects of HSD on Obesity and Diabetes
So, as discussed, researchers around the world are beginning to understand not only that high levels of systemic cortisol are certainly bad, but also that it is the levels of cortisol within each individual cell that ultimately determine your risk for abdominal obesity, diabetes, high cholesterol, and high blood pressure—the combination we call the metabolic syndrome.
We are now finding that it is the activity of the HSD enzyme—specifically, how fast it converts inactive cortisone into active cortisol—that determines the rate of fat storage in many people. For example, you could have low stress (or be very good at controlling your stress levels) and therefore have low cortisol levels in your blood, but if you had a high HSD activity, then your fat cells would always "see" (or be exposed to) a relatively high level of cortisol. This means your fat cells would always be receiving a potent signal telling them to "store more fat"—so no matter what you did in terms of exercise or diet or stress management, you would always be fighting against your own metabolism. Sound familiar?
In most healthy people, overweight or not, systemic (whole body) cortisol levels are typically "normal"—but what constitutes a normal cortisol range is extremely wide. If your cortisol levels fell outside of the "normal" range on standard laboratory assessments, then you would be so disabled as to be almost bedridden. Instead, most of us who are able to walk around will have cortisol levels within a normal range, but those levels are still probably a lot higher than they need to be. As described in other parts of this book, your cortisol production is probably far too high if you have any of the "big 3" risk factors: chronic stress, restrained eating (dieting), or sleep deprivation—even if you're considered to be "normal" based on standard laboratory measures. Who wants to be normal? And, if normal means a "normal" level of cortisol overexposure, then forget it.
When cortisol circulates in the bloodstream it is only present for about two hours. After that, the body does a pretty good job of deactivating the cortisol so it cannot do any more damage. If, however, you experience another stressful event (and another and another), then you continually expose yourself to more and more cortisol. But remember, equallyalso important to consider is the cortisol inside your cells—the stuff activated by the enzyme HSD—and it is this "tissue specific" form of cortisol that may be the worst of all. Luckily, we know of a wide range of natural substances, from licorice to fruit extracts, that can help to control HSD activity. Some of these are discussed in Chapter 8.
As mentioned, the highest levels of HSD activity are seen in the adipose (fat) tissue, liver, and brain—which may be one reason why chronic stress and cortisol overexposure have such a detrimental effect on obesity (adipose tissue), diabetes (liver), and memory (brain). Within your fat cells, a high level of HSD activity results in a dual signal to both store more fat (called "hypertrophy"—where each fat cell gets bigger and bigger) and to increase their proliferation (called "hyperplasia"—an increase in the number of individual fat cells). If all of this weren't bad enough, research has shown that HSD activity tends to increase with age, resulting in a threefold difference between younger (twenty-something) and older (fifty-something) people—and possibly accounting for our increasing waistlines as we age.
A team of Scottish and Swedish researchers from the British Heart Foundation, Swedish Heart and Lung Foundation, and Swedish Medical Research Council has shown that blood cortisol levels are often not elevated in all cases of obesity; rather, high "intra-adipose" (within fat cells) cortisol levels may be the main culprit in excessive belly-fat storage. This group of scientists has found that high HSD activity levels are associated with both obesity and with insulin resistance. They have also determined that women between the ages of fifty-three and fifty-seven tended to have higher HSD activity and a higher percentage of total body fat compared to men in the same age range—but the relationship between high HSD and more belly fat was the same for both men and women. Overall, this research indicates that both men and women are susceptible to abdominal weight gain from overactive HSD in their fat cells, but women appear to be at a slightly higher risk (which may further increase during menopause).
