Skinny, but with the health hallmarks of obesity
Claire Walker Johnson was a medical mystery. No matter how much she ate, she never gained weight.
And yet Johnson, with a long narrow face, had the conditions many obese people develop – Type 2 diabetes, high blood pressure, high cholesterol and, most strikingly, a liver buried in fat.
She and a very small group of very thin people like her have given scientists surprising clues to one of the most important questions about obesity: Why do fat people often develop serious and sometimes life-threatening medical conditions?
The answer, it turns out, has little to do with the fat itself. It’s about each person’s ability to store it. With that understanding, scientists are now working on drug treatments to protect people from excess unstored fat and spare them from dire medical conditions.
The need is clear. One in four adults worldwide have at least three conditions associated with obesity such as diabetes, high cholesterol and high blood pressure – a combination of disorders that doubles their risk of heart attacks and strokes. In addition, 2 to 3 per cent of adults in America, or at least 5 million people, have a grave accumulation of fat in their livers caused by obesity that can lead to liver failure.
The detective work that led to this new scientific understanding of fat began with a small group of scientists curious about a disorder that can be caused by a gene mutation so rare it is estimated to affect just one in 10 million people, including, it turned out, Johnson.
For much of her life, Johnson, 55, had no idea anything was amiss. Yes, she was very thin and always ravenous, but in Jamaica, where she was born, many children were skinny, she says, and no one thought much of it. She seemed healthy, and she developed normally through adolescence.
After coming to the United States as a college student, she saw a doctor for some bumps on her arms and was stunned to learn that they were cholesterol crystallising from her blood. Her cholesterol level was sky high.
Further exams revealed that she had other problems fat people can develop – a huge fatty liver, ovarian cysts, extraordinarily high levels of triglycerides.
Johnson’s doctor was baffled. The usual instructions to patients to lose weight made no sense in this case. “He said, ‘I don’t think I can help you,'” she recalled.
She ended up in the office of an endocrinologist, Dr Maria New, who also was stumped but determined to find answers. She measured Johnson: 170 centimetres. She weighed her: 54 kilograms.
New spent years asking specialists at every medical conference she attended about Johnson. One day in 1996, she was giving a lecture at the National Institutes of Health and posed her usual query: Did anyone know what might be wrong with her skinny patient?
Dr Simeon Taylor, who was chief of the diabetes branch at the National Institute of Diabetes and Digestive and Kidney Diseases, popped up from his chair. He had seen several patients like Johnson. They have lipodystrophy, he said, a rare genetic disorder that is characterised by an abnormal lack of fatty tissue.
Taylor and his colleagues had been studying people with the disorder “as a curiosity,” he told New. He was interested in insulin resistance, the cause of Type 2 diabetes, and had assumed it resulted from obesity. But people with lipodystrophy had the most severe insulin resistance he had ever seen, and they were far from obese.
He was hoping to start a study with a new drug, a synthetic version of a hormone called leptin, that might help the patients. The study began in 2000 with Johnson as one of its first participants.
Leptin is released by fat cells and travels through the blood to the brain. The more fat on a person’s body, the more leptin is released. When fat levels are low, leptin levels in the brain are low, and the brain responds by increasing the person’s appetite, prompting the person to eat and gain weight. For someone like Johnson, who has almost no fat cells to signal the brain, the brain gets almost no leptin. To the brain, it seems as if she is starving. As a result, she receives continuous signals to eat.
With leptin treatment, Johnson’s brain was tricked into responding as though she had abundant fat. Her insatiable hunger vanished. Fat disappeared from her liver, her blood glucose became normal, and so did her cholesterol and triglyceride levels.
But why did she and other lipodystrophy patients have these conditions in the first place, and why did they vanish? What was going on?
A couple of studies involving mice produced some clues. Dr Marc Reitman, chief of the diabetes, endocrinology, and obesity branch at the National Institute of Diabetes and Digestive and Kidney Diseases and his colleague, Dr Charles Vinson, of the National Cancer Institute, genetically engineered mice to have lipodystrophy. The mice, like Johnson, had almost no fat tissue. And like her, they developed all of the conditions associated with obesity.
What would happen, the researchers asked, if the mice had a bit more fat tissue?
They transplanted fat tissue into the rodents, and two weeks later, the mice had normal levels of glucose, insulin and triglycerides. Their livers and muscles went back to normal, too.
If that worked, the scientists wondered, could a limitless amount of fat tissue prevent the syndrome, even if copious amounts of fat were stored in that tissue?
