Controlling HSD Activity Naturally

Let's recap: More HSD activity means more belly fat, and you don't want that, so you need to control your HSD. In humans, we know from a number of research studies that down-regulation (slowing the activity) of HSD is protective against weight gain and enhances hepatic (liver) insulin sensitivity, leading to better blood-sugar control.

Until about ten years ago, obesity and weight gain were, in general, attributed largely to overeating and a lack of exercise. In the last decade, however, exciting new findings have greatly increased our knowledge about factors contributing to the pathogenesis of obesity and its subsequent health effects. As discussed throughout this chapter, the enzyme HSD, which is predominantly found in adipose (fat) tissue, liver tissue, brain tissue, and cells of the adrenal gland, is now known to be directly related to obesity rates in animals and humans.

For example, mice with high levels of HSD activity have two to three times higher cortisol levels within their fat cells—but normal levels of cortisol in their blood. This matches the situation in many human test subjects. We know that animals with elevated HSD levels tend to weigh 25 to 35 percent more—and have larger appetites—than animals with normal levels of HSD, with most of the excess fat confined to the belly region. So, again, although cortisol is an important signal for fat storage throughout the body, when it becomes elevated within abdominal fat cells it becomes one of the most potent stimulators of excess belly fat—and the metabolic syndrome that follows.

In a series of experiments conducted by researchers from Harvard University, the British Heart Foundation, Merck pharmaceuticals, and a Swedish biotechnology firm, not only has HSD overactivity been identified as a cause of obesity and diabetes, but reducing its activity has been shown to reduce belly fat—despite a high-fat and high-calorie diet! As described in the last section, biotech and pharmaceutical companies have recognized the importance of HSD for obesity and diabetes treatment. As mentioned previously, as of this writing, every major pharmaceutical company in the world is investigating synthetic inhibitors of the HSD enzyme as a potential cure for obesity and diabetes.

Danish scientists have recently found that higher levels of growth hormone are associated with reduced HSD activity, a finding that may explain some of the primary effects of growth hormone in reducing body fat (especially belly fat) and increasing muscle mass. As we age, growth-hormone levels decline dramatically, setting the stage for HSD activity to increase. Whereas growth hormone (GH) accounts for as much as 10 to 46 percent of the change in HSD activity, we know that HSD activity can also be regulated by other hormones, such as sex steroids (estrogen and testosterone) and thyroid hormones. It follows that because growth hormone inhibits the activity of HSD, when GH levels fall (as they do in aging), HSD activity goes up, and we gain more fat and lose the ability to control blood sugar effectively. We have known for many years that people with low GH levels also suffer from muscle loss and fat gain, but we did not know until recently that the mechanism for these effects was due to a problem with HSD metabolism. This research indicates that it may be even more important to naturally regulate HSD activity as we age.

Increasing the activity of HSD in a mouse will lead to significant weight gain, specifically within the abdominal area, within as little as nine weeks—even when the mouse is restricted to a low-fat diet. How depressing is that? Have you ever felt that your attempts at restricting your diet to lose weight have very little effect at all? It may be that HSD is working overtime in your body to maintain (and increase) your abdominal fat stores. In humans, we see the very same effects that we see in mice, where accumulation of visceral fat depots (belly fat) is highest in individuals with the highest HSD activity. Although we are now learning that HSD activity can be artificially disrupted or "blocked" with synthetic drugs, we also know that we can do the very same thing with naturally occurring compounds from fruits, vegetables, and herbs. Some of the strongest controllers of HSD activity are found in foods rich in flavonoids, such as apples and onions (quercetin), grapefruit (naringenin), and soybeans (genistein and daidzein). The most potent of the flavonoids for balancing HSD activity are found in the form of substances known as polymethoxylated flavonoids (PMFs) found in oranges (nobiletin and tangeretin), which can be up to three to five times stronger than other flavonoids.

Licorice (from the licorice plant, Glycyrrhiza glabra), contains glycyrrhetinic acid (GA), a flavonoid that inhibits HSD. In animal studies, increasing flavonoid consumption by feeding GA for fourteen weeks has been shown to reduce HSD activity by 30 percent, cortisol levels by 34 percent, and body weight by 28 percent—all from including a bit more flavonoids in the rats' drinking water! Unfortunately, GA also raises blood pressure, so it cannot be used long-term to control HSD and block fat storage in humans. However, when GA was studied as a weight-loss agent in humans (taken along with a drug to control the rise in blood pressure), GA led to a dramatic drop in cortisol levels, a significant loss of body weight, and a specific reduction of abdominal fat—with no significant alterations in diet or exercise patterns (just as had happened with the mice).

What this means for you and your personal HSD profile is that consuming more flavonoids should be a major dietary goal. Eating more apples and onions (for quercetin), grapefruit (for naringenin), and soybeans (for genistein and daidzein) can't hurt—and doing so may help provide a small measure of inhibition of HSD activity. That said, I would recommend consuming more dietary sources of these particular flavonoids rather than trying to add higher levels from dietary supplements. For dietary supplementation of HSD-inhibiting flavonoids, it would make more sense to focus on the PMFs because of their significantly higher metabolic potency compared to other dietary flavonoids. However, PMFs come from citrus peels, which you're probably not eating very many of. Instead, they have been isolated and made available in the form of supplements. You can read more about PMFs and other natural dietary supplements in Chapter 8.


I very much wish that cortisol metabolism were really as simple and straightforward as we once thought. Our previous, and overly simplistic, view that "more stress = more cortisol = more belly fat" and "less stress = less cortisol = less belly fat" still holds true in some regards—and reminds us that we certainly do not want to have high levels of systemic cortisol (as described in the last chapter and in more detail in Chapter 6). But our growing understanding of the role of the HSD enzyme in cortisol metabolism within individual cells alerts us to the fact that we really need to be focusing simultaneously on controlling cortisol exposure both outside of cells (blood levels caused by high stress and poor lifestyle) and inside of cells (caused by overactive HSD and suboptimal levels of GH and testosterone).


Shawn Talbott

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