The Science Behind Obesity

CURE, Fall 2005, Volume 4, Issue 3

Understanding fat and how it affects cells gives clues to a possible tie to cancer

Yvette Cardozo has struggled with her weight all her life. She has tried weight loss medications and fad diets. She exercises regularly and consumes fewer than 2,000 calories a day, but at 5 foot 8 inches and 190 pounds, she is classified as overweight. “I can’t tell you how frustrating it is to have people tell us to eat less and exercise more when it flat out doesn’t work for me and never has,” says Cardozo, a 60-year-old writer and photographer from Seattle.

Cardozo knows researchers have linked obesity with certain cancers. It stays in the back of her mind, especially with her family history of cancer and obesity. Both of Cardozo’s parents died of cancer—her father of spinal cancer at age 49 and her mother of colorectal cancer. Her sister died of cardiac arrest, possibly due to adult-onset diabetes, both obesity-related conditions. But even with diet, exercise and annual cancer screenings, she wonders if she ’s doing enough.

Obesity is the second leading cause of preventable death in the United States after tobacco with nearly 200 million Americans categorized as overweight or obese, according to the Centers for Disease Control and Prevention. As a national health objective for the year 2010, the National Institutes of Health is working to cut the obesity rate among adults by half—to less than 15 percent. But unlike tobacco users, the rapidly increasing number of overweight or obese Americans has doubled to more than 64 percent in the past 20 years.

Obesity is defined by body mass index (BMI), a combined measurement of weight and height. A BMI of 25 to 29 is considered overweight, and a BMI over 30 is considered obese. Though health experts hesitate to confirm a link, recent research shows obesity may also contribute to several major cancers, including colon, endometrial, kidney and esophageal cancers and breast cancer in postmenopausal women. The obesity-cancer association may also lead to an increased risk of dying from cancer.

Scientists haven’t discovered why obesity may predispose certain people to cancer, but several obesity-fighting measures, including diet, exercise and weight loss drugs, may lower cancer risk. Many cancer survivors have already tapped into these potentially lifesaving measures, reporting in recent studies that they are healthier in regards to diet, exercise and other lifestyle changes after diagnosis.

With obesity and physical inactivity also linked to heart disease, diabetes, hypertension and stroke, doctors are concerned about the number of obesity-related deaths. “We are really at risk in this country for turning around two centuries of progressively longer life expectancies,” says Richard Boland, MD, chief of gastroenterology at Baylor University Medical Center in Dallas. “It’s conceivable that in the next 20 to 30 years, we could see that peak and actually turn around, and that would be terrible

Obesity occurs when the body takes in more calories than it can burn off, but a lot more science lies underneath the fat.

“A person who has the genetic predisposition in the right environment—and we have the right environment here in the United States—has a higher chance of developing obesity,” says Caroline M. Apovian, MD, director of clinical research at the Obesity Research Center at Boston Medical Center. While genetics does play a role in excess weight gain, the obesity pandemic has only skyrocketed in the past 20 years. Before drive-through restaurants, people stored fat as a survival mechanism when food was scarce. The human body has not adapted to a society with abundant high-fat foods and a sedentary lifestyle.

As new research looks at whether diet, genetics, physical activity, or weight plays the greatest role, scientists examine several potential biological causes, including myriad hormones, such as estrogen, leptin, ghrelin, and insulin.

Unfortunately, when people try to lose excess weight, the body works against them. For overweight people, the body produces several hormones and other chemicals to preserve its fat stores. These hormones alert the brain when weight is lost, which decreases energy expenditure, lowers metabolism and increases hunger. The body thinks it’s starving, so it tries to save as much fat as possible.

Once a person achieves weight loss, it becomes harder to keep the weight off. Levels of leptin, a hormone produced by fat cells, decrease as fat cells shrink. When leptin levels go down, the brain recognizes that the body has less fat and works to prevent further weight loss while trying to regain its stores.

