How extra pounds boost your risk.

Why worry about XXL size pants? According to a 2006 survey by the American Cancer Society, 83 percent of Americans know that extra flab boosts their odds of a heart attack and 57 percent know that obesity ups their risk of diabetes. Yet only 17 percent know that a growing girth could make them more prone to cancer.

"Five years ago, I would have understood that," says the cancer society's Eugenia Calle. But today, the public's failure to see the connection is even more out of sync with the science.

"I'm just astounded by how much new information is coming out on obesity and cancer," says Calle. "I can barely keep up."

Here's the latest.

Cancers of the breast, colon, esophagus, kidney, uterus. In 2002, the International Agency for Research on Cancer concluded that people who are overweight or obese have a higher risk of all five. Now there's evidence for more.

"I would add gallbladder, liver, pancreas, and advanced prostate cancers to the list," says Eugenia Calle, an expert on cancer and obesity at the American Cancer Society. Extra pounds account for an estimated 20 percent of all cancer deaths in the United States. And the percentage is growing ... because Americans are growing.

"We're seeing cancers now linked to obesity that we haven't seen in the past," says Susan Taylor Mayne of Yale University. "And that's scary because of the high prevalence of overweight and obesity."

Our expanding national waistline could reverse some of the progress that we've made against cancer, she adds.

"Rates of cancer mortality have been declining because of gains in tobacco control," says Mayne. "But we can lose that headway if we lose the war on obesity."

Why are researchers seeing a stronger link between obesity and cancer than in the past? "We may not have picked up a link 20 years ago because fewer people were overweight 20 years ago," says Yale's Susan Taylor Mayne.

For example, experts estimate that in the United States, excess weight explains roughly:

* half of all uterine and esophageal cancer,

* a fifth (in women) to a third (in men) of all colorectal cancer,

* a third of all kidney cancer,

* a quarter of all pancreatic cancer, and

* more than a fifth of all postmenopausal breast cancer. (1)

But in Europe, where obesity rates are lower--like ours were 20 years ago--excess weight explains a lower percentage of most cancers. (1)

"The list of cancers related to obesity is growing," says Mayne. "It's alarming."

How much of a spare tire do you need before your risk climbs? It depends. For some cancers, risk starts to rise even before you cross the line that defines "overweight." (See "Extra Weight & Cancer Risk," pp. 4 & 5.)

"With breast, colon, and endometrial cancer, you can see an increase in risk at the high end of the normal-weight range compared to the low end," says the American Cancer Society's Eugenia Calle. "And then the risk increases in an almost linear fashion from the very lean to the very heavy."

That's partly because the "normal-weight" range is quite large. "Two people of the same height could be 30 to 50 pounds apart and still be normal weight," she explains.

For some cancers, only heavier people appear to be at risk. "For example, it seems like there's no increase in the risk of pancreatic cancer until you get very heavy," says Calle. But that may simply reflect incomplete data.

"Most studies have used Body Mass Index, or BMI, as a measure of obesity, and that's not the best measure for all cancers," she says. "For example, now we're looking at waist circumference and pancreatic cancer and finding a stronger effect."

The lengthening list of cancers linked to obesity, says Mayne, suggests that "it may be a systemic effect." That's because fat tissue isn't just dormant storage space. It's an active organ, releasing and receiving signals from other organs.

So far, three main theories explain how those signals may help turn healthy cells into tumors.

I. The Insulin Pathway

Insulin is the hormone that allows blood sugar to enter cells, where it is either burned for energy or stored as fat.

But if you have too many overstuffed fat cells, they can become resistant to insulin. It's as though the cells were trying to shut the door that would let in even more sugar.

With insulin losing its punch, the pancreas ramps up its output of the hormone.

"If you have more or bigger fat cells on board, the pancreas is forced to produce more insulin," says Michael Leitzmann, an epidemiologist at the National Cancer Institute.

High insulin levels are especially likely if you have what experts call "central obesity" (see "Waist Not ..." p. 7).

"These are people who have an apple-shaped body with a big waist instead of the pear-shaped people with big hips," explains Karen Margolis of the University of Minnesota and HealthPartners Research Foundation in Minneapolis.

