The cardiovascular system appears to be one victim. Macrophages play an important role in the development of the fatty plaques that lead to atherosclerosis. And cytokines can make tissues resistant to the effects of insulin and cause inflammation in the blood vessels. Meantime, too much insulin can promote salt retention—and soaring blood pressure. "If I hadn't lost the weight when I did, they say [I'd have had] a heart attack or stroke," says Sheri Fanning, 41, a geriatric care manager and now weight-loss coach in Sparta, Wis., who has heart disease in her family and recently experienced a dangerous blood pressure spike.
Five years ago, Fanning tipped the scale at 192 pounds, and her doctor delivered an ultimatum: Go on hypertension meds for life. Instead, Fanning credits a physician-directed program that offered thrice-weekly weigh-ins, counseling, and a calorie-restricted diet for helping her to get down to a healthy 130 pounds. Taking up marathoning, triathlon, and competitive road biking certainly did its part, too. Though she's been on blood pressure medication since her recent crisis, she was able to keep her numbers down for years without drugs; her doctors say that shedding those pounds and keeping them off probably saved her life.
Cancer experts, too, now strongly advise burning excess fat. In fact, the top recommendation in the new cancer prevention guidelines issued by the American Institute for Cancer Research and the World Cancer Research Fund puts it this way: "Be as lean as possible within the normal range of body weight." That means keeping your body-mass index between 21 and 23—or, for someone who is 5 foot 4, staying between 122 and 134 pounds. "A BMI of 25 increases the risk of postmenopausal breast cancer more than [a BMI] of 21," says Meir Stampfer, who researches nutrition and epidemiology at the Harvard School of Public Health. Extra fat is strongly believed to raise the risk of six types of cancer—esophageal, pancreatic, colorectal, breast (in postmenopausal women), endometrial, and kidney—and possibly gallbladder cancer, too.
The mechanisms that link obesity and cancer are not known, but the usual suspects—insulin resistance and inflammation—are likely players. Research released at December's American Association for Cancer Research conference on cancer prevention found that women with diabetes are 1.5 times more likely to develop colorectal cancer than those who aren't diabetic. "It's possible that fairly high levels of insulin—higher than seen in the prediabetics—are necessary to encourage cancer growth," says Andrew Flood, an epidemiologist at the University of Minnesota. And cytokines released from fat tissue are known to promote tumor growth and cell death.
Fatty liver. The workhorse of the body takes a beating, too. For example, when a person carries a surplus of fat, the liver—which is responsible for the breakdown of insulin, sugars, hormones, and lipids—less effectively produces a protein that helps move fat out. So most chronic overeaters end up with fat stored in this organ. Nonalcoholic fatty liver disease, when severe, results in rampant inflammation and scarring and is projected to be the most common reason for liver transplant by 2020.
"I probably had a week to live," says Bill Mackey, an engineer in Rochester, Minn., who once weighed 350 pounds and got a transplant in 2003 after developing liver failure. Through a yearlong recovery and adjustment to antirejection drugs, Mackey, 60, dropped down to 225 pounds, though he has crept back up to 275 these days. His doctor says this is typical in such patients, as is some reaccumulation of fat in the liver. "That tells you this is not a liver problem," explains Mayo's Charlton. "It's a whole-body problem, an endocrine problem associated with hormones, overnutrition, and some susceptibility factor we're still trying to identify."
Deep belly fat, also known as visceral fat, may especially endanger the liver. "Having fat in that visceral area can potentially increase the flow of fatty acids to the liver and have a next-door-neighbor effect," says Elizabeth Parks, associate professor and expert on liver metabolism at UT-Southwestern Medical Center in Dallas. And "maybe the visceral fat is releasing more cytokines [than fat stored elsewhere]." Genes seem to determine—at least in part—where a person stores fat, so lean people aren't necessarily off the hook if they don't exercise or eat a healthful diet.
Corrected on : Corrected on 1/9/07: An earlier version of this article misstated the name of the American Institute for Cancer Research.