Philipp E. Scherer, director of the Touchstone Diabetes Center at the University of Texas Southwestern Medical Center in Dallas, and his colleagues tested the idea. They engineered mice that could make an almost limitless amount of fat tissue. As a result, there was no end to the amount of fat the animals could store. They were, Scherer said, “the fattest mice under the sun, the mouse equivalent of an 360 kilogram human being.”
The fat mice were metabolically normal.
Now, with years of research, the picture has become clear. And so has a new view of the role of fat itself in causing the medical problems of obesity.
At the heart of all these conditions and what is known as “metabolic syndrome,” or having at least three of the conditions associated with obesity, is an inadequate ability to store fat. (Dr C. Ronald Kahn, chief academic officer of the Joslin Diabetes Clinic, said two German physicians called the syndrome “metabolic” nearly 40 years ago. Conditions like elevated cholesterol, diabetes and even high blood pressure appear to be linked through disruptions in metabolism, in this case the abnormal storage of kilojoules.)
The body turns excess food into fat and tries to store it in fat tissue. If there is not enough fat tissue, the fat is stuffed into other organs, like the liver and the heart, as well as the muscles and the pancreas. There it poisons the body, causing metabolic syndrome.
Fat people develop metabolic disorders because their brain is driving them to eat more food than their bodies can store as fat. Their fat tissue has reached its limit. People with lipodystrophy have so little fat tissue that they, too, cannot store the fat their body makes to store extra kilojoules from the food they eat.
This is also why some people find that their metabolic disorders improve with just a small weight loss – they are eating less and their fat tissue can respond properly.
“People traditionally thought of adipose tissue as this inert storage, this white amorphous blob,” said Dr Sam Virtue of the University of Cambridge. In fact, he said, “it is a very dynamic organ.”
It also explains why 10 to 20 per cent of obese people never develop metabolic disorders, Scherer said. These healthy obese are like his fat mice, with an unusual ability to expand their fat tissue to store kilojoules.
Researchers have moved on to the next phase of the investigation, trying to identify the poison in fat that is causing all these problems and find a way to block it.
At least two chemicals seem to be involved.
Dr Gerald I. Shulman, a Yale professor of medicine and co-director of the Diabetes Research Center there, and an investigator at the Howard Hughes Medical Institute, has focused on diacylglycerol, produced from fatty acids – made from the food a person eats – and deposited in places like the muscles and liver instead of fat tissue. With diacylglycerol, Shulman found, insulin cannot signal cells. The result is insulin resistance and Type 2 diabetes.
“Diacylglycerol is the culprit,” he says. One sure way to get rid of it in liver and muscle cells is to lose weight – to stop providing the body with more calories than its fat tissue can handle, he notes.
That is not so easy. “Every patient I see, I say, ‘Let’s lose some weight and increase activity.’ They all nod their heads. ‘That’s a great idea.’ Maybe one in 100 does it, and even when they are successful, we know how easy it is to gain the weight back.”
Shulman is exploring another route, developing benign new variants of a toxic drug that he hopes will be safe and will reduce levels of fat and inflammation in the liver. The drug, dinitrophenol, was once widely used as an over-the counter medication for weight loss, but the Food and Drug Administration took it off the market in 1938 after a few people taking it dropped dead from severely high body temperatures.
He and his colleagues have modified dinitrophenol so, at least in rats, it does not raise body temperature or cause weight loss. But it lowers diacylglycerol levels in the liver and cures Type 2 diabetes and nonalcoholic fatty liver disease, and other metabolic problems associated with obesity.
The problem will be developing it for humans. Would people want to be in a clinical trial using a variant of a drug that originally had potentially lethal side effects?
“This is a proof of concept,” Shulman says. “I do think this is a way forward.”
Others are focusing on another class of compounds, called ceramides. Scherer, who is studying them, says they are produced from fat floating in the blood and are unable to get into fat tissue for storage or degradation. They, too, cause insulin resistance. Ceramides can also kill cells if their levels become high and can bring on inflammatory responses. And inflammation, Scherer adds, is a hallmark of obesity.
He and others are looking for the best drugs to stanch the activity of enzymes used to make ceramides. Like Shulman, he finds that he can show that his idea works in mice. But, he says, “that’s easy to do in a mouse.”
All of this raises a provocative question. “It is so accepted that obesity is bad for you, but why is it bad for you?” Virtue says. “If I put a 20 kilogram weight on your back and asked you to walk around all day, you would be a superhealthy person.”
And that, says Dr Rudolph Leibel of Columbia University, is the beauty of the work on lipodystrophy. People like Johnson have shown a pathway that leads to the diseases of obesity.
“The first step toward curing it is to know why,” Leibel says.
New York Times
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