It's clear that insulin resistance increases the risk of diabetes and heart disease. Now cancer may join those ranks. "It's likely that the insulin pathway and insulin resistance are important for cancers of the colon, liver, pancreas, and kidney," says Calle.

How? Insulin prompts the body to make insulin-like growth factor 1 (IGF-1). In test tubes, both insulin and IGF-1 make cells proliferate. (1)

"Insulin itself stimulates growth, so it could act directly on cancer cells," says researcher Edward Giovannucci of the Harvard School of Public Health. "And insulin sensitizes the cells to IGF-1."

It's not that overweight people necessarily have more IGF-1. Rather, "insulin decreases IGF-1 binding protein, so there's more free IGF-1 in the blood," he explains.

Here's what researchers know about cancers linked to the insulin pathway.

* Liver. "Peripheral fat in the thighs and hips--where a lot of women carry their fat--is not that metabolically active," says Calle.

On the other hand, the "visceral" fat around the waist is constantly sending out signals that promote inflammation or growth elsewhere in the body.

(Inflammation, which is often outwardly invisible, is the immune system's attempt to fight off and repair the damage caused by germs, irritants, or other insults.)

"We're not talking about the subcutaneous layer of fat between the skin and muscles," adds Calle. "We're talking about the fat behind the muscle wall that surrounds the organs." (See "Waist Not ..." p. 7.)

"People don't realize that once you get beyond a certain level of ad posity, fat starts to infiltrate muscle and organs like the liver."

In the past, excess alcohol accounted for most fatty livers. "But the most common cause of abnormal liver tests in the United States now is non-alcoholic fatty liver disease," says Calle.

A fatty liver starts out benign, but it can lead to cell injury, scarring, and inflammation. "It can progress from fatty liver to hepatitis to cirrhosis to liver cancer," says Calle.

So far, studies suggest that the obese have anywhere from 1 1/2 to 4 times the risk of liver cancer. (1,2) But the disease is still rare in the United States, so it's harder to get a precise risk estimate.

* Colon. Colon cancer isn't rare. It kills more non-smokers than any other cancer.

In the National Institutes of Health-AARP Diet and Health Study, which tracked more than 300,000 men and 200,000 women for five years, the heaviest men had twice the risk of colon cancer, while the heaviest women had a 50 percent increase in risk. (3) But that doesn't mean that everyone else is in the clear.

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"The risk increases even for people who are mildly overweight, which isn't reassuring for people who have a couple of extra pounds," explains the National Cancer Institute's Michael Leitzmann.

Why does obesity seem to matter more in men than women? Fat around your waist is the culprit, and men are more likely to gain weight there.

Giovannucci and colleagues found that men with a waist measuring at least 43 inches had a 2 1/2 times greater risk of colon cancer than men with a waist smaller than 35 inches. (4) And a big belly often goes hand in hand with excess insulin.

"In human and animal studies, insulin levels are correlated with risk," says Giovannucci. For example, the higher a rat's insulin level, the more its colon cells proliferate. (5)

"The data linking insulin to risk is stronger for colon than for any other cancer," says Giovannucci.

* Pancreas. Pancreatic cancer is deadly. Only one in five patients is alive one year after diagnosis, and only one in 25 survives five years. The only known risk factors are cigarette smoking, diabetes, and obesity.

"In the past six years, a huge number of studies using prospective data have shown a very strong association between obesity and pancreatic cancer," says researcher Dominique Michaud of the Harvard School of Public Health.

In most studies, being obese doubles the risk. (6,7) "For people who are overweight, the link isn't as strong as it is for other cancers," says Michaud. "It shows up more for the obese."

A few studies, like the European Prospective Investigation into Cancer and Nutrition (EPIC), which tracked more than 430,000 men and women for six years, found a stronger link with waist size than with obesity per se. (8) But other than EPIC, "there's very little data on waist circumference," Michaud notes.

It's still not clear how excess fat leads to pancreatic tumors. "It's probably a consequence of sustained higher levels of and insulin in the blood," suggests Michaud.

