The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Ever wondered if loss of weight causes a reduction in the number of your fat cells? Wouldn’t it be wonderful if that was true? You go on a diet, you lose weight and a bunch of cells, and you’d never gain weight again. Except it ain’t true, as anybody who went on a diet knows; unless you stick with your diet forever you will gain back the weight you had lost. Why is that?

Your fat cell allowance

In theory,there are two ways you can increase your body fat: you can increase the number of fat cells in the body, and you can store more fat in each cell. The second way, increase of the fat content per cell, has been amply documented; the reason we have so much evidence for that mode of weight gain is that it is quite easy to document. All that needs to be done is take biopsies of adipose tissue before the and during the weight gain and measure the fat content. And if you want to really nail it: take an additional biopsy after a weight loss diet, and document the drop in lipid content.

But what about the number of fat cells? That’s much tougher to measure, for obvious reasons: you can’t do a total body fat cell count. Or can you?

In animal studies, this question can be addressed by labelling DNA nucleotides with radioactive isotopes such as ¹⁴C. Differentiated fat cells do not divide, and so radioisotopes, incorporated in their DNA in the last round of division before differentiation, remain there throughout the cells' life. The time of radiolabel incorporation, is therefore the 'birth date' of these cells. But the potential toxicity of radioisotopes means that such studies cannot be performed in humans.

Kirsty Spalding and her colleagues at the Karolinska Institute in Stockholm cleverly thought of the next-best option. Atmospheric levels of ¹⁴C have remained relatively constant for centuries, with the only major increase occurring between 1955 and 1963, when nuclear bombs were being tested above ground. A chain of reactions ensures that, at any given time, the radioisotope content of human DNA matches that of the atmosphere. The authors could thus follow fat-cell dynamics in individuals born around 1955–63.

Spalding et al studied the dynamics of fat-cell number in some 700 adults, both lean and obese, and combined their data with previous observations in children and adolescents.

As the results show, fat cells have a high turnover: new cells are continually being born to replace their dead predecessors. The average age of a fat cell seems to be about 10 years in both lean and obese individuals, and the number of fat cells as a proportion of all cells remains constant in each weight group. But the total number of new fat cells was higher in obese subjects, suggesting that they are replenishing an existing larger pool.

What’s the take home lesson for lean people? and for obese people?

Do the lean among us need to worry about our diet if we have fewer fat cells? Yes, we do: our fewer fat cells can still store large amounts of fat. Also, can obese people do anything about their weight? After all, they've already accumulated a large pool of fat cells in childhood and adolescence? Again, the answer is yes. Again, the answer is yes. They can still reduce the volume, if not the number, of their fat cells. But there is another tantalizing message here: researchers should uncover the mechanisms underlying fat-cell turnover. If they do, one could conceivably slow down the replenishment of fat cells that came to the end of their ten-year life span. End result: progressively lower fat cell mass. This is still not a panacea; as we know from studies of people who had undergone liposuction--they slowly regain their previous weight by storing more fat in the remainig cells.

Liposuction: it's futile, lady.

Oh well, pass the fois gras!

By Dov Michaeli MD, Ph.D

It is a well-known phenomenon: people under stress hit the fridge, and gorge on candy and fatty food. A gallon of ice scream in one sitting is not unheard of. But people who think deeply about such things asked themselves: why don’t they (people under stress) gorge on veggies? And what is the nature of the connection between stress and obesity? Is it simply overeating equalsobesity, or is there a deeper connection, involving the brain? After all, stress is a mind thing.

The physiology of acute stress

Almost every physiological action in our body is controlled by two systems: the autonomic nervous system, and the endocrine system.

