Born to Be —

Welcome to yet another Theme Week. This week we will be discussing a series of lectures from the Howard Hughes Medical Institute, which hosts an annual series of science lectures, including obesity in 2004. They feature two distinguished speakers: Dr. Ronald Evans and Dr. Jeffrey Friedman (who discovered leptin) in four lectures on the nature of their research. I would highly recommend watching all four, as they are highly informative and interesting. Many thanks to Attrice for sharing this excellent resource!

Something we must constantly remind the dismissive types is that obesity research is in its infancy (as in the belly button stump has yet to fall off). Although we’ve known about the effects of leptin since the 1950s, the hormone itself was only discovered 16 years ago by Dr. Jeffrey Friedman.

Dr. Friedman explains the role leptin plays in appetite and weight management in Lecture 1, but I’ve got the relevant info if you want to watch later. Dr. Friedman explains (PDF):

Now, to illustrate the power of these genes, I’m gonna tell you about a case report of a child in England who was of normal weight at birth but began to develop morbid obesity beginning in infancy. In addition to being overweight, he markedly over-ate, was prediabetic at the age of 4. He weighed 90 pounds with 57% body fat. His 8-year-old cousin was similarly affected, and this young girl weighed 200 pounds, which is what I weigh. Now, a clue that this might have been an unusual cause of obesity came from the fact that the child came from a highly inbred pedigree. A lot of populations don’t discourage first-cousin marriages. So in those cases, rare genetic differences often get expressed with a frequency that’s not seen in the general population. And that was the case in this kid, who was found to be deficient for this hormone leptin. A hormone is a molecule that is released from one area and travels through the body to affect another tissue. And so leptin is a hormone I’m gonna tell you more about, but because it’s a hormone, it could be made in the laboratory and given back to this kid. And let’s see what happens when you give this kid leptin back. He’s gotten taller, lost weight. Fat has fallen, and he’s much less prediabetic than he was. His insulin levels have fallen. In addition, the people who did this work — a colleague in England, Stephen O’Rahilly — gave this kid a test meal before the first leptin injection and gave it to cousins of this child who were similarly affected, and some of these kids ate as many as 2,000 calories at a single meal before they got leptin. That’s about the daily caloric intake of an individual my size, and this kid, at the age of 4, was eating it at one sitting. They give the kid some number of leptin injections, and now he eats the correct amount of calories at that single meal. So what’s driving appetite in this kid is not lifestyle. It’s not willpower. It’s the lack of leptin.

As Dr. Friedman said, this is a rather rare, and extreme, condition. The photographs he shows comparing before and after leptin injections is incredible. But he goes on to explain that there is everyone has a certain level of sensitivity to leptin. Those with low leptin sensitivity have greater appetites and weights. And the intersection of leptin, obesity and arthritis, heart disease, diabetes and inflammation suggests a complicated tapestry of influence.

This is just another piece of the fat puzzle.

More and more, that puzzle is looking like a genetic and evolutionary inevitability. We could no more avoid creating a shift in weight than we could avoid inventing the wheel.

Our nature, as humans, is to progress and progress always has a price. We’ve improved our longevity, so some of us will get Alzheimer’s. We’ve sexually liberated ourselves with contraceptives, so some of us will get STDs. We’ve created food stability (for the most part), cushy office jobs and near universal convenience, so some of us will be fatter.

Some people are fat because they have larger appetites, while others are fat because their mothers were fat and their mothers’ mothers were fat and so on through history. And although there are health risks correlated with obesity, the fact is that 75% of obese people will never get diabetes. And for the other 25%, we know how to treat it.

If exercise isn’t a possibility, or isn’t working, there are drugs that can effectively mitigate Type 2 diabetes. In Lecture 3, Dr. Ronald Evans explains (PDF) how his research into peroxisome proliferator-activated receptor (or PPARs) has helped in the fight against diabetes. First he explains what PPARs do:

So, there are 3 receptors for fatty acids. They’re all very similar to each other. They’re called PPAR’s. And the 3 related receptors are called alpha, gamma, and delta. One feature of the receptors is that they are expressed in different levels in different tissues. And so PPAR-gamma is expressed at particularly high levels in adipose tissue and a few other tissues in the body. PPAR-alpha is expressed at high levels in the liver, and PPAR-delta is widely expressed but particularly high in skeletal muscle.