Inflammation may also play a role, she adds, "because people who are obese have higher levels of inflammation."

Again, it's the visceral fat cells deep in the belly that appear to be at fault. "Those fat cells are different," Michaud explains. "They're actively causing trouble."

* Kidney. Although kidney cancer accounts for only about 2 percent of cancer deaths, the incidence is rising in the United States and worldwide. Smoking, diabetes, high blood pressure, and obesity all seem to raise the risk, but it's not clear if a large waist matters more than a large number on the bathroom scale.

In many studies, excess fat anywhere in the body raised the risk. (9) But in the Women's Health Initiative, which tracked about 140,000 U.S. women for nearly eight years, those with the largest waists (for a given hip size) had double the risk. (10)

"Central obesity was the strongest risk factor in these women," says the University of Minnesota's Karen Margolis, who co-authored the study.

What's more, U.S. women who had lost or gained over 10 pounds more than 10 times during their lifetime had a 2 1/2 times greater risk of kidney cancer than those with stable weights.

"It appears that weight cycling has a pretty strong relationship with kidney cancer, particularly at the extreme," says Margolis. "But we don't know why."

II. The Estrogen Pathway

If you're overweight but don't carry the extra pounds in your waist, are you off the hook?

No. Fat--whether it's around your hips, thighs, waist, or wherever--produces steroid hormones like estrogen.

"Another main way that obesity can raise the risk of cancer is through the estrogen pathway," says the American Cancer Society's Eugenia Calle.

In premenopausal women, estrogen comes largely from the ovaries. "After the ovaries stop functioning, the primary source of estrogen production is adipose [fat] tissue," Calle explains. "And estrogen is associated with endometrial and breast cancer."

As with IGF-1, obesity depresses levels of binding proteins.

"There's not as much sex-hormone-binding globulin levels in the circulation, so less estrogen is bound" and free estrogen goes up, says Calle. And that increases risk. Some specifics:

* Breast. The risk of postmenopausal breast cancer rises by 30 percent in overweight women and SO percent in obese women. (11) For years, researchers couldn't detect the link because they didn't separate women who take estrogen pills from those who don't.

"Weight is not related to breast cancer in postmenopausal women who take hormones," says Calle. That's because the pills raise estrogen levels--and the risk of cancer--whether the women are skinny or plump.

"The sharp decline in the number of women taking postmenopausal hormones means that weight matters to an increasing segment of the population," she adds.

More than other cancers, postmenopausal breast cancer is related to how much weight you gain as an adult. (12) "That's in part because obesity may lower the risk of breast cancer in pre-menopausal women," says Calle.

Why? Obesity seems to impair their ability to ovulate. "So the woman with the highest risk was normal weight and had regular periods when she was young and became obese when she got older," Calle explains.

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In a study of 44,000 postmenopausal women who weren't taking estrogen, those who gained 21 to 40 pounds after age 18 had a 68 percent higher risk of breast cancer that spread beyond the breast than those who gained 20 pounds or less. The risk was nearly double for those who gained 41 to 60 pounds and triple for those who gained more than 60 pounds. (13)

"Excess adiposity is an important contributor to breast cancer risk in postmenopausal women, especially for tumors that are most likely to spread," says Calle.

* Uterus. Cancer of the endometrium (the lining of the uterus) is twice as likely in overweight women and 3 1/2 times more likely in obese than in normal-weight women. (1)

"That was the first cancer we recognized as related to obesity," says Calle. And it's clear why excess fat threatens the uterus. "We know that endometrial cancer is associated with estrogen that's unopposed by progestin."

Decades ago, researchers found that women who took estrogen pills had a higher risk of uterine cancer, but the risk disappeared in women who took estrogen combined with progestin.

Recently, researchers have detected a higher risk among women with central obesity. In a study of 223,000 European women, the risk of uterine cancer in those with at least a 35-inch waist was 76 percent higher than in those with a waist smaller than 32 inches. (14)

"Once you get to some level of obesity, you're going to have a certain amount of central adiposity no matter where you carry your weight," says Calle.