The autonomic nervous system has this name because it is, well, autonomic: it marches to its own drum, if you will, independently of our whims, wishes or commands. This system is made up of two sub-systems: the sympathetic and the parasympathetic. Basically, they are the Yin and Yang of the autonomic nervous system: the sympathetic nerves secrete noradrenaline, a close relative of adrenaline, and it does everything you’d expect it to do: it accelerates the heart rate, increases blood pressure, in short: it readies the body to react to acute stress situations. My favorite example: you spot a lion coming at you. You want to supply ample blood to your muscles so you can run for your life, or if you are foolish enough, fight the lion; hence the increase in heart rate and blood pressure. The parasympathetic system secretes the neurotransmitter acetyl choline , and it has exactly the opposite action: it slows down the heart and reduces blood pressure.

The endocrine system reacts to stress by releasing two ‘stress hormones’: cortisol from the brain and adrenaline from the adrenal gland. Their action is similar to that of the sympathetic nervous system: increase blood pressure and heart rate.

The other type of stress

So far so good; but how does increased heart rate cause obesity? The answer is: it doesn’t. What I just described is the response to acute stress, and our bodies are well-adapted to handle it. But modern life added another type of stress: chronic stress. And here, a peptide, called neuropeptide Y, or NPY, comes into play. Its existence has been known for several years, but its function was largely unknown. It is expressed throughout the brain, but is especially abundant in circuits that regulate feeding and response to stress. Not surprisingly, like many other brain hormones, it is also secreted in tissues outside the brain that are involved in metabolism; it is secreted by sympathetic nerve endings in adipose tissue. Its function there has only recently been defined by Kuo and his coworkers. It increases adipogenesis (formation of fat tissue) by triggering both the formation of new adipocytes (fat cells) from immature preadipocytes, and by increasing the blood supply to the adipose tissue by formation of new blood vessels (a process called angiogenesis). Even more intriguing: the new fat tissue was not formed just anywhere in the body; it was formed in the abdomen, and specifically around the internal organs of the abdomen. This is exactly the fat distribution that is implicated in the genesis of metabolic syndrome. And to clinch the case: it does it only under severe chronic stress conditions. When mice were subjected to 2 threatening and severe chronic stress protocols, they secreted NPY; when they were subjected to non-threatening mild stress—no NPY. In biological experiments demonstration of a relationship between the “dose” (e.g. severity of the chronic stress) and “response” (e.g. secretion of the peptide), lends credibility to the observation, simply because in biology almost everything is dose-dependent.

Why do we prefer sweets and fats?

The mice in the experiment secreted NPY only if allowed to eat fatty or sugary food. Regular mouse chow did not support secretion of the hormone even under severe chronic stress conditions. We know that high calorie food triggers the reward circuits in the brain. In fact, chronic feeding of high calorie foods activates all the circuits and brain centers that are involved in addiction. That, in turn, induces more eating, which increases the degree of addiction, which… you get the drift. Bottom line: obesity.

The details of the connection between secretion of NPY and high calorie food still need to be worked out. Why didn’t regular, low calorie food have the same effect? What are the specific neural circuits involved in this calorie/reward/peptide axis of evil? What is the mechanism for the specific accumulation of fat around internal organs? Will withdrawal of high-calorie food result in reversal of the accumulation of fat back to normal?

Obviously, many unanswered questioned are triggered by this research. But this is the hallmark of good science: every answer raises many more questions.

In summary

NPY is the link between stress and obesity. Its action:

• Secreted from the sympathetic nervous system only under conditions of chronic severe stress
• Increases adipogenesis by triggering adipocytes formation from preadipocytes, and by increasing blood supply to the adipose tissue
• Secreted only when high calorie diet is available
• Involves the activation of reward circuits in the brain
• And last but not least, it induced a state of metabolic syndrome (obesity, insulin resistance) in the experimental mice.

What is the relevance of this research to human obesity/metabolic syndrome?

Obviously, this phenomenon needs to be demonstrated in humans. Demonstration that NPY levels are markedly higher in chronically-stressed individuals will be a big step forward. Inhibition of secretion of NPY through drugs or stress reduction techniques will add weight to the hypothesis.

