Phil Bruno was super-sizing again. It was just past 5:30 on a spring evening in 2004, and he was driving home from work. He pulled into a White Castle, one of many fast-food outlets lining Route 100 in his hometown of Manchester, Missouri, a suburb of St. Louis. He was only a mile from his house, where his wife, Susan, was cooking the usual big Italian dinner for their family of five, but he was hungry now. The urge was automatic.

Ten minutes later, with a bag of burgers steaming on the seat beside him, he pulled into a McDonald’s and ordered a Double Quarter Pounder with Cheese, an apple pie, and a chocolate shake to wash it all down. “I did this because I would be embarrassed to order too much from one drive-through,” Phil explained to me. “I didn’t want the person at the window to look at me funny.”

Phil had always loved food, which was part of the fabric of his tight-knit Sicilian-American family: Grandma and her lasagna were right down the street. But he’d been athletic in his youth, playing high school football and carrying a robust but reasonable 215 pounds on a six-foot-three-inch frame. Then, in his mid-twenties, he’d stopped working out, as many of us do when life starts to chew up our time. Over the years, his regular meals and high-calorie bingeing had turned him into a physical and emotional wreck. His joints ached whenever he used the stairs, his heart hammered, and he was possessed by a strange, burning thirst that no amount of ice water could quench. “I was 47 years old,” he says, “but I felt like I was 80.”

Prodded by a friend, Bruno finally went to see his long-time family physician, Don Livingston, in early 2004. The results were harrowing: his blood pressure was at a firehose-like 230 over 150, his blood sugar was off the charts, and his A1C—an important blood marker for diabetes—was 16. (It should have been under six.) He weighed a scale-crushing 470 pounds.

Phil had developed Type 2 diabetes, but that was just one of his problems. He walked out of the doctor’s office with prescriptions for 12 different medications and supplements, from fish oil to blood-pressure medicine to Lipitor for his cholesterol to Glucophage for his diabetes. And he never forgot Dr. Livingston’s ominous words at the end of the visit. “Bruno,” he had said, “you should be dropping dead any second.”

Everyone knows that being fat is bad for you, but most people can’t explain exactly why. Some reasons are obvious. Fat tends to go hand in hand with diabetes, and more weight means increased stress on joints and the heart. More puzzling to researchers is that excess fat seems to be linked with cancer of the kidneys, colon, and liver, and even to cognitive decline.

Scientists have discovered that fat infiltrates our vital organs, bathing them in a nasty chemical stew that wreaks havoc in the body.

Until fairly recently, fat was thought to be inert, evolution’s wobbly way of letting humans store energy for lean times. And we’ve long known that it’s better to be slightly overweight than underweight, as a recent study in the Journal of the American Medical Association reiterates.

Starting in the 1990s, though, scientists began to realize that fat is best understood as a single huge endocrine gland, one that wields powerful influence over the rest of the body. “For a typical North American, their fat tissue is their biggest organ,” says James Kirkland, M.D., director of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic.

Not everything about fat is bad, of course. Fat tissue under the skin, known as subcutaneous fat—the kind that makes young people look succulent and ripe—is essentially padding that protects the body from injury, and it also helps fight infection and heal wounds. “Sub-q” fat produces an important hormone called adiponectin, which appears to help control metabolism and protect against certain cancers, notably breast cancer.

The bad news is that, as we age, we gradually lose this good fat, which is one reason why our hands get bonier. Instead, men and women alike tend to build up blobby fat on our midsections. Over the past decade or so, Kirkland and other scientists have discovered that this so-called visceral fat infiltrates our vital organs, bathing them in a nasty chemical stew that wreaks havoc in the body. Visceral fat produces an array of cell-signaling proteins called cytokines, including interleukin-6 (IL-6), which causes chronic inflammation, and TNF-alpha, for tumor necrosis factor, which has been linked to cancer.

Kirkland and other researchers have come to believe that, in addition to the problems associated with diabetes and heart disease, fat may actually help accelerate the aging process. In a 2008 experiment, scientists at the Albert Einstein College of Medicine at Yeshiva University surgically removed abdominal fat from obese lab rats and found that the rodents lived significantly longer than their chubby cousins. In a more recent study, not yet published, the Einstein team found that surgical fat removal prevented some colorectal cancers in mice that were genetically predisposed to those tumors.