“It seems that people who lose weight and keep it off have to work with fewer calories to maintain their weight, probably because of leptin levels,” Apovian says. “Leptin levels are constantly down afterward, so the body’s trying to gain that weight back and it drops the metabolic rate. They have to work harder to keep the weight off.”

The hormone ghrelin also regulates the body’s weight. The gastrointestinal (GI) tract produces this hormone after fasting and before meals, signaling the brain to increase hunger. While over 10 other GI products signal the body to stop eating, many of which are being researched as weight loss treatments, ghrelin tells the body to eat more.

While numerous studies link obesity and certain cancers, scientists haven’t discovered why the association exists or to what degree.

Twenty-four years ago, a paper published in the Journal of the National Cancer Institute estimated that a third of cancer-related deaths could be attributed to diet, defined in the report as nutrition, not caloric intake. Increased research actually produced more questions than answers, including what each study meant by diet. Unlike the JNCI article, recent studies cite BMI or weight distribution. Also contradictory to the JNCI report was a major study in 2003 that found excessive weight and obesity may contribute to only 17 percent of cancer deaths.

While BMI is the easiest and most widely used method to determine obesity, factors such as body shape, muscle mass, diet and physical activity may be more important than numbers on a scale. Citing studies that show ethnic groups develop obesity-related diseases at different BMIs, organizations such as the International Obesity Task Force have made recommendations to the World Health Organization to revise the BMI standards for various ethnic groups.

Alfred Neugut, MD, PhD, head of cancer prevention at Herbert Irving Comprehensive Cancer Center at New York’s Columbia University, says little scientific research exists on obesity-associated cancers. “It’s not an easy subject to study. Do people have a higher risk because of their weight or their lifestyle?” Dr. Neugut queries.

As new research looks at whether diet, genetics, physical activity or weight plays the greatest role, scientists examine several potential biological causes, including myriad hormones, such as estrogen, leptin, ghrelin and insulin.

Insulin helps convert the sugar glucose to energy inside the cell. When the body’s fat cells produce free fatty acids, resistin and several other hormones, they impair the body’s ability to use insulin to convert glucose to energy, causing a buildup of glucose. The pancreas perceives insufficient levels of insulin as the cause of the excess glucose, so it begins producing additional insulin. As insulin levels rise in the body, insulin-like growth factor 1 (IGF1) also rises, promoting normal cell growth and possible tumor cell growth. An obese person’s body then begins to utilize the glucose at higher insulin levels than a normal-weight person.

Add to this the theory linking some cancers, namely breast and ovarian cancers in postmenopausal women, to alterations in sex hormones, including estrogen. “The hypothesis is that in postmenopausal women who are overweight or obese, the fat is actually a source of estrogen,” says Shine Chang, PhD, associate director of the National Cancer Institute’s Office of Preventive Oncology. Before menopause, the ovaries produce most of the body’s estrogen.

Overweight postmenopausal women increase their risk of developing breast cancer by half over normal-weight women.

In heavy postmenopausal women, estrogen levels are higher than in normal-weight postmenopausal women. Estrogen-sensitive tissues have continued exposure to estrogen after menopause, leading to stimulation of estrogen-responsive breast tumors. Overweight postmenopausal women increase their risk of developing breast cancer by half over normal-weight women.

Researchers with the Women’s Intervention Nutrition Study (WINS) examined whether a dietary fat reduction would lower the risk of recurrence and increase survival in postmenopausal women with breast cancer. While the study showed a decreased risk of recurrence and increased survival, women who had estrogen receptor (ER)-negative breast cancer actually lowered their relative risk of recurrence more than the women with ER-positive breast cancer, a finding that surprised Rowan Chlebowski, MD, PhD, lead author of the study and an oncologist at the Los Angeles Biomedical Research Institute.

“Our original hypothesis was that estrogen change would mediate any benefit,” says Dr. Chlebowski. “If the effect is greater in ER-negative disease, it suggests other factors mediate, such as insulin-related hormones.” Weight loss, increased fruits and vegetables, less red meat and increased exercise may have contributed to the benefit, but as with other studies in this area, the difficulty becomes distinguishing what caused the positive results.