The big prize: demonstration of weight reduction through reduction of NPY secretion will be a boon to us and to our strained health care budget.

Here is a thought that may have occurred to you: can our increasingly stressful lifestyle be partly responsible for the obesity/metabolic syndrome epidemic?

Another thought: rather than wait for the results of these experiments to yield the ultimate proof, why not toss out all the sweets and high calorie foods, and stock the fridge with “good for you” veggies? No activation of the reward system in your brain=no NPY secretion. Not very appetizing solution, I know. I’d rather wait for the results of the human experiments, and then decide.

Epilogue

My estimate is that to carry out the required experiments in humans would cost about $10-20M. To develop and clinically test an NPY inhibitory drug could cost anywhere from $50-100M. Can the health care mavens quickly calculate what would be the ROI (return on investment) on this sum?

Yesterday’s New York Times ( May 8, 2007 ) carried a front page article by one of the paper’s premier science reporters, Gina Kolata. The article, titled “genes take charge, and diets fall by the wayside”, is an excerpt of her newly published book “Rethinking thin: the new science of weight loss- and the myths and realities of weight loss”. In the article she reviews the succession of studies started in the late 1950’s by Dr Jules Hirsch at Rockefeller University , which culminated in recent studies demonstrating conclusively that the tendency to weight gain and obesity is genetically determined. Ms. Kolata describes the heartbreak of dieting, a constant struggle of losing weight, trying to maintain, gaining, dieting again, and so on and so on. Psychological testing showed the toll this struggle can take; people are perpetually unhappy, many are chronically depressed, some are suicidal.

One of the major conclusions Kolata cites is that each body has a metabolic “comfort zone”, and dieting to go below this zone is painful, metabolically unsound, and essentially futile.

I admit I haven’t read the book yet, but if the excerpt reflects the message of the book, I strongly disagree.

Why?

For several reasons:

· Yes, a metabolic range specific to each body makes a lot of intuitive sense. But to accept it we need to see the genetic/molecular/physiological mechanisms. The evidence is still not in. Having been around the block a few times, I never cease to marvel at nature outsmarting us, and upending our ‘no brainers’ and ‘slam dunks’.

· The fact that genes control our metabolism does not mean that they are the sole players. Genes interact with the environment, and the outcome of this interaction is all important. The old debate of nature vs. nurture set up a false choice; nature and nurture operate together in biology. The best example is diabetes type 2. An individual may have the genes that predispose to this disease. But it will be expressed clinically only if that individual overeats and exceeds a certain BMI.

· The most obvious evidence that genes are not the final word in weight regulation is the recent obesity epidemic. If  "obesity genes",which undoubtedly have been with us for eons, were such an all-controlling factor, why is it that only in the last few years did this epidemic break out? The answer is well-known: we take in a lot more calories, and we exercise a lot less. Yes, the genes were there all along, but they were not expressed.

I believe that research into the genetic basis of obesity and diabetes is absolutely essential. But it should not become an excuse for the fatalistic attitude of “it’s beyond my control”. Counteracting and ovecoming the genetic dictate may be unpleasant, tough, exasperating—but it beats the alternative.

Dov Michaeli MD, Ph.D

The April 12, 2007 online edition of Science (www.sciencemag.org/cgi/contrent/abstract), has important news from the field of obesity/diabetes type 2 research.

Is FTO the culprit?

FTO is an obscure gene that was discovered in mice who were born with fused toes (hence the name), and since that earthshaking discovery nobody bothered to study it, or find out what its function is, or in which pathway it participates.  In other words, the gene is, well, totally obscure.

And so it lay dormant until a group of scientists from nine institutions in Britain and one in Finland examined the genomes of 38,750 adults and children. Lo and behold, FTO stood out like a sore thumb (or toe)—people who had 2 copies (alleles) of a variant (or mutation) of the gene were 67% likelier to have a BMI of 30 or higher, and the ones who had only one allele of the mutation had a 37% likelihood of being obese (BMI of 30 and higher). Furthermore, the fat distribution was interesting: the gene was associated with both higher weight (regardless of differences in height) as well as wider waists and thicker concentrations of fat mass. These parameters are associated with increased incidence of heart disease and diabetes type 2.