Unfortunately for Phil Bruno, surgery wasn’t an option: liposuction only removes the good subcutaneous fat, which is why several recent studies have associated the procedure with negative health outcomes. In humans, says Einstein researcher Nir Barzilai, visceral fat can’t be removed safely because it’s so deeply intertwined with blood vessels and organs. So Bruno called on the only thing in his body that was powerful enough to fight it off: muscle.

On June 6, 2004, roughly a month after his grim diagnosis, Bruno did the one thing his doctor hadn’t prescribed: he went to a gym. Dr. Livingston had suggested he lose weight, but he stopped short of recommending exercise. That’s typical. One study found that less than half of U.S. physicians discuss exercise with their patients.

After getting his heart checked out via a stress test—it was enlarged, but his arteries were clean, thanks to Grandma’s olive oil—Phil walked into his local Gold’s Gym on a Sunday morning. He looked around uncertainly before settling on the one piece of equipment that seemed feasible for a 470-pound man: the exercise bike. He got himself aboard and managed to pedal for five minutes before he had to stop, wheezing and panting and feeling self-conscious. Yet he came back the next day and the next. Soon he could manage 30 minutes on the bike, leaving a bigger sweat puddle on the floor each time. He saw every drop as a blob of fat exiting his body, one tiny step toward his goal.

In those early weeks at the gym, Bruno would often walk past a glass-walled indoor-cycling studio. With its atmosphere of pounding music and lithe bodies pumping away on stationary bikes, the room seemed off-limits to someone like him. It took Bruno another week or two to work up the courage to go in for a class, and he instinctively skulked to a bike in the back corner. The instructor, a fit blonde, came over and greeted him. “I’m Beth,” she said, smiling. “Let’s help you get set up.”

Beth Sanborn was a local triathlete who was training for her second Ironman. She helped keep Bruno motivated as he suffered through the 45-minute class, puffing and churning away. He soon became a regular, showing up six times a week. He got to know everyone, and his relentlessly upbeat personality made him a favorite of the instructors. “I had never seen anybody that big,” Sanborn recalls. “He was the hardest-working person in my class. A man on a mission—he really was.”

Bruno often rode until his shorts were bloody, because they don’t make bike shorts (or seats) that fit people who weigh more than 400 pounds. “It wasn’t pretty,” he says. By September, he decided to take on an even bigger challenge: he would try a 100-mile bike ride, a century to combat MS, which his wife Susan had been diagnosed with a few years previously. He hadn’t been on a real bike in 20 years, but he dragged his old Trek out of the basement, dusted it off, and took it to the shop.

He made it all the way to mile 63, stopping on a slight incline when the road seemed like it was starting to wobble and melt. He felt pains in his chest, and, ominously, he had stopped sweating, a possible sign of heatstroke. The sag wagon pulled up and the event staff rushed to his aid, grabbing his arms to keep him from collapsing. “The thought actually went through my mind that if I die here on the road,” Bruno told me, “at least I’m doing something to change my life.”

Without knowing it, Phil had kicked off a war for control of his body, with fat on one side and muscle on the other. Just as fat was long thought to be neutral, muscle was considered a passive organ that did what the brain told it to do. But muscle is now known to be one of the most dynamic systems in the body; when it contracts, it undergoes huge changes at the cellular level. And its mortal enemy is fat.

In any sedentary, inactive person—including people who aren’t actually obese—fat invades the muscles, slipping in between muscle fibers like the marbling in Wagyu beef. Worse, fat infiltrates individual muscle cells in the form of lipid droplets that make the cells sluggish. According to Gerald Shulman, M.D., a prominent diabetes researcher at Yale, these pools of fat, which occur in both the liver and the muscles, block a key step in the conversion of glucose, leading to the insulin resistance that’s a prerequisite for diabetes. This explains why some sedentary people of normal weight are still at risk for the disease. “It’s not how much fat we have but how it’s distributed,” Shulman says. “When the fat builds up where it doesn’t belong, in the muscle and liver cells, that’s what leads to Type 2 diabetes.”

