HSD: The Body's "Fat Storage" Enzyme
One of the complicating factors in the stress/cortisol/fat relationship is a little enzyme deep within fat cells called HSD—short for 11-beta-hydroxysteroid-dehydrogenase-1. (Aren't you glad we can just call it HSD?) HSD functions to convert inactive cortisol (called cortisone) back into active cortisol, which then functions as a potent fat-storage signal within fat cells, especially abdominal fat cells (those in the belly region). Recent research tells us that HSD activity is higher in abdominal fat cells than it is in fat cells in other parts of the body—which may be the reason why cortisol exposure is associated with higher levels of fat in the abdominal region as compared to fat levels in other parts of the body, such as the thighs or buttocks.
What Is HSD and What Does It Have to Do with Cortisol?
HSD is located within almost every cell in the body, but its highest levels are found in adipose (fat) tissue, liver tissue, and brain tissue. Within all the cells in each of these kinds of tissue, HSD is referred to as a "membrane-bound microsomal enzyme"—meaning it is attached to the membrane of a structure called the endoplasmic reticulum that resides inside of cells. Because of its position inside each cell, HSD can force the cells to "see" or be exposed to high levels of cortisol, even when blood levels of cortisol are perfectly normal. This effect has led many stress researchers to refer to HSD as a "local amplifier" of cortisol exposure, because no matter what a person's systemic (blood) levels of cortisol look like (low, medium, or high), a highly active HSD enzyme will force each individual cell to be exposed to a high level of cortisol—from the inside! It is a bit like trying to avoid the air pollution outside by staying in your house—but HSD sabotages your efforts because it acts like a window fan to suck the bad air into the house and concentrate the pollution there. Yuck!
For many years we have known that obesity is associated with increased cortisol exposure, but this relationship was not always a consistent link between obesity and elevated blood levels of cortisol. In some studies, people with high stress and lots of abdominal stress fat had normal or low levels of cortisol in their blood (or urine or saliva), indicating that there was no systemic cortisol overexposure. What we now know is that certain enzymes are dysregulated in obesity—most notably the HSD enzymes in fat tissue—effectively leading to a "high" cortisol level within fat cells at all times. Unfortunately, this means that no matter how good you are at controlling your stress response and, thus, the level of cortisol in your blood, you could still have high levels of cortisol within your fat cells because of a high HSD activity.
Don't misunderstand me here. The overall level of cortisol exposure throughout your body (i.e., systemically) is still as important as it ever was, but we understand now that blood levels of cortisol are only half the story—and it is cortisol levels inside your cells that represent the other half. In general, higher levels of abdominal fat and total body fat are associated with higher total levels of cortisol in the body. A number of researchers have found that different distributions of fat accumulation are associated with specific changes in cortisol metabolism. Increased abdominal HSD activity, which causes increased generation of active cortisol from inactive cortisone, is generally associated with higher amounts of abdominal fat. This "local" or "peripheral" metabolism of cortisol has rejuvenated the long-standing hypothesis that cortisol contributes to abdominal fat accumulation—and the potency of HSD (how active it is) has emerged as the key. For decades, research has shown that elevated levels of cortisol lead to more body fat and problems with blood-sugar control. The relationship has always looked relatively clear-cut: More stress leads to more cortisol, which leads to more body fat. In recent years, however, these links have become less straightforward; research findings have shown plenty of people with high stress and high cortisol levels—yet no obesity. Research has also shown people who are overweight—yet have low stress or normal cortisol. What's going on? Shouldn't these stressed-out people be getting fat? Not always. Shouldn't these overweight folks, especially those with lots of abdominal "stress" fat, have very high cortisol levels? Not always.
Although the link between stress and cortisol is mostly a direct one (more stress = more cortisol production), and the link between cortisol and abdominal fat is also pretty clear (more cortisol = more belly fat), the picture gets more complicated when we start to talk about individual stress levels and individual cortisol exposure and individual body fat levels.
Researchers from the University of Helsinki, in Finland, have shown that cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance (prediabetes). These sites are abdominal fat tissue and the liver—and fat accumulates in these areas because of the activity of HSD. Higher activity of HSD means a higher rate of fat storage and a faster accumulation of fat stores. In abdominal areas, a high HSD activity leads to a rounder waistline, while in the liver it means a higher risk for diabetes.
Researchers in Berlin, Germany, have suggested that the regulation of cortisol levels within cells by HSD is just as important as cortisol levels in the plasma. This means that the adrenal glands are not the only place in the body for "production" of cortisol; fat calls can produce their own fat-storing cortisol via reactivation of inactive cortisol by the HSD enzyme. This leads to higher cortisol levels within fat cells and a further increase in fat storage and the size of fat cells. Overall, according to the German scientists, it is this mechanism of "self-production" of cortisol within individual fat cells that may represent the most important pathogenic signal for central (abdominal) obesity.
HSD activity is genetically determined, so a person will have either high, low, or "normal" activity—and thus a corresponding level of cortisol conversion and fat storage. None of the lifestyle factors (stress, exercise, etc.) are known to directly affect HSD activity (except via alterations in other hormones, such as growth hormone), which is what makes the enzyme such a tempting target for the drug companies. (More on this topic appears later in this chapter.)