What to make of it?

Before we shout Hallelujah, let’s examine it more carefully:

•  The study is indeed credible; a large sample size, reputable scientists in excellent medical institutions. But I can recall at least 4 other genes that were touted as the “obesity genes”, and later turned out to be totally unrelated. The science was good, but the field of genome-wide analysis is still in relative infancy, and interpretation is rife with pitfalls.
• Even if further studies corroborate FTO as a culprit in the heartbreak of obesity, it is unlikely to be the only one. Obesity and diabetes type 2 are multigenic diseases; and the interaction between them will add even more complexity to the picture.

The promise

But if FTO turns out to be the real thing, then several benefits will come out of this research:

1. A diagnostic test can be developed quite rapidly, to alert people who are at increased risk of metabolic syndrome.

2. Identifying the function of FTO will allow the development of drugs that will counteract the effects of the mutated gene.

Can I then go and pig out?

Alas, no. First, development of such a drug will take a minimum of 10 years, more likely even longer.

But even more important: genetics is only part of the story; the environment (read lifestyle) is just as important. Even if you don’t have the genes for obesity—abuse your body long enough, and your girth will tell all.

What to do?

The answer to this question is quite simple: eat less, exercise more. Regardless of genetics—it works! In some people a lot slower, a lot more painful; in others (whom we all envy) it's  “no sweat”. But barring some rare metabolic diseases, it is within our control. No excuses!

Dov Michaeli, MD, Ph.D

Animal studies suggest that certain common chemicals may trigger increased fat cell activity, or adipogenesis. Sometimes, I think just looking at certain delectable goodies makes my fat cells grow. But this, my friends is a serious report about a serious subject.

According to a story in the Washington Post, Bruce Blumberg, a developmental and cell biologist at the University of California at Irvine, presented research at annual meeting of the American Association for the Advancement of Science on compounds he calls "obesogens" -- chemicals that promote obesity.

Blumberg studied the effects of tributylin, a chemical used as an antimicrobial agent in industrial water systems, as an antifungal in marine and agricultural settings, and is used in the production of plastics.

“What we discovered," Blumberg said, is that tributyltin disrupted genetic interactions that regulate fat-cell activity in animals. "Exposure to tributyltin is increasing the number of fat cells, so the individual will get fatter faster as these cells produce more of the hormones that say 'feed me,'" Blumberg said. The exposed animals, he added, remain predisposed to obesity for life.

Another suspected obesogen is bisphenol A. It is used in plastic products ranging from refillable water containers to baby bottles. It is also a part of the epoxy resins that line the inside of food cans and are used as dental sealants. A study by the Centers for Disease Control and Prevention found bisphenol A in 95 percent of the people tested, at levels at or above those that affected development in animal studies.

According to Frederck vom Saal, another researcher quoted in the Washington Post article,  research indicates that developmental exposure to low doses of bisphenol A activates genetic mechanisms that promote fat-cell activity. "These in-utero effects are lifetime effects, and they occur at phenomenally small levels" of exposure, vom Saal said.

The American Chemical Council (ACC) pooh-poohs the idea that these chemicals are harmful to human beings. But many researchers disagree. Vom Saal even goes so far as to call the ACC's statements about the safety of these agents a "blatant lie."

It is too early to say definitively who is right and who is wrong. But, the animal research is certainly suggestive enough to justify larger scale animal studies, including studies designed to look at the toxicity of these chemical in human beings.

For those of you who are hoping it’s the toxins in plastic that made you fat, I have to say that I sympathize, but even if these chemicals are playing a role in packing our fat cells with fat, it is highly likely that the biggest culprit in the global obesity epidemic is still going to be too many calories and too little exercise.

Pat Salber