On a strictly mechanical level, more fat means less muscle, which means fewer mitochondria, the cellular power plants that are most plentiful in muscle tissue. The majority of fat contains almost no mitochondria. This explains one of the nagging problems with obesity: the more fat you accumulate, the harder it becomes for your body to burn off that stored energy.

With his intense cycling, Bruno was growing new muscle, obviously, and that helped. “The more muscle you have, the more mitochondria you have, so you can burn more fat,” says Iñigo San Millán, an exercise physiologist at the University of Colorado in Denver, who has worked with elite cyclists for two decades. San Millán notes that slow-twitch muscle fibers, the most prominent muscle type in endurance athletes, are far more mitochondria-dense than any other kind. So they’re much more efficient at burning fat.

Second, Bruno’s new muscle tissue was actually changing his body chemistry in ways that science is just beginning to understand.

For decades, researchers suspected that muscle exerted some kind of influence on other organs, starting with the liver, which acts as the body’s fuel depot. When we work out intensely or for long periods, the liver is prompted to send out more glucose, the primary fuel for physical activity. It was long thought that those signals traveled via the nervous system and brain, but experiments in the '90s on patients with spinal paralysis revealed that there had to be some other pathway, because their livers still responded to muscle stimulation, as did their brains. They even experienced runner’s high.

In 2003, biologists Mark Febbraio, from Australia, and Bente Pedersen, of Denmark, figured out that muscle is an endocrine organ, just like fat, and that exercising muscle produces chemical secretions—which they called myokines—that communicate with the rest of the body. As Pedersen puts it: “Skeletal muscle is the organ that counteracts fat.”

Febbraio and Pedersen identified the most common myokine as none other than IL-6, the inflammatory cytokine that’s also produced by excess fat. But when released during exercise, they found, IL-6 actually had beneficial effects, telling the liver to increase the rate of fat oxidation. “When we made this discovery, people really didn’t believe us, because IL-6 was considered a bad actor in many diseases,” says Febbraio, a former professional triathlete. “But the thing is, in exercise it’s actually anti-inflammatory.”

The difference had to do with time. Obese patients tended to have low but constant levels of IL-6, which caused chronic inflammation. When patients exercised, their IL-6 levels would spike, then dissipate over a few hours. The patients who exercised had much lower baseline levels of inflammation.

Since then, dozens of these myokines have been identified. Febbraio believes there could be hundreds more and that they’re largely responsible for the beneficial effects of exercise. They act on bones, the pancreas (which secretes insulin), and the immune system. Researchers think they may also act on muscle itself, promoting growth and healing, and on the brain, triggering the release of derived neurotrophic factor, which heals and protects neurons.

“There’s a growing body of evidence suggesting that healthy muscle may lead to a healthier liver, a healthier gut, a healthier pancreas, and a healthier brain,” says Nathan LeBrasseur, a Mayo Clinic scientist who specializes in muscle tissue.

New research from Canada indicates one way this might work. Mark Tarnopolsky, a scientist at McMaster University in Hamilton, Ontario, has identified six muscle-specific compounds that drive mitochondrial growth in every type of human tissue.

One newly discovered myokine even tries to convert fat itself into an energy-consuming system like muscle. In 2012, a Harvard-based team identified a hormone called irisin, secreted during exercise, that tricks plain, blobby, “white” fat—and even deep visceral fat—into acting like “brown” fat, a far less common form that is dense with mitochondria and burns energy just like muscle does. Bruce Spiegelman, the Harvard scientist who led the team that discovered irisin, is now looking for a drug compound that might trigger its release.

But Febbraio cautions that exercise in a pill is not in the cards. “It’ll never happen, because the benefits of exercise are a multifactor thing,” he says. “You could never design a drug that would replace exercise.”

Just ask Bruno. For him, exercise wound up replacing the drugs.

Fat is stubborn, demanding stuff. Much of the time it’s telling you to eat more, which is one reason why most attempts at dieting are doomed to fail. Our fat wants to keep us fat, and most of us lack the impressive willpower of the legendary Scotsman who somehow managed to stop eating solid food for more than a year.

