Not only can that explain why treatment is so difficult and results so wildly variable, but it can explain why prevention efforts often fail.

If obesity is many diseases, said Dr. Lee Kaplan, director of the obesity, metabolism and nutrition institute at Massachusetts General Hospital, there can be many paths to the same outcome. It makes as much sense to insist there is one way to prevent all types of obesity — get rid of sugary sodas, clear the stores of junk foods, shun carbohydrates, eat breakfast, get more sleep — as it does to say you can avoid lung cancer by staying out of the sun, a strategy specific to skin cancer.

One focus of research is to figure out how many types of obesity there are — Dr. Kaplan counts 59 so far — and how many genes can contribute.

So far, investigators have found more than 25 genes with such powerful effects that if one is mutated, a person is pretty much guaranteed to become obese, said Dr. Stephen O’Rahilly, head of the department of clinical biochemistry and medicine at Cambridge University

But those genetic disorders are rare. It is more likely that people inherit a collection of genes, each of which predispose them to a small weight gain in the right environment, said Ruth Loos, director of the genetics of obesity and related metabolic traits program at the Icahn School of Medicine at Mount Sinai. Scientists have found more than 300 such altered genes — each may contribute just a few pounds but the effects add up in those who inherit a collection of them, Dr. Loos said.

There are also drugs that, in some people, can cause weight gain. They include medications for psychiatric disorders, some drugs for diabetes, some for seizure disorders, beta blockers to lower blood pressure and slow the heart rate, and steroids to suppress the immune system, for example. People taking them, however, may not realize the drugs are part of their problem. Instead, they blame themselves for a lack of self-control as their weight climbs.

Certain diseases also cause weight gain, Dr. O’Rahilly noted. They include hypothyroidism, Cushing’s syndrome and tumors of the hypothalamus.

To help people find an effective way to lose weight, obesity medicine specialists say they start by asking if there is an obvious cause for a person’s excess weight, like a drug that can be switched for something else. If not, they suggest patients try one thing after another starting with the least invasive option, and hope something works.

“There are 40 therapies I can throw at a patient,” Dr. Kaplan said. “I will try diets and aerobic exercise and sleep enhancement. I have 15 drugs.”

Dr. Caroline Apovian, director of the nutrition and weight management center at Boston Medical Center, said most people can lose weight but keeping it off is the key. For most, she said, finding something that works “is still trial and error.”

Andrea Gardner, a registered nurse who lives in Weymouth, Mass., is in the midst of that process. She has tried one diet after another, losing weight and gaining it back. She is 5 feet 5 inches tall, and her body, she says, seems to want to settle at a weight of about 185 pounds, which is not acceptable to her.

She continues to work with Dr. Apovian, ever hopeful that this time a diet and, she said, willpower, will do the trick.

But about 15 to 20 percent of patients respond to measures short of surgery, with response defined as a change in their body weight that is maintained without constant hunger or cravings. While people seldom end up thin, their permanent weight loss is a proof of principle, showing that treatments can lower the weight the brain forces a person to maintain.

The last resort, for those whose obesity is extreme, is bariatric surgery, which elicits a permanent and substantial weight loss in almost everyone.

In the meantime, there is Dr. Sacks’s challenge.

His study involved 811 overweight and obese adults, randomly assigned to follow one of four diets and undergo behavioral counseling to help them stick to their diets. The diets ranged over the span of what has become popular. Two diets were low in fat but one low-fat diet was high in protein and the other had average amounts of protein. Two others were high in fat and one of those high-fat diets had an average amount of protein while the other was high in protein.

The research was designed to answer the question of whether one diet was any better than another and it provided an answer: None of the diets elicited much weight loss on average, and no diet stood out from the others.

But buried in those averages were the outliers: In every one of the four diet groups were a few superresponders who dropped huge amounts of weight and a few nonresponders who did not lose any. And as soon as his paper on the diets was published, with the conclusion that no diet stood out and none elicited much of a weight loss, he started hearing from people who challenged him.

“People would say, ‘How can you say all these diets have no effect when I lost 100 pounds on diet X?’ Others would say the same thing about the opposite diet.”

Dr. Sacks believes them. He knows people who have lost weight and kept it off with diets, including a colleague in his department. “He lost 30 or 40 pounds in the 1970s and kept it off all these years,” Dr. Sacks said.

But why him and not someone else following the same regimen?

“Beats me,” Dr. Sacks said.