Studies consistently show an increased risk of colon cancer with obesity, mostly in obese men. Weight distribution or increased abdominal fat may be more important in colon cancer risk than overall BMI, and men tend to have more abdominal fat than women. Colon cancer may also be diet or exercise driven. A 2002 review of several studies on exercise and colon cancer risk found that even moderate physical activity reduced risk by half, and exercise often lowered risk regardless of BMI.

Boland says most colon cancers are weakly tied to genetics, but the predisposition to colon cancer can be brought out with other factors, such as a diet high in fat and red meat and a lifestyle with little or no exercise.

“It’s hard to know what might be going on with being obese, because people who eat too much might not exercise enough, but those that exercise are possibly more conscious about what they eat and are less likely to eat red meat and fat.” The issue of a low-fiber diet contributing to colon cancer is less apparent. Several studies showed patients with adenomatous polyps who underwent a several-year change to a low-fiber diet demonstrated no change in their risk for recurrent colon polyps.

Though research identifies a complex association between obesity and cancer, a cause-and-effect link has not been made.

More elusive is the obesity and prostate cancer connection. “The one thing surfacing now is the role between obesity and poor prognosis for prostate cancer,” says Wendy Demark-Wahnefried, PhD, a nutritionist and former director of the Program of Cancer Prevention, Detection and Control Research at Duke University.

Two studies reported in 2004 found that obese prostate cancer patients are more likely to have aggressive tumors and experience cancer recurrence after surgery compared with patients with a BMI under 30. A study reported in August 2005 confirmed these results, showing men with a BMI over 35 are more than twice as likely as normal-weight men to develop prostate cancer. Dr. Demark-Wahnefried is working on a study in prostate cancer, testing whether a low-fat diet with or without flaxseed lowers prostate cancer risk.

It may not be just how much you weigh, but where you store excess weight. Higher levels of estrogen and prolactin, primarily female hormones, appear to promote fat deposition on the lower body, which may be why women typically have a pear-shaped body. Corticosteroids contribute to abdominal fat, resulting in an android shape typically seen in obese men. An overweight or obese person who carries weight around the midsection has a higher risk of developing diabetes, heart disease or hypertension than a person who carries weight on their hips, buttocks and thighs. Studies show this may also be true for obesity-associated cancers. Many cancer risk studies use BMI to determine obesity, but BMI doesn’t take body composition into consideration, which may be important in determining cancer risk.

The different types of fat could also determine risk. Subcutaneous fat, typically found underneath the skin of the hips, buttocks and thighs, is not considered as unhealthy as visceral fat. The increased health risk comes from visceral fat found inside the abdomen and around the organs. Visceral fat and subcutaneous fat also feel different. A person with a soft, pudgy belly probably has a lower risk of obesity-related diseases than a person with a hard belly, which signifies visceral fat.

Many frustrated dieters have turned to interventional weight loss methods, a multibillion-dollar-a-year industry in the United States. Many weight loss drugs produce only a modest loss and only two are approved for long-term use.

But even modest weight loss could be beneficial. A 5 to 10 percent weight loss can decrease lipid levels and blood pressure, increase good cholesterol levels and lower the risk of diabetes and heart disease. A 2003 study looked at the effect of intentional weight loss on cancer risk in over 21,000 postmenopausal women and reported a 14 percent decrease in relative risk. Women who lost at least 20 pounds, resulting in a healthy BMI, had the same risk as healthy-weight women who never lost weight. But the effect of weight loss on cancer risk remains unclear.

Though research identifies a complex association between obesity and cancer, a cause-and-effect link has not been made. Researchers are just now beginning to understand all the various factors that may be involved. While individual studies conflict, the overall message is clear.

“Eat a healthy diet and exercise,” says Chang. “These will improve quality of life no matter who you are, whether you’re a person at risk or a cancer survivor.” And while Chang and others wait for proof before saying weight loss reduces cancer risk, “there are so many reasons to work at keeping one’s weight down—not just for cancer prevention but for a lot of chronic diseases. It just feels good to live that way.”