PPAR-gamma is one of the few master regulators in the body, which means it is necessary for the formation of adipose tissue. If you don’t have the PPAR-gamma receptor, your body cannot create fat tissue. Manipulating this hormone receptor can impact both insulin sensitivity and appetite, which led to multiple discoveries:

Now, in 1995, we discovered that PPAR-gamma can respond to a certain class of drugs … The drugs coming in, which, when it binds, will trigger a conformational change in the receptor … If we give the drug for PPAR-gamma, you can increase the production of adiponectin. So giving the drug causes this increase, and this promotes insulin sensitivity, which is an important feature because big fat cells often lead to insulin resistance. By doing that, this adipose, or fat pad, can be large, and yet the patient or the individual that has this can be insulin-sensitive. Without the drug, they would be insulin-resistant. And so we can use this genetic manipulation to shift the information that’s emanating from the adipose tissue to benefit an individual. But remember, it does not take the fat away. It leaves the adipose tissue there. So you’re not getting any thinner, but you’re having a healthier fat pad.

This suggests a person’s weight and diabetic status can be largely influenced by the functioning of PPAR-gamma, which is genetically determined. Dr. Evans and his team also found that the genetically-determined role of PPAR-gamma could be influenced by drug therapy. This alone is an illuminating discovery. But it is his work in PPAR-delta that gives me pause.

PPAR-delta, as you may recall, is highly expressed in skeletal muscle and influences how we burn energy. Activating PPAR-gamma had such remarkable effects that one might expect similar results when tweaking PPAR-delta. Dr. Evans explains:

The PPAR-delta receptor … is particularly interesting because this is associated with oxidative metabolism. That is, this receptor, instead of promoting fat storage, promotes fat burning by increasing the ability of muscle cells and other cells to take in long-chain fatty acids and break them down and convert them into ATP for energy. Now, can we use this receptor as a genetic regulator to help manipulate this pathway? And so, one of the questions is, can we, with Delta Man, sort of like Superman here, can we use the PPAR-delta receptor and a drug or its ligand to rev up metabolism?

So, Dr. Evans and his team work on revving up the PPAR-delta receptors and the results are astonishing. He takes two mice: one that has been trained to run and one with the revved-up PPAR-delta receptor. He puts them both on the treadmill to see how the genetically-engineered runner will compare.

And you can see basically they’re both pretty good runners … So if we go a little bit later into the experiment, here we’re now at an hour and a half — 90 minutes into the experiment. This is the wild type mouse. This is the PPAR-delta revved-up mouse. Aw. That’s… but he did a good job. 90 minutes. [Note: At this point, the wild type mouse has stopped running, but the PPAR-delta mouse continues] … the revved-up PPAR-delta mouse did something rather remarkable. He kept running on that treadmill for another hour — vastly more than we had ever expected in his very first run. So this basically was a genetically engineered long-distance runner. It was an awesome change. Usually in science, we expect changes of 5% or 10% if we’re lucky.

By manipulating the genetic structure of a mouse, they are able to create a long-distance runner who has not had a single day of training. What’s more, when they activated PPAR-delta in obese mice, they had additional startling results:

And this is also an obese mouse. Eats the same amount of food, basically gets the same amount of exercise as his littermate here, but this one has its PPAR-delta metabolism revved up. Now, it’s not normal weight, but it does show you that revving up metabolism in the muscle can cause increased burning of the adipose — the energy stored in the adipose tissue and lower the weight of this animal about 30%— a very substantial weight. And so this is a genetically thin mouse. Even without getting exercise, it’s getting a benefit from the training.

And in this lies our lesson: How your body responds to leptin, how your PPAR-gamma receptors respond, are genetically-influenced, yet can be turned on and off by a series of drugs. We are more and more coming to accept that obesity is hard-wired in many of us.

What we rarely consider, however, is that those people we know who are in perfect health, who run every day, who have high endurance and strength, may also be influenced by genetics. If the genetic influence on PPAR-gamma can nudge some people toward obesity, why couldn’t we say the same for PPAR-delta.

We tend to think of people who are physically strong as being self-controlled, driven and somehow responsible for the entirety of their accomplishments. But without their genetic endowment, without a high-functioning PPAR-delta receptor, would the average triathlete by capable of those same accomplishments? If their bodies weren’t already primed to be highly efficient energy-burning machines, would they have been motivated to push themselves further and harder? How much of their accomplishments would be possible without the evolutionary head-start they may receive from an efficient PPAR-delta system?

These are questions we cannot ignore. They form part of our limited understanding of how the human body processes energy and how those processes impact our physical being. We remind people of the strong genetic influence on weight so they will not allow social messages to cause us to question our worth. Maybe we need to remind people of the strong genetic influence on muscle so they will not allow social messages to cause them to overvalue their worth.