Every obesity medicine specialist has seen it happen — someone repeatedly tried and failed to lose weight and keep it off. It turned out they were trying the wrong thing. Here are some people who finally found a weight-loss plan that worked.

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Connie Anne Phillips’s weight inched up gradually in adulthood and her attempts to control it went nowhere. As publisher and chief revenue officer at Glamour magazine, she was always entertaining clients, hosting them at breakfasts, lunches and dinners. Weight loss seemed an impossibility.

In 2011, she went to Dr. Louis Aronne, an obesity medicine specialist at NewYork-Presbyterian/Weill Cornell Medicine Center in Manhattan. He suggested a weight-loss plan that would allow her to maintain her lifestyle. The key was a low glycemic load diet, choosing foods to keep her blood sugar from spiking.

“I just had to learn to make the right choices,” Ms. Phillips, 51, said.

She learned to eat protein before carbohydrates. It was O.K. that she loves pasta, but now she precedes it with a piece of broiled fish or grilled chicken.

“Now I would never start my day with a glass of juice and a bagel.” Ms. Phillips said. Instead, she has egg whites with vegetables or low-fat Greek yogurt.

Twenty pounds melted away and she has kept them off without effort.

When he arrived for his first appointment with an obesity medicine specialist in April 2014, Scott Goldshine was certain his only hope was bariatric surgery. He had been skinny when he was younger — his nickname was Bones — but around age 30 he began putting on weight and simply could not halt the relentless accumulation of pounds.

Soon he weighed 265 pounds. He is 5 feet 7 inches.

“I was a miserable human being,” Mr. Goldshine, 56, said.

So he scoffed when Dr. Aronne said, “I think I can help you.”

He was — and still is — the general manager at Zabar’s, a famous New York deli, spending his days around food he loves. And his cravings were relentless.

“I couldn’t go behind the bread counter without taking a couple of slices of bread and a couple of rugelach,” he said. But that was only the start. There was the “big fat piece of crumb cake” almost every day. There were the cookies he’d grab from the catering platters. There were the “gigantic sandwiches.”

Customers noticed his weight gain. “They would come up to me and rub my stomach and say, ‘You’re getting fat,’” Mr. Goldshine said.

Dr. Aronne saw something interesting in Mr. Goldshine’s records. He was taking pioglitazone for diabetes, a drug that makes some people gain weight. Dr. Aronne replaced it with Invokana, a diabetes drug that can contribute to weight loss — and Mr. Goldshine lost a small amount. Then Dr. Aronne added a drug that combines bupropion, an antidepressant, and naltrexone, a drug used to combat cravings for drugs like opioids. He chose it, he said, because patients often say it helps turn off constant thoughts of eating.

It worked.

“I pretty much eat my same diet, but so much less,” Mr. Goldshine said.

He lost about 75 pounds, and has kept them off without conscious effort.

For Eric Scarmardo, 53, a manager at a Chicago prescription benefit management firm, the solution to a frustratingly stubborn weight problem turned out to be blindingly simple. But it took him years to discover it.

His problem began when he was 25 and just out of law school, working, he said, “ridiculous hours” for a large Chicago firm, eating without thinking. Within a year, his weight climbed from about 200 pounds to 220 on his 5-foot 10-inch frame. Ten years later, he weighed close to 300 pounds.

He tried, repeatedly, to lose weight with elaborate diet and exercise programs that typically lasted about a week.

Finally, he went to Dr. Robert Kushner, an obesity medicine specialist at Northwestern University’s Feinberg School of Medicine.

“The first message was that all that matters is calories,” Mr. Scarmardo said. Dr. Kushner insisted that Mr. Scarmardo keep a detailed log of what he ate, weighing and measuring every morsel.

“It was difficult at first, but now it has become part of my routine,” Mr. Scarmardo said. He even asks restaurants to weigh his food before serving it to him; most comply.

He lost 42 pounds and has kept them off for two and a half years.

R. C. Binstock, a 58-year-old novelist and technical writer in Cambridge, Mass., has always been heavy. He felt ashamed, accepting others’ judgmental views.

“I am fat because I am weak, I am fat because I am inadequate. I am fat because I am morally flawed,” he castigated himself.

So when he went to Dr. Sriram Machineni at Massachusetts General Hospital in Boston two years ago, he vowed that this would be his last attempt before bariatric surgery.

