My initial research training, which occurred at NIH, was focused on insulin and insulin action and insulin receptors. This goes back to the mid-1970s. So my focus both then, and for quite a number of years after that, was on how insulin works and on so-called insulin resistance. And obesity is certainly one of the two most common states of insulin resistance that exist. So those fields have always been related. If you're interested in insulin resistance, you're interested in obesity and if you're interested in obesity, you're interested in insulin resistance. My earliest focus, and my earliest research success, was in identifying what at the time was a completely novel cause for insulin resistance, some uncommon disorders due in one case to auto-antibodies that bind to the insulin receptor and block them and in another case to mutations in the insulin receptor gene. This was in the late 1980s. About that time I started doing research more directly focused on obesity, on what actually causes obesity.

  Your most-cited paper is the "Role of leptin in the neuroendocrine response to fasting" in Nature in 1996. (382 [6588]: 250-2, 18 July). What prompted you to do that experiment and why is that research so influential?

Let me just back up and give you the context of it. There were two models that were extensively being used in the study of obesity and diabetes: the ob mouse and the db mouse. It was evident from previous studies over many years that both were genetic syndromes, autosomal receptive and two different genes. There was some reason to think that obesity and diabetes might be related to one another in a pathway, but no one knew what the pathway or the genes were. Then Jeff Friedman at Rockefeller reported cloning of the ob gene in Nature. What became evident from that research was that the ob gene encoded a new hormone, leptin, which was primarily made in fat. It was a secreted hormone-like molecule and the ob gene that had this mutation did not make the hormone. The absence of that hormone caused this tremendous syndrome of obesity, over-eating, insulin resistance, and fat accumulation everywhere. Then it was shown that if you took recombinant leptin and gave it back to the mice, it would cure the disease. The animals would start eating regularly; they'd lose the extra weight, etc. Parenthetically, the db mouse was also shown to have a mutation in the leptin receptor, but it doesn’t respond when you give it back leptin. It has high levels of its own leptin but is blind to it.

Now the notion that got raised by Jeff Freidman and then immediately got adopted by everybody was that the physiological function of leptin was to prevent obesity. It seems logical. If you don't have it, you get massively obese. If you give it back, you cure obesity. That is what every single person said in every article that started coming out. My lab was one of the first, along with Friedman's, to show that if you looked at a more typical population of obese animals—and other labs did this with humans—you found high levels of leptin and yet they were still obese. This fit very nicely with my previous interest in insulin resistance. I started talking about the concept of leptin resistance. A lot of obese animals and a lot of obese humans seemed to have something called leptin resistance. So what was leptin really doing? Was it "designed" evolutionarily as an anti-obesity hormone? Those were the key questions.

To make a long story short, I had the idea that people may have been missing the boat as to what this molecule was really doing most of the time. The idea I had was that maybe it was not really there to prevent obesity; that's not its primary evolutionary function. Maybe its primary function is to signal the opposite, that there's inadequate energy. The way it was decided was to look at two things: one was to see if the levels quickly went down when we starved animals. It was an easy enough experiment. And we showed it did. Then we designed an experiment with Rex Ahima, who was then an endocrinology fellow with me, to test the hypothesis that the fall of leptin that occurs when food is restricted in an animal is actually a powerful signal to the brain for all the things that we know start to change when you starve an animal. So we did the experiment of taking normal mice, food restricting them for, say, 48 hours, which causes a lot of major changes in hormone levels, reproductive activity if they're females, and of course hunger, and we did that with or without replacing their leptin, to see if keeping their leptin levels up prevents all these changes. That's all we did. And the answer was that the falling of leptin from normal low level in a normal animal is the dominant factor that tells your brain that you're starving. So the title was "The role of leptin in the neuroendocrine response to fasting." What we said at the end of that paper was that maybe it is not true that evolution utilized this hormone to prevent obesity and, in fact, it makes no evolutionary sense to prevent obesity. Starvation was always a much greater threat than obesity. You would think it would be a disadvantage to survival to always be lean, even if there's a lot of food available. Because if there's then a famine you're the first to die. Having some fat stores would make you more likely to survive. So we argued that it never made sense that the role of leptin was to prevent obesity, rather the role was to signal the switch from a fed to a starved state. But if you don’t make enough leptin, the brain always thinks its starving and if there's enough food around, you get obese. And that's an entirely different story.

  Were you surprised by the article's impact?

