STRESS, AND WHY ALL OBESITY IS NOT CREATED EQUAL

By Paul J. Rosch, MD stress124@earthlink.net

Paul Rosch, MD, FACP, is clinical professor of medicine and psychiatry at New York Medical College and is President of the American Institute of Stress, and Honorary Vice-President of the International Stress Management Association.

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Obesity is an established risk factor for hypertension, stroke, heart attacks, heart failure and a host of other things ranging from lung and kidney disease to diabetes, insulin resistance and certain cancers. It's easy to comprehend how a lot of excess weight can elevate blood pressure and put a strain on the heart, lungs and kidneys or that increased caloric intake can boost blood sugar to trigger repeated releases of insulin that eventually exhaust the pancreas and cause diabetes. But it's not that simple. All obesity is not created equal and where that extra fat is deposited may be more important than how much of it there is.

It is well established that people with apple-shaped figures, due to increased abdominal fat, are at greatest risk for these problems. Recent research has shed some light on the reasons for this as well as the causes of deep belly fat. Eating too much and not exercising enough are certainly contributing factors but may not be as important as stress. Cortisol, a steroid hormone manufactured in the adrenal cortex appears to be the major culprit.

Cortisol secretion is increased in Cushing's syndrome, a disorder that is associated with increased abdominal fat. Most cases of Cushing's syndrome are due to a tumor that produces excess amounts of ACTH, a pituitary hormone that stimulates the adrenal cortex to secrete cortisol. Following removal of the tumor, this excess abdominal fat diminishes or disappears as cortisol levels return to normal. This led to the hypothesis that some forms of obesity might represent a mild form of Cushing's syndrome but since most obese people do not have elevated cortisol levels that theory was discarded.

However, about 25 years ago, researchers compared cortisol concentrations in samples of subcutaneous and deep abdominal fat obtained from patients undergoing surgery, most of whom were of normal weight. The belly fat had higher levels of cortisol and it was subsequently found that this was due to greater activity of an enzyme that regenerates cortisol from inactive precursors. This finding resurrected interest in the role of cortisol but there was little progress until a few years ago, when advances in genetic engineering made it possible to link the gene for this enzyme in mice to a promoter that only activated it in fat tissue. Genetically altered mice bred in this fashion had 2.5 times more enzyme activity and 14 to 30% higher concentrations of cortisol in their belly fat than normal mice. Although, as in most obese humans, blood cortisol was not increased, these pot-bellied mice subsequently began to exhibit insulin resistant diabetes, hypertension and other manifestations of the metabolic syndrome that increases risk for coronary heart disease in humans. The clinical relevance of this is supported by a recent report that obese men have higher levels of this cortisol recycling enzyme activity in their fat tissue than leaner controls.

Stress causes increased pituitary secretion of ACTH that also results in an elevation of cortisol and a shift in fat distribution to the abdomen. Chronically stressed primates with high cortisol levels develop a corresponding increase in abdominal fat deposits. A study of Swedish men similarly found that with those with the highest levels of chronic stress also had the highest cortisol measurements and the greatest amount of deep belly fat. Since the only way to accurately determine the amount of hidden abdominal fat is with expensive CT or MRI scans, most researchers usually rely on the waist/hip ratio (WHR) that only requires a tape measure. In one report, premenopausal women with a high WHR reported more chronic stress and had greater reactivity to stressful challenges compared to low WHR controls. In another study, a high WHR in middle aged men was associated with increased depression, anxiety, sleep disturbances and other stress related symptoms. There are gender differences since men are more apt to gain weight in the belly whereas women tend to accumulate peripheral fat and such pear-shaped individuals are less likely to suffer the metabolic complications of obesity. Indeed, Danish researchers reported last month that older women with excessive fat in the arms, legs, hips and buttocks had significantly less atherosclerosis than those whose fat was primarily abdominal. The reason appears to be that peripheral fat secretes hormone-like substances that decrease insulin resistance, some of which might be useful in preventing or treating metabolic syndrome. Obesity due to stress and cortisol is not apt to occur in younger individuals because of the protective effects of other steroids like testosterone, estrogen and progesterone. It is after age 40, when these sex hormones begin to decline that we start to see what is often referred to as" middle aged spread". Although men whose waist size is greater than 40 inches and women whose waists are wider than 35 inches are at particular risk, significant increases in abdominal fat can be found in those whose measurements are a few inches less.

Abdominal fat contains more cortisol receptors than other tissue and it has been suggested that circulating cortisol is preferentially attracted here so the liver can have easy access to fuel that may be needed for physical activity during stressful situations. Deep belly fat releases large amounts of free fatty acids into the portal circulation that continually stimulate the liver to produce glucose. In that regard, it should be noted that stress causes increased secretion of adrenaline and other hormones from the adrenal medulla that also increase fatty acid and blood sugar levels. When stimulated in vitro, abdominal fat cells secrete many more inflammatory molecules than fat cells from subcutaneous sites. Abdominal fat cells produce large amounts of IL-6 and other inflammatory cytokines that can contribute to diabetes, insulin resistance and coronary disease. This is important since there is a striking correlation between increased abdominal fat and increased levels of C-reactive protein (CRP), a marker of inflammation that has been found to be superior to LDL for predicting coronary events.

The $64 dollar question is "What controls the release of fatty acids and cytokines from visceral fat depots in the first place"? It is believed that the signal comes from the brain since this release is cyclic rather than constant. The brain tends to control many activities by emitting pulsed signals at regular frequencies and chemicals are released from deep belly fat in nine-minute cycles much like other activities that are controlled by the cerebral cortex. How this signal reaches its target is not clear since no humoral or central nervous system effects can be detected. However, there is increasing evidence to support the concept of an electrical circulatory system in the body that mediates the myriad and instantaneous biochemical and physiologic changes that occur in "fight or flight" responses to stress. Björn Nordenström has proposed that these communication pathways are analogous to ancient Chinese concepts of meridians that conduct Qi energy, with its antagonistic yin and yang components being similar to positive and negative charges. Although much more research is required, it is quite evident that not all obesity is created equal and that cortisol and stress can play a decisive role in determining these differences.

SUGGESTED READING

1. Björntorp P. Visceral obesity: a "civilization" syndrome. Obes Res 1993;1:206-222.
2. Rosch PJ, Clark CC. De-Stress, Weigh Less. 2001; St, Martin's Press, New York.
3. Björntorp P. Centralization of body fat pp 213-224 in Björntorp P, ed. International Textbook of Obesity. 2001; John Wiley & Sons, Chichester.
4. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557-65.
5. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999;282:2131-2135.
6. Reaven GR. Importance of identifying the overweight patient who will benefit the most by losing weight. Ann Intern Med 2003;138:420-423.