What if obesity isn't one disease but a series of diseases like cancer?

Dr. Frank Sacks, a professor of nutrition at Harvard, likes to challenge his audience when he gives lectures on obesity.

“If you want to make a great discovery,” he tells them, figure out this: Why do some people lose 50 pounds on a diet while others on the same diet gain a few pounds?

Then he shows them data from a study he did that found exactly that effect.

Dr. Sacks’s challenge is a question at the center of obesity research today. Two people can have the same amount of excess weight, they can be the same age, the same socioeconomic class, the same race, the same gender. And yet a treatment that works for one will do nothing for the other.

The problem, researchers say, is that obesity and its precursor — being overweight — are not one disease but instead, like cancer, they are many. “You can look at two people with the same amount of excess body weight and they put on the weight for very different reasons,” said Dr. Arya Sharma, medical director of the obesity program at the University of Alberta.

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.

More than 25 genes:

https://www.ncbi.nlm.nih.gov/books/NBK279064/

Finding something that works is still trial and error.

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.”

Zooming out a bit, the data on obesity are screaming "multiple causes" because weight distribution is lognormal.  Because obesity rates have risen recently it's unlikely that many factors are purely genetic.  See

That's good.

Perhaps it's both. Some genes make a person react adversely to some environment conditions.

e.g.

Some genes react to calories. 

Some genes react to carbs. 

Some genes react to sugar. 

And so on.