Dr. Machineni suggested lifestyle modification. Mr. Binstock refused. He was already doing all that and it did not help.

Dr. Machineni moved on to medications, trying one after another. Each time the drug would work at first but then Mr. Binstock’s food cravings returned.

Eventually, Dr. Machineni found a drug combination that had a lasting effect — the diabetes drug metformin, which can have a side effect of weight loss, and lorcaserin, or Belviq, a new weight-loss drug that acts on the brain to control appetite.

Mr. Binstock lost 55 pounds and maintained it.

“I was able to see a food I love and say, ‘I am just not going to have that,’” Mr. Binstock said.

“I will never be ashamed of my body again, ever,” he said.

Most of Dr. Jennifer Kerns’s family was fat. And so was she. Dr. Kerns, 42 — now an obesity medicine specialist at the Veterans Affairs Medical Center in Washington — reached a peak weight of 300 pounds. She knows all too well how hard it is to lose weight and keep it off. Diets would work, but then the weight would come back.

So, in 2006, she tried what she hoped would be the solution to her weight problem; she became a contestant on “The Biggest Loser” reality television show. Her expectation was that with an extreme regimen and the competition, she would get control of her weight. And once she lost the weight, she thought she would keep it off.

“The Biggest Loser” contest certainly helped her lose weight — she dropped 108 pounds — but she was unprepared for how hard it would be to keep those pounds off. At first she thought regular vigorous exercise would do it, but her weight began climbing. Eventually, she discovered a lifestyle program that lets her keep her weight between 155 and 180 pounds — her weight fluctuates because each time she relaxes her guard the pounds return.

The program is centered on what she calls an iron grip on her diet.

Dr. Kerns keeps tempting foods such as desserts and especially anything containing chocolate out of her house. She brings her own breakfast, lunch and snacks to work. She uses an app on her phone to count calories.

“I am hyper-aware of everything I eat,” she said. “It is an active effort.”

She works out vigorously on an elliptical cross-trainer for 30 minutes a day, nine days out of 10. She weighs herself every day.

She just had her first baby, Graham Kerns Marvel, and kept up her routine during pregnancy, exercising, weighing herself every day, and controlling her diet. She only gained 31 pounds.

But it never gets easier.

So why does she do it?

She has seen family members grow extremely obese with uncontrolled diabetes and high blood pressure. By keeping her weight down, she has avoided those problems.

And she knows how harshly obese people are judged in our society.

“Nobody wants to be obese,” Dr. Kerns said.

Elias Elias, president of Griff Technologies in Milton, Mass., thought he knew why he was fat. His life was stressful. To relax, he liked to go out and have a good time, eating and drinking.

His weight problem began 40 years ago as a teenager when he began taking steroids to treat three autoimmune diseases — psoriasis, ulcerative colitis and ankylosing spondylitis, an arthritis of the spine. Steroids are known to cause weight gain. With long-term use, a person’s weight can be permanently reset at a higher level, his doctor, Dr. Lee Kaplan, an obesity medicine specialist at Massachusetts General Hospital said.

New drugs came along, allowing him to stop taking steroids, but the damage was done. His weight kept climbing until it reached 252 pounds. He is 5 feet 9 inches.

He tried dieting, but to no avail. He blamed himself for lacking willpower.

Finally, in 2007, he went to see Dr Kaplan.

Dr. Kaplan prescribed, phentermine, a stimulant.

“It was miraculous,” Mr. Elias said. Suddenly, the drive to eat excessively was no longer there. Pounds began to fall off. In six months his weight dropped to around 190 pounds and stayed there for seven years.

Then, in early 2014, he wondered if he should stop taking the drug. It did not seem to be working any more. His weight had begun climbing. Dr. Kaplan told him the drug still was effective but usually became less so over time. So, to test that theory, Mr. Elias stopped taking it. His weight climbed even higher and settled around 240 pounds.

He thinks he can still lose the weight he gained but, he said, “I lost the motivation.” As he sees it, his personal problems have sapped his zest to control what he eats.

“My success ended up for me being a double-edged sword,” Mr. Elias said. “Now that I know it is doable, I am procrastinating in terms of restarting the focus.”

But Dr. Kaplan said Mr. Elias really needs a different drug. When phentermine was exerting its maximum effect, Mr. Elias ate less no matter what else was going on in his life. In fact, Dr. Kaplan said, it is not really in his power to diet his way back to that low weight and stay there.