III. Local Impact

For some cancers, obesity seems to boost risk because it leads to problems in nearby tissues (rather than by altering circulating hormones). For example:

* Esophagus. Two distinct cancers show up in the esophagus. With a five-year survival rate of 16 percent, both are deadly.

But there are differences. The incidence of squamous cell carcinoma (which is common in alcoholics, who are often underweight) is flat or dropping, while rates of adenocarcinoma (which is common in the overweight) are on the upswing.

"The incidence of adenocarcinoma is going up more in men than in women and no one knows why," says Yale's Susan Taylor Mayne. Obesity may have more impact in men, she suggests.

At first, researchers thought that a wider girth led to esophageal cancer because it caused acid from the stomach to flow back into the esophagus, causing inflammation.

"Obesity may be acting to promote cancer in part via acid reflux, but it may also be acting independently," says Mayne.

"In our study, when we controlled for reflux, we still found a strong effect of obesity, so risk is not just driven through reflux." (15)

* Gallbladder. The gallbladder is a pear-shaped organ below the liver that collects and stores bile (a fluid made by the liver to digest fat). In about a quarter of all cases, gallbladder cancer is found early (usually when the organ is removed for other reasons), and the five-year survival rate is 80 percent.

But more often, the tumor is discovered too late to be surgically removed. If that happens, only 5 percent of patients live for two years.

While gallbladder cancer is rare, excess weight accounts for more than a third of all cases in the United States. How?

"Obesity is associated with gallbladder stones," explains Calle. "The stones provide a local inflammatory environment," which sets the stage for cancer.

Uncertain Pathways

Researchers are still in the dark about how obesity may raise the risk of some cancers. For example:

* Prostate. Prostate cancer strikes one out of six men sometime in their lifetime. But only one in 34 dies of the disease.

Researchers saw no consistent link with weight until they separated men with local, less aggressive cancers from those with more aggressive or fatal cancers. (16)

"Obesity is associated only with the more aggressive prostate cancers," says Harvard's Edward Giovannucci. "So it's possible that obesity doesn't cause prostate cancer, but makes prostate cancer more likely to progress."

For example, when researchers followed more than 285,000 men from the National Institutes of Health-AARP Diet and Health Study for five years, the risk of dying of prostate cancer was 25 percent higher in those who were overweight than in those who were normal weight. And the risk was twice as high in the most obese men. (17)

Among the possible explanations: "Obesity may increase the blood supply to the tumor or increased growth factors like insulin could cause it to progress," suggests Giovannucci. "Or it's possible that not all prostate cancers are alike."

In other words, aggressive cancers may have a different cause than those that don't spread.

"It looks like there are at least two distinct types of prostate cancer," explains the National Cancer Institute's Michael Leitzmann.

"We can separate them according to the grade--how abnormal the cancer cells are--and according to the stage--whether they've spread beyond the prostate gland or not."

And obesity may promote only the aggressive (higher grade, higher stage) cancers. In fact, excess fat may protect against localized prostate cancers-those "you'll die with, not from," says Leitzmann.

Why? Higher levels of insulin, free IGF-1, and leptin (a hormone that's secreted by fat cells) are potential culprits. (7) So is testosterone.

"Heavy men have lower testosterone levels," explains Leitzmann. "We know that testosterone leads to the start of prostate cancer."

But testosterone also helps maintain the structure and function of the prostate cells, says Leitzmann. "So the cells are more likely to go awry if testosterone levels are low."

That's speculative, he adds. "But it's possible that high testosterone levels make you more likely to get the disease, but low testosterone levels make the disease worse once you get it."

(1) Nature Reviews 4: 579, 2004.

(2) N. Engl. J. Med. 348: 1625, 2003.

(3) Am. J. Epidemiol. 166: 36, 2007.

(4) Ann. Intern. Med. 122: 327, 1995.

(5) Endocrinol. 147: 1830, 2006.

(6) Cancer Epidemiol. Biomarkers Prev. 14: 459, 2005.

(7) Gastroenterol. 132: 2208, 2007.

(8) Cancer Epidemiol. Biomarkers Prev. 15: 879, 2006.

(9) Int. J. Cancer 118: 728, 2006.