Not at all. I absolutely knew it was going to have enormous impact. It was actually a very simple experiment. One of the easiest that I've ever done. From the moment I thought of it, I believed it would have a lot of impact, or at least it would if I got it done before somebody else did it. Most people just weren't thinking about it that way. And now that paper is very influential because it is part of the story of leptin. Almost everybody who thinks about the field and writes a paper about the discovery of leptin, somewhere along the line makes a comment that the role of leptin could be this, or it could be that…

In some sense, I always viewed myself as being primed for this work. I'd been interested in understanding the molecular basis for obesity. I knew the field of obesity and diabetes fairly well and I had even made some efforts for several years before the discovery of the ob gene to try to find a molecule like leptin. I was already thinking about it very actively and doing some experiments to identify it. When it was identified by Jeff Friedman, from the minute I heard about it, I knew I would be working on that subject. I knew I had the ability to think clearly about it and do the right experiments. The challenge was that now everybody and their grandmother started working on this hormone, so it was extremely competitive. The challenge was whether I had sufficient insight to make a difference or whether we would just be run over by the 200 other laboratories and 10 other companies trying to understand this molecule. It would have been very easy to say, "no, let someone else do it." And how effective could we be, starting six months or a year behind the people who made the original discovery? On the other hand, people often overestimate those kinds of problems. If you have some good ideas, the best idea is to just go for it.

  Since your 1996 paper, where has obesity research gone?

Well, a lot has happened. First of all, there have been many, many more studies supporting the idea that the main action of leptin is to signal the switch from a fed to starved state. And the endocrine effects of leptin are now being far more widely demonstrated. For example, the role of leptin in reproduction is now pretty well accepted, and that is a very, very active field to pursue. The other thing that is an offshoot of this, and where we have been very much engaged as well, is the question of what actually causes the leptin resistance that keeps leptin from preventing obesity. We've been pretty active in that area, identifying some potential molecules that are in the brain and that limit the action of leptin. We identified a molecule called SOCS3, which is receiving a lot of attention as a potential mediator of leptin resistance.

I have another observation in the obesity field that I think will be really big. It will be published in Science in a few weeks. It is a direct outflow of the leptin research but is going to be a big story and is going to get a lot of attention. I'll give you two or three different short versions of the story and then try to bring them all together. The actual paper reports on a phenotype of a new mouse genetic model we created. The claim coming from the paper is that we have shown that the activity of a particular enzyme in fat tissue could explain a lot of the syndrome X, visceral obesity syndrome—a combination of relative excess of fat accumulation in the abdomen, diabetes, insulin resistance, hyperlipidemia in the blood, hypertension, those kinds of things. So the enzyme is known as 11HSD1. The second story is Cushing Syndrome. That's a syndrome where the individual has too much of the hormone cortisol, from the adrenal cortex. There's accumulation of fat, especially in the abdomen, a high likelihood of developing diabetes, insulin resistance, and a high frequency of high blood pressure and high lipids in the blood. Those are very common features of Cushing's Syndrome. Because that's the known cause of those features, and since millions and millions of people have diabetes, and some increase in the fat in abdomen, and hypertension, and all the rest, people wondered for years if there is an increased production of cortisol in typical obesity syndromes. And, in general, the answer to that is no. There are not high levels.

So how does that relate to this story? Because it's become apparent from work over the past 10 years in a variety of labs that this enzyme, 11HDS1, is expressed in different tissues and it takes an inactive version of cortisol and makes it active again, but only inside the cell, where it’s present. So it actually locally produces an excess of cortisol, without necessarily giving any evidence of that in the blood. A number of different, fairly weak lines of evidence, suggested to several people, and to me in particular, that this could be a mechanism to explain obesity. If this enzyme were overactive in fat, maybe you could have a form of obesity, diabetes, and everything else that would be due to this local overproduction of cortisol. So we decided to test it by making a mouse that would overproduce this enzyme.

We made the mouse and what turns out to be really exciting is it has an unbelievable phenotype from the point of view of understanding this set of disorders. The mouse did what I was hoping it would do. On the one hand, it has increased activity of this enzyme in fat. On the other, it develops obesity, an accumulation of fat predominantly in the abdomen. It develops diabetes and insulin resistance. It develops high triglycerides. It eats more than normal mice and it gets hypertension, although that's not in the paper. What it says is if you cause an increased production of this hormone in fat, that’s enough to give you this whole set of features present in maybe 20% or 25% of the U.S. population. What makes it especially exciting, and the reason why it's in Science is that about six months ago, Brian Walker's group in Edinburgh measured this enzyme in the fat of obese people and found it increased about four-fold. The more obese, the higher the activity. And it was only increased in fat, as far as they could measure. So they did the human study. If you take their study and put it together with our mouse, it could very plausibly make the case that however it comes about, the increased activity of this enzyme in fat may be enough to cause obesity, hypertension, diabetes and all the rest.

That's essentially what the story is and it makes a very good drug target, because inhibiting enzymes is what pharmaceutical companies love to do. I think it's going to be quite a story. I really believe that this is a major cause of a very prevalent disease.

Dr. Jeffrey S. Flier
Beth Israel Deaconess Medical Center
School of Medicine
Harvard University
Boston, MA, USA