By ANAHAD O’CONNOR
They are a mystery to researchers: people who are significantly overweight and yet show none of the usual metabolic red flags. Despite their obesity, they have normal cholesterol levels, healthy blood pressure levels and no apparent signs of impending diabetes.
Researchers call them the metabolically healthy obese, and by some estimates they represent as many as a third of all obese adults. Scientists have known very little about them, but new research may shed some light on the cause of their unusual metabolic profile.
A study in the journal Diabetologia has found that compared with their healthier counterparts, people who are obese but metabolically unhealthy have impaired mitochondria, the cellular powerhouses that harvest energy from food, as well as a reduced ability to generate new fat cells.
Unlike fat tissue in healthy obese people, which generates new cells to help store fat as it accumulates, the fat cells of the unhealthy obese swell to their breaking point, straining the cellular machinery and ultimately dying off.
This is accompanied by inflammation, and it leads to ectopic fat accumulation — the shuttling of fat into organs where it does not belong, like the liver, heart and skeletal muscle. A fatty liver frequently coincides with metabolic abnormalities, and studies suggest that it may be one of the causes of insulin resistance, the fundamental defect in Type 2 diabetes.
In the healthy obese, however, the fat tends to remain in the subcutaneous padding just beneath the skin, where it appears to be fairly innocuous.
“The group that doesn’t gain fat in the liver as they get obese seems to avoid inflammation and maintain their metabolic health,” said Dr. Jussi Naukkarinen, a research scientist specializing in internal medicine at the University of Helsinki. “There is a complete difference in how they react to obesity.”
It is clear that obesity is tightly linked to a host of chronic illnesses, among them heart disease, hypertension and Type 2 diabetes. That there are metabolically normal obese adults suggests that there is a way to safely carry excess fat. But to what extent is not clear.
Metabolically healthy obesity is found more frequently among younger adults, as a large study in the journal Diabetes Care demonstrated in August. There is growing evidence that it may be a transition state, and that if followed long enough, some, if not many, people in this category will eventually develop the expected metabolic disturbances.
That study followed several thousand Australians for up to a decade, about 12 percent of whom were initially deemed metabolically healthy obese. “We found that about a third of these people progressed down the road to being metabolically unhealthy,” said Sarah Appleton, a research fellow at the University of Adelaide. “Metabolically healthy obesity may essentially be a transient state.”
But there is evidence that not everyone will progress down that road, or at least not so quickly. In Dr. Naukkarinen’s new study, for example, the obese subjects had become obese at similar ages and remained so for about a decade — yet some showed no metabolic disturbances.
“The metabolically healthy obese individuals are in the minority,” he said. “Most people tend to go along the not so healthy lines. But you do see some who have been obese for a long time and maintain their healthy profile.”
Dr. Naukkarinen and his colleagues have studied obesity for years by focusing on identical twins, allowing them to take into account the influence of genetics, environment and other factors. One idea they had was to study pairs of identical twins in which one twin is obese and the other is not.
After contacting thousands of families in Finland, they came across 16 such pairs of identical adult twins, six male and 10 female. Once they got them into a lab and began testing, half of the obese twins quickly stood out.
“The first thing that popped out was when we looked at the amount of fat stored in their livers,” Dr. Naukkarinen said. “There was a significant difference.”
The 16 pairs were split evenly into two groups. In both, the average weight difference between the siblings was about 40 pounds. But in one group, the obese siblings had higher blood pressure, worse cholesterol levels and poorer measures of blood sugar and insulin production, as well as seven times the amount of fat in their livers. In the other group, the obese twins’ blood work and liver fat was similar to that of their lean twins.
Extensive tests of each person’s fat tissue revealed some other surprises. The healthy obese had 11 percent more adipocytes, or fat cells, in their subcutaneous fat tissue than their normal weight twins. But the unhealthy obese had 8 percent fewer fat cells than their leaner siblings, despite a higher body fat percentage.
The fat cells of the unhealthy obese were larger than those of any other group. They were swollen and riddled with inflammation. The breakdown and mobilization of their fat stores was suppressed, and a closer look showed that their mitochondria were malfunctioning. Their ability to burn fuel and produce adenosine triphosphate, or ATP, the body’s energy currency, was reduced.
Properly functioning mitochondria stimulate the creation of new fat cells, which may explain in part why the unhealthy obese had fat cells that were limited in number and bloated to extremes.
But it’s not clear what happens first. Is inflammation the initial stressor that impairs the mitochondria? Or do the mitochondria malfunction first, leading to inflammation that arrives to clear away the engorged and dying fat cells?
Studies show that the fat tissue of some obese adults can accumulate more immune cells than actual fat cells. Under a microscope, their fat cells are surrounded by white blood cells called macrophages, the dump trucks that engulf and dispose of pathogens and cellular debris.
“If your mitochondria are working poorly, the adipose cells don’t divide properly, and that can lead to cell death,” Dr. Naukkarinen said. “But if you have adipose tissue that is inflamed, the inflammation makes the mitochondria function poorly – it’s toxic to them. So we see a vicious cycle.”
Metabolically healthy obesity may be one side of a vast spectrum. On the other are people who suffer from lipodystrophy, a severe lack of fat cells. People with this disorder are typically gaunt, carrying little or no subcutaneous fat. But they are also extremely insulin resistant, and they tend to have fatty livers and ectopic fat accumulation. There are many people with Type 2 diabetes who are also physically very lean.
It remains to be seen to what extent environment, exercise and genetics determine metabolically healthy obesity. But Dr. Naukkarinen said that anti-inflammatory drugs have been shown to protect mitochondrial function and improve diabetic symptoms and glucose metabolism. And he suspects that heavy alcohol consumption and exposure to high glycemic foods that create spikes in blood glucose and insulin levels, like sugar and white flour, may also play a role.
But more study is needed.
“People haven’t really paid that much attention to metabolically healthy obesity, but I think it can teach us a lot about usual obesity,” he said. “It’s only recently that people studying depression have done happiness studies showing what goes right, and I’m thinking about the metabolically healthy obese phenomenon in the same way.”