(10) Am. J. Epidemiol. DOI: 10.1093/aje/kwm137.

(11) Am. J. Epidemiol. 152: 514, 2000.

(12) JAMA 296: 193, 2006.

(13) Cancer 107: 12, 2006.

(14) Cancer Causes Control 18: 399, 2007.

(15) J. Natl. Cancer Inst. 95: 1404, 2003.

(16) Cancer Epidemiol. Biomarkers Prev. 15: 1977, 2006

(17) Cancer 109: 675, 2007.

Waist Not ...

Extra padding anywhere seems to boost your risk of cancers of the breast, uterus, esophagus, gallbladder, and prostate. But other cancers--colon, liver, pancreatic, and kidney-are more closely linked to the visceral fat that's underneath your stomach muscles (see illustration).

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Unlike subcutaneous or retroperitoneal fat, which is less active, visceral fat is busy pumping out a slew of hormones--like leptin, adiponectin, and IGF (insulin-like growth factor)--that cause trouble.

"That's why central obesity is related to diabetes, heart disease, and cancer," says Dominique Michaud of the Harvard School of Public Health. "We wouldn't have all those complications if overweight people were just carrying extra weight around."

How do you know how much of your fat is visceral?

You can't tell without a CT-scan, MRI, or other imaging technique. But your waist circumference is a good proxy, because a big belly usually means rich deposits of both visceral and subcutaneous fat.

(When studies measure waist circumference or waist-to-hip ratio, they report on participants' "central obesity" or "abdominal obesity," rather than visceral fat.)

Women with a waist bigger than 35 inches and men with a waist bigger than 40 inches have a higher risk of heart disease and diabetes. But for cancer, the cutoffs are less clear.

The question is: how can you keep fat away from your innards?

On one hand, genes seem to decide whether you end up with an apple or pear shape--with more weight around your middle or around your hips.

Hormones also play a role, since women tend to go up in waist size after menopause. But that doesn't mean you're helpless.

Here's what we know so far:

* Don't fall for gimmicks. Despite what you see in ads for weight-loss pills, potions, and gadgets, there is no way to target belly fat when you're losing weight. Sit-ups, crunches, and other exercises can strengthen abdominal muscles, but they don't melt belly fat any more than other fat deposits.

* Count calories in and out. Cutting calories coming in or boosting calories going out has the same impact. In a six-month study of 35 overweight men and women, there was no difference in visceral fat loss among people who cut calories by 25 percent or who cut calories by 12.5 percent and burned 12.5 percent more calories than usual. (1) Both lost about 10 percent of their weight and 27 percent of their visceral fat. Of course, exercise can also help lower the risk of heart disease, diabetes, and cancer, even if you don't lose weight.

* Cut calorie-dense, nutrient-poor foods. It's easier to slim down if you fill up on vegetables, fruit, and other foods that aren't calorie-dense. Limit calorie-dense fatty foods (especially if they're high in saturated and trans fats) and carbohydrates (especially sweets, white potatoes, and breads, cereals, rice, and pasta made with refined flour). And don't drink your calories, whether it's alcohol, soda, or juice.

* Don't just sit there. The more time you spend on the couch, in the car, or at the computer, the more fat you invite into your abdominal home.

In a study of 175 overweight, sedentary men and women, one group walked 12 miles a week (which took about 3 hours), a second group jogged 12 miles a week (2 hours), a third group jogged 20 miles a week (3 hours), and a fourth group stayed inactive. (2)

After six months, the 20-mile joggers had lost 7 percent of their visceral fat, while the 12-mile walkers and 12-mile joggers--who burned roughly the same calories--had lost no visceral fat. But the real surprise was the control group. In just six months of inactivity, their visceral fat jumped 9 percent (see graph). And in a recent rat study, inactivity made rats grow more fat cells. (3)

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The bottom line: What matters is how many calories you burn when you exercise--whether it takes you 1 hour, 2 hours, or whatever--not whether it's high intensity (like jogging) or moderate intensity (like walking). But what matters most is that you get off your derriere.

So, for now, eat less and move more--all easier said than done, of course.

