Jean-Pierre Després on the Role of Visceral Fat in Metabolic Syndrome

Special Topic of Metabolic Syndrome Interview, December 2011

Jen-Pierre Després

In our Special Topics analysis of Metabolic Syndrome research over the past decade, the scientist whose work ranks at #1 by total papers is Dr. Jean-Pierre Després, with 90 papers cited a total of 2,486 times. His record in Essential Science IndicatorsSM data from Thomson Reuters includes 244 papers, the majority of which are classified under Clinical Medicine and Biology & Biochemistry, cited a total of 7,519 times between January 1, 2001 and August 31, 2011.

Després is currently the Director of Research in Cardiology at the Institute of Cardiology and Pulmonology and Professor in the Department of Kinesiology at the Faculty of Medicine of Université Laval in Quebec City, Quebec, Canada.

BELOW, SCIENCEWATCH.COM CORRESPONDENT GARY TAUBES TALKS WITH DESPRÉS ABOUT HIS HIGHLY CITED WORK AS IT RELATES TO METABOLIC SYNDROME.


SW: Your highly cited research is on the subject of abdominal obesity , or visceral adiposity, and its relationship to heart disease and metabolic syndrome. What got you interested in this initially?

I was a marathon runner and a student in what was then called physical activity sciences. Now it's called kinesthesiology and I was fascinated, because of my training as a marathon runner, by the remarkable adaptation of the human body to regular exercise and endurance activity. But despite the fact that that I was running 100 miles per week, I was never as skinny as some of these marathoners who are just bones and muscle.

That for me was fascinating: when exposed to tremendous amounts of energy expenditure, there is still considerable individual variation in the way the body copes. And some of us can still have spare energy in the form of adipose tissue.

SW: How heavy were you?

I'm normal weight. I'm just not extremely thin like the marathon runners you see at the Olympics. My BMI is something like 24. So back in the beginning of the 1980s, when I was a young man, we started doing adipose tissue biopsies and studying lipid metabolism. I did my Ph.D. studies with Claude Bouchard, who was then at Université Laval in Québec City, Canada, before he became director of the Pennington Biomedical Research Center in Baton Rouge, Louisiana. He was a great mentor.

We first performed these adipose tissue biopsies in marathon runners. One of the studies we did was in ex-obese gentlemen who had lost a considerable amount of weight and who became fairly good marathon runners. They had been obese but now had a BMI in the normal range. We discovered that their fat cells had remarkably shrunk, but they still had a large number of fat cells, making them very prone to regain weight and fat if they ever stopped exercising. That was my entry into this field—studying body composition and the way body fat would adapt to regular vigorous endurance exercise.

"What we initially reported is that if you have too much fat in the abdominal cavity, you have the whole constellation of metabolic abnormalities and an increased risk of diabetes and heart disease. The next question is why is that the case?"

I then did my post-doc at the University of Toronto in an environment far, far away from athletes and studying the effect of exercise. I was in a laboratory studying human adipose tissue physiology, studying the metabolism of lipoproteins and cholesterol in human adipose cells. My mentor there had a collaboration with a heart surgeon from whom we would get adipose tissue samples during the coronary bypass procedures. I was fascinated by the fact that when they were preparing patients for surgery, I would see all these middle-aged men with their tiny legs, no butt, but this round belly. I thought there's something here.

Two studies, both published in the BMJ in 1984, conducted by Swedish investigators—Per Bjorntorp, who became a good friend, and his colleagues—had a huge influence on my career when they reported that waist and hip circumference had a strong relationship with heart disease, completely independent of BMI. Almost at the same time a group of investigators at the University of Osaka published a paper showing that they could measure abdominal fat with great precision using a CT scan.

So this is what I decided to do. I went back to Laval University as a young independent investigator and started a systematic study using CT scans to measure abdominal fat in men, women, young adults, and older adults, and I started publishing papers showing that this correlated with insulin resistance, dyslipidemia, inflammation, and increased risk of coronary heart disease. And this, again, was independent of the BMI, that the amount of fat in the abdomen was the closest correlate to these metabolic abnormalities, this constellation of complications that we now call metabolic syndrome.