Known to science only as A.B., this person was 27 years old and weighed 450 pounds when he turned up at a hospital at the University of Dundee in the mid-1960s. With the encouragement of researchers, A.B. began subsisting on nothing but vitamins and brewer’s yeast, and researchers measured his progress regularly. The weight came off, but slowly: he lost less than a pound a day. In the end, he managed to slim down to 180 pounds, but it took him 382 days.

As Bruno kept exercising, he not only lost weight but also felt less hungry. His burning thirst was gone, and his long-suffering knees and hips felt better. he threw himself into his spin classes.

João Correia, a 38-year-old publishing executive from New York City who went through a less extreme version of Bruno’s and A.B.’s drastic slim-downs, says that the process transformed not only his body but his mind. “I had a totally different relationship with food when I was fat,” he says. A pro cyclist in his youth, Correia quit riding in his twenties, moved up the ladder of Manhattan publishing, and ate too many expense-account dinners. By age 30, he’d packed 205 pounds onto his five-eight frame, and he was still always hungry. “My ability to consume food at that weight was huge,” he recalls. “I used to be able to go to a restaurant and have six courses and a bottle or two of wine.”

The reason was a hormone called leptin, which is produced by fat tissue. Ordinarily, leptin tells the brain, “Dude, we’re fat. It’s time to stop eating.” But the brains of obese people often become deaf to leptin, so they don’t get the message.

When Correia started working for a fitness-oriented publisher, he realized he had to do something, so he got back on the bike, doing laps in Central Park before and after work. He cut back on eating, which wasn’t easy at first. Unexpectedly, as Correia’s waistline shrank, so did his appetite. You’d think that, as the fat melted off, his leptin levels would decline, making him hungrier. But research has shown that exercise actually helps restore sensitivity to leptin. So his body knew when it was time to stop eating. “I wasn’t ever hungry,” he says. Within three years, he’d lost so much weight—and gotten so fast on the bike—that he actually turned pro again, riding first in the U.S. for the Bissell team, then in Europe for the high-level (but short-lived) Cervélo Test Team.

Things weren’t quite as easy in Bruno’s case. For one thing, unlike Correia, he’d never been an elite athlete. And while Correia’s body mass index peaked at 31, just above the threshold for obesity, Phil’s BMI had been 58. His immense size meant that he may have been unusually insensitive to leptin and other signals of satiety. Going on a conventional diet was out of the question for him; he’d tried that before.

This time around, he proved himself to be every bit the equal of A.B., though his strategy was different. Rather than starve himself, he started by simply cutting out fried food, fast food, and soda. Instead, he and Susan would cook grilled chicken or fish for dinner with some greens; they snacked on fresh fruit and unsalted almonds rather than potato chips. He also (mostly) said goodbye to lasagna.

“The first 50 pounds melted off,” he says. “But when you’re eating three Quarter Pounders with Cheese at a time, any change is an improvement.” Bruno’s initial goal was just to be able to use his home scale. (At first, he was still so big that he had to go to the grocery store to weigh himself, on the same scales used to weigh food pallets.) But he also loved food, and he would still eat an extra chicken breast at dinner if he felt like it. Better that than a Quarter Pounder. He drew inspiration from motivational figures ranging from Jesus Christ to football coach Tony Dungy.

As he kept exercising, Bruno found that he not only lost weight but also felt less hungry. His burning thirst was gone, too, and his long-suffering knees and hips felt better. He threw himself into his spin classes. “We saw quite a remarkable change,” says Jim Wessely, a spin-class friend who is head of emergency medicine at St. Luke’s Hospital in St. Louis. “When he first came in, he was this huge, morbidly obese guy who could barely spin for more than a few minutes. Now he would really go at it.”

A year after Bruno was diagnosed with Type 2 diabetes, he went back to Dr. Livingston for tests. The doctor was astonished: Bruno’s insulin resistance was gone, and his blood values were almost back to normal. His A1C, which had been 16, was now down to 5.5. Livingston had never seen anyone do that. Bruno no longer needed his medications.