Researchers from the National Institutes of Health (NIH) have discovered that HSD activity is significantly higher in people with obesity. These findings support previous reports that have suggested that weight gain in many people is disproportionate to food intake. This is what lots of people report, and it's what we routinely see in the clinic: People gain more weight than what we can account for by their dietary or physical-activity patterns. This suggests, and the NIH researchers confirm, that adipose tissue may have its own set of messengers that signal the fat cells to store more fat, independent of food intake. These tissue-specific signaling patterns have been suspected for over thirty years, but simple measurements of cortisol levels in the blood, urine, or saliva have been reported in obese patients as decreased, increased, and unchanged, creating confusion among researchers and health professionals. Now we know that it is excessive intracellular activity of the HSD enzyme that turns low levels of cortisol into one of the most potent fat-storage signals, particularly in abdominal fat cells. By slowing the activity of HSD, even just a little bit, we should be able to reduce its production of active cortisol and thus short-circuit its fat-storing effects. Researchers from the National Institute of Diabetes have found that increased HSD activity in abdominal fat tissue contributes to the worsening of obesity and insulin resistance (prediabetes). In a series of studies that followed subjects for up to five years (an average of two and a half years across all subjects in the study), this group of scientists was investigating why some previous studies had found systemic cortisol levels to be high or low or normal in obese subjects. They reasoned that something else must be going on to explain obesity rates—and they suspected that although systemic cortisol levels are important, it may be tissue-specific cortisol levels that influence weight gain and the development of obesity. (Recall that "tissue-specific" refers to the cortisol levels inside a given cell, such as within an individual fat cell.) Even though previous studies had shown HSD levels and overall activity to be related to fat levels in overweight humans, before this study (published in September 2006), no long-term study had been conducted to definitively link HSD to weight gain. Not only did this latest research find a direct relationship between HSD and abdominal fat gain, but it also found a significant association of HSD activity with changes in body weight over time. It was the first clear evidence proving that the higher one's HSD levels, the higher her or his cellular cortisol levels, and the larger the weight gain s/he will experience over time. The mechanism identified by these scientists went beyond what we already knew about cortisol serving as a "fat-storage" signal for fat cells (i.e., more cortisol = more fat storage); it showed that cortisol is also a potent signal for young fat cells (called "preadipocytes") to grow into mature fat cells (called "adipocytes") and rapidly start storing fat. These researchers stated that HSD activity has "a causative role in promoting obesity and its metabolic consequences."
In an interesting series of metabolism studies, scientists from the Mayo Clinic have shown that cortisol can be released into the blood from tissues other than the adrenal glands. As we've seen, abdominal adipose tissue (belly fat) has been identified as a tissue that can create its own supply of cortisol (leading to weight gain). In addition, the liver and other internal organs can also produce a supply of cortisol that can have health effects throughout the body, including increasing the risk of obesity. Writing in the Journal of the American Diabetes Association, the Mayo scientists confirmed that the liver and related internal organs converted a large proportion of inactive cortisol into active cortisol via the HSD enzyme—and that the total amount of cortisol produced (or "reactivated") was "equal to if not greater than" the amount produced by the adrenals. Think of it—you could be calm as a cucumber, perfectly managing your stress and cortisol production from the adrenal glands, but you are still overexposed to cortisol because your liver and fat cells are producing cortisol on their own! The researchers went on to calculate that the adrenals, fat cells, and liver all contribute about one-third each of total body cortisol—meaning that your yoga class as a stress-management tool is only influencing about a third of your total cortisol exposure.
Researchers from the University of Birmingham, in England, have some especially depressing news for people trying to lose weight by extreme dieting. Studying the metabolic effects of a very low calorie diet (eight hundred calories per day) for ten weeks, they found that the stress of the diet significantly increased cortisol levels throughout the body, but also increased HSD activity within fat cells by 3.4 times. This indicates not only that diets are stressful (you already knew that), but also that your fat cells are fighting against you! As you struggle to lose weight, your fat cells increase their HSD activity, leading to more cortisol, a stronger signal to store fat, and a gradual return to your prediet body weight. I could not agree more with the researchers' concluding remark that "inhibition of HSD may be a novel therapeutic strategy" for treating diabetes and obesity.
Scottish hormone researchers have recently described the link between elevated HSD activity and abdominal obesity in both stressed and nonstressed situations. We know that many cases of overweight and obesity occur with normal (nonelevated) cortisol levels. In these cases, as described throughout this chapter, it may be that elevated activity of the HSD enzyme is to blame. Indeed, these researchers describe an elevation of HSD levels and activity in human fat cells that may support a disrupted metabolism leading to abdominal fat gain, whether or not stress or cortisol levels are elevated. In another scientific report, this same research group outlines the benefits associated with inhibiting HSD activity as a novel strategy to lower intracellular cortisol levels, without affecting circulating cortisol levels and overall ability to respond to stress. Early experiments in humans show that inhibiting HSD activity allows a normal stress response to occur when it needs to (i.e., when you encounter something stressful), but reduces the effects of excessive stress in fat tissue and brain tissue, and also reduces metabolic effects related to diabetes risk.
According to scientists in the Division of Cardiovascular Medicine at the University of Arkansas, the epidemic of abdominal obesity and the metabolic syndrome in the United States and around the world "may be a stress response, with an underlying abnormality in the enzyme 11 beta-hydroxysteroid dehydrogenase." The researchers go on to lament the fact that there are no pharmaceuticals currently available for the inhibition or control of HSD activity (while observing that drug companies are rapidly inventing synthetic chemicals for just this purpose). What they fail to note is that a variety of natural controllers of HSD activity are available now as dietary supplements (see Chapter 8).