How to measure your waist circumference:

1. Place a tape measure around your bare abdomen just above your hip bone.

2. Be sure that the tape is snug, but does not compress your skin, and is parallel to the floor.

3. Relax, exhale, and measure.

(1.) J . Clin. EndocrinoL Metab. 92: 865, 2007.

(2.) J . Appl. Physiol. 99: 1613, 2005.

(3.) J . Appl. Physiol. 102: 1341, 2007.

Extra Weight & Cancer Risk (Women)

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As a woman's BMI rises above the normal range (18.5 to 24.9), her risk of dying of several cancers also rises. For example, the risk of dying of uterine cancer is 50 percent higher for women who are overweight (a BMI between 25.0 and 29.9) than for women who are normal weight. For the most obese women (a BMI of 40 or higher), the risk is roughly six times higher. The line for gallbladder cancer stops early because there were too few deaths among the most obese women in this study to separate those with a BMI of 35 or greater. (To find your BMI, see "How Fat is Fat?" p. 6.)

Source: Data from New EngL J. Meal. 348: 1625, 2003.

Extra Weight & Cancer Risk (Men)

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As a man's BMI rises above the normal range (18.5 to 24.9), his risk of dying of several cancers also rises. For example, the risk of dying of colorectal cancer is 20 percent higher for men who are overweight (a BMI between 25.0 and 29.9) than for men who are normal weight. For the most obese men (a BMI of 35 or higher), the risk is almost double (84 percent higher). This study had no separate data for men with BMIs of 40 or greater. (To find your BMI, see "How Fat is Fat?" p. 6.)

Source: Data from New EngL J. Med. 348: 1625, 2003.

How Fat is Fat?

The numbers apply to both men and women, but they're
Not foolproof. Very muscular people may have a high
BMI without health risks. And frail or older people
may be unhealthy even though they have a low BMI.

(To calculate your BMI: Find your height, then look across
that row. Your BMI is at the top of the column that comes
closes to your weight.)

BODY MASS INDEX (BMI)

                        NORMAL                    OVERWEIGHT

HEIGHT    19    20    21    22    23    24    25    26    27    28

                                 WEIGHT (pounds)

4'10"     91    96   100   105   110   115   119   124   129   134
4'11"     94    99   104   109   114   119   124   128   133   138
5'0"      97   102   107   112   118   123   128   133   138   143
5'1"     100   106   111   116   122   127   132   137   143   148
5'2"     104   109   115   120   126   131   136   142   147   153
5'3"     107   113   118   124   130   135   141   146   152   158
5'4"     110   116   122   128   134   140   145   151   157   163
5'5"     114   120   126   132   138   144   150   156   162   168
5'6"     118   124   130   136   142   148   155   161   167   173
5'7"     121   127   134   140   146   153   159   166   172   178
5'8"     125   131   138   144   151   158   164   171   177   184
5'9"     128   135   142   149   155   162   169   176   182   189
5'10"    132   139   146   153   160   167   174   181   188   195
5'11"    136   143   150   157   165   172   179   186   193   200
6'0"     140   147   154   162   169   177   184   191   199   206
6'1"     144   151   159   166   174   182   189   197   204   212
6'2"     148   155   163   171   179   186   194   202   210   218
6'3"     152   160   168   176   184   192   200   208   216   224
6'4"     156   164   172   180   189   197   205   213   221   230

                     NORMAL                  OVERWEIGHT

HEIGHT       29        30    35    40

                WEIGHT (pounds)

4'10"       138       143   167   191
4'11"       143       148   173   198
5'0"        148       153   179   204
5'1"        153       158   185   211
5'2"        158       164   191   218
5'3"        163       169   197   225
5'4"        169       174   204   232
5'5"        174       180   210   240
5'6"        179       186   216   247
5'7"        185       191   223   255
5'8"        190       197   230   262
5'9"        196       203   236   270
5'10"       202       207   243   278
5'11"       208       215   250   286
6'0"        213       221   258   294
6'1"        219       227   265   302
6'2"        225       233   272   311
6'3"        232       240   279   319
6'4"        238       246   287   328

                          OBESE

Source: National Heart, Lung, and Blood Institute.