Yet Bruno knew he was far from fixed. Because of his individual metabolism, he’d been primed for weight gain his entire life. He had to fight a constant, escalating battle against his morphological fate. He remained dedicated to him regimen, going to spin class five or six days a week; eventually, he got certified, and he soon became one of the most popular instructors at that branch of Gold’s Gym. Relentlessly positive and a born organizer, he led a regular outdoor group ride on Sundays, and he captained the Golden Flyers, a 100-strong fundraising team for charity rides like the Tour de Cure (for diabetes) and the MS 150. Fitness consumed him. “I’m a financial adviser with Wells Fargo,” he says, “but most people think I’m a spinning instructor with Gold’s Gym.”

In four years, he had lost more than 200 pounds, whittling his body down below 260. He was still big, and he still wasn’t satisfied: he wanted to lose that last 50, to get down to where he’d been in high school. He kept moving, kept riding, knowing he could never stop. “It’s kind of like holding a beach ball under the water,” he told me last winter. “As long as you keep doing what you’re doing, it’s easy. As soon as you quit, then boom—it’ll pop right up.”

And then, last summer, he had to stop. He was walking out to his car after work one day in July when his legs suddenly gave out. He couldn’t stand; they were pretty much paralyzed. He managed to crawl over to a nearby car and haul himself up onto the bumper. With the help of two friendly strangers, he hobbled over to his car and got in. He had just enough sensation in his right leg that he could drive himself home.

Bruno went to the hospital that night, and doctors were mystified. He had a spinal tap, and an MRI, that revealed pinched nerves from inflammation at the base of his spinal cord. The cause was not clear. The doctor gave him steroids for the inflammation but warned that it could be a sign of something much more serious, possibly even fatal.

The inflammation subsided, luckily, but it left Bruno unable to work out, much less teach his spin classes. He skipped the MS ride in September for the first time since 2004. Inevitably, his weight started creeping back up again. By the end of the summer, he’d gained back 60 pounds. And some of the diabetes symptoms had returned.

“My legs feel like they’re filled with sand at times, the extreme thirst and hunger is back, it’s hard to breathe, I have weakness and back pain,” he told me in November. “The intense exercise I had been doing has helped me through this fight so far, but I can feel it fading as more time goes by. I’m frightened, depressed, and just not doing well at all.”

Then he had another setback, and he wound up spending six days in the hospital with heart issues—atrial fibrillation, related to the enlarged heart he’d acquired from all those years when he was heavy. Ironically, a-fib is also known to be a side effect of long-term, intense exercise, particularly in middle-aged (or older) men.

The last time we spoke, in December, Bruno had been placed on more medication, to thin his blood and prevent clotting, and on beta-blockers, to try and regularize his heartbeat. Still, he was determined to make it through his spin class that Saturday, and he surprised himself by riding hard for an hour and 10 minutes. “Everyone welcomed me back with open arms,” he says. “It was awesome.”

It’s been nearly nine years since Phil Bruno shambled into Beth Sanborn’s spin class. “I love telling people the Phil story,” she says. “Just imagine how he must have felt walking into the gym, not even a spin class. I know people who are only 50 pounds overweight, and they think they have to lose weight before setting foot in the gym.”

Since that time, Bruno has lost nearly 250 pounds, and while he’s gained some of it back, he insists that all that cycling has continued to help him, continued to protect him, even as he has backslid a little. Could his health problems be a kind of delayed-reaction result of having been so overweight for so long? That’s not how he chooses to see it. He thinks it would have been worse if he hadn’t walked into Gold’s that day. As he put it recently: “The bright spot in all this craziness is that my working out over the years has saved my life.”

Scientist Bente Pedersen, who helped discover the existence of myokines, would agree. She argues that the most dangerous issue that Bruno and people like him face is not being heavy per se but being sedentary. In papers she defines a “diseasome” of inactivity, a collection of nasty health consequences stemming from lack of exercise—independent of an individual’s body weight.

“It’s much better to be fit and fat,” she says, “than skinny and lazy.”

Bill Gifford wrote about the Lance Armstrong Foundation in February 2012