SW: Researchers often talk about fat accumulation in the liver as being a cause of metabolic syndrome. Does your research suggest it's all the fat in the abdominal cavity, not just the liver fat?

What we initially reported is that if you have too much fat in the abdominal cavity, you have the whole constellation of metabolic abnormalities and an increased risk of diabetes and heart disease. The next question is why is that the case? As much as we have said in our papers, "watch out for this excess visceral fat; this is a marker of the risk of developing comorbidities," we never suggested it was a direct causal relationship.

So the question is why is this excess visceral fat associated with these metabolic abnormalities? In 2006, I published with my wife, Isabelle Lemieux, a review paper summarizing 20 years of our work describing what the possible scenarios linking excess visceral fat with these metabolic complications could be (Després JP, Lemieux I, "Abdominal obesity and the metabolic syndrome," Nature 444:881-7, 2006).

The first was a hypothesis proposed by Per Bjorntorp that the fat cells in the abdominal cavity release a lot of free fatty acids, and this process is resistant to the anti-lipolytic effect of insulin, the insulin does not adequately shut down the release of fatty acids from these cells as it normally should. So free fatty acids are still coming out of the fat cells despite the fact that patients might have sky-high insulin. Those free fatty acids are drained by the portal vein, and they expose the liver to a high concentration of free fatty acids. The liver incorporates those into triglycerides and tries to pump them out in VLDL particles. And if the liver can't keep up with this flux of free fatty acids, that's when we end up accumulating liver fat.

There's quite a bit of literature showing a rather close correlation between the amount of visceral fat and liver fat. If you have too much fat in your liver, you're in big trouble, because the liver is such a central organ in the regulation of blood glucose and insulin levels, lipoproteins, triglycerides, and so on. The more liver fat, the more deteriorated your overall risk factor profile will be.

So some people have suggested that the connection between visceral fat and metabolic syndrome is all explained by liver fat. That debate is wide open; it's still uncertain whether or not we can completely rule out excess visceral adiposity as a cause. The problem with this free fatty acid model is that there's research showing that in the portal vein, about 80% of the circulating free fatty acids are coming from subcutaneous fat, not visceral fat.

"Most, I'm not saying all, but by far most, individuals with the metabolic syndrome have fat stored in the wrong place, irrespective of their BMI."

SW: And what are the second and third scenarios?

The second scenario is that when adipose tissue is enlarged, it becomes an endocrine organ—the site of production of many inflammatory cytokines along with a decrease in the production of a potentially important adipokine: adiponectin. This means the liver is now exposed to a different cytokine environment, and this could also contribute to induce an insulin resistant state.

The third scenario is my favorite: maybe putting on visceral fat is a marker of the relative inability of subcutaneous fat to act as a protective metabolic sink. So when we're sedentary and have this lousy lifestyle and access to energy-dense food, some of us are able to put on subcutaneous fat and somehow get away without complications, whereas others gain less subcutaneous body fat and become very sick because they store fat at undesired sites such as the liver, the heart, the skeletal muscle, and so on. And there's a lot of data to support this hypothesis.

SW: Can you give us some examples of what these data show?

Where I work we have a group of surgeons who are doing procedures on massively obese patients—some weighing 400 or 500 pounds. Some of these patients are very sick; some have locomotion problems, but some of them, despite their massive obesity, have no risk factors, no features of metabolic syndrome.

Obviously all those patients are undergoing surgical procedures, and a remarkably consistent finding in those massively obese patients is that they don't always have the features of metabolic syndrome. When the surgeons open up their abdominal cavities, they find their subcutaneous fat pads might be six, seven, even eight inches thick, but they have very little visceral fat; their livers are clean. The subcutaneous depot has acted as a vacuum cleaner, sucking up energy and protecting the liver, heart, pancreas, and muscle from storing fat in the wrong places—what we call ectopic fat deposition.

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