NIH CLINICAL CENTER GRAND ROUNDS
Episode 2010-03
Time: 1:06:20
Recorded January 20, 2010

Two tenure-track investigators from the Clinical Endocrinology Branch, NIDDK Division of Intramural Research, will address obesity research in Grand Rounds on Jan. 20. Dr. Giovanni Cizza will present "Updates in Obesity Research." Dr. Kong Chen, who directs the Metabolic Research Core, will present "Measuring Energy Expenditure in Humans: Tales for the Metabolic Chamber."

ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future - this is NIH Clinical Center Grand Rounds.

(Music establishes, goes under VO)

ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds, recorded January 20, 2010. On today's presentation, two tenure-track investigators from the Clinical Endocrinology Branch, NIDDK Division of Intramural Research, will address obesity research. Dr. Giovanni Cizza will present "Updates in Obesity Research." Dr. Kong Chen, who directs the Metabolic Research Core, will present "Measuring Energy Expenditure in Humans: Tales for the Metabolic Chamber."

We take you to the Lipsett Ampitheater at the NIH Clinical Center in Bethesda, Maryland for today's presentation.

CIZZA: Good afternoon everybody. Thank you for this kind introduction. It's a real honor to present today. As you know, I'm Giovanni Cizza and the title of my talk is measuring energy expenditure in humans.

This is the picture of Geronimo, the apache leader. You can see he looks lean and fierce. And this is his great grandchild. The rifle is the same but the clothes are a few sizes larger. What could have happened in these few generations? The genome did not change, however the environment changed and the environment genome interaction dramatically changed. In this particular case, chronic stress probably related to social subordination may have played a big role.

In the next 25 minutes I will try to answer the following question: why do we eat more and why do we move less? Is there something around or in us? Are we missing something? Will we ever find a cure for obesity?

The prevalence of obesity has increased over the last 100 years since 1980. This is evident in the U.S., Europe and almost in every country for which data is available. The exact reasons behind this pandemic are unclear. The two big causes are usually cited as increased food intake and decreased physical activity. However, solid evidence to link these conditions still lacks.

This is a simple slide to define obesity. Dr. Chen will then show more sophisticated ways but these are methods commonly used in bmi, which is a measurement that compares height and weight. It is used quite often. It does not differentiate between men and women. Does not differentiate between muscular and obese individuals. And these are two limitations.

In the table you can see the cut off. 18-25 is considered normal. Overweight is 26-30. Obese 30-40. Morbidly obese, 40 or greater. In addition, circumference, one of the components of the metabolic syndrome, something i won't be able to touch upon, is a good indicator of abdominal obesity. Fat accumulation in these areas is especially a problem in men. I think we should use more often weight circumference together with bmi. The cut off with circumference is 40 inches for men and 35 for women. Finally, next circumference is used in medicine because it tracks sleep apnea as being shown to be associated independently with increased insulin resistance in morbidly obese subjects.

In characterizing clinical obese subjects it's important to establish a detailed weight history. Why losing weight is difficult, maintaining the weight loss after diet is even more difficult and unfortunately, most of the subjects gain back the weight within 12-18 months to sometime end up even heavier than before. The endocrinology of the postobese state is well-known. It is characterized by decreased energy expenditure, and by decreased thyroid level.

The decreasing energy expenditure is substantial. 300-500 kilocalories a day. In studies, we have shown how to reverse this state. Twice daily leptin administration for 5 weeks in post obese subjects that lost 10% of the body weight restores leptin levels to pre-weight loss. This reverses the prebese state to go back to normal and energy expenditure goes back to normal. Unfortunately, adaptation to weight changes are orchestrated by the hip thalamus in a normal symmetrical fashion.

Decline in leptin with late loss sets into motion a set of responses that eventually defeat further weight gain. In contrast, increase in leptin, elicits little if any physiological response, and fat continues to accumulate.

It is important that the characterization of the subject is not solidly based on cross sectional data but take into account weight history. There are ethnic and age differences as shown by the work of our group.

There are major ethnic differences between blacks and white in the relation of bmi with circumference, fasting triglyceride to clinical outcomes. The ration for black men is greater than whites and is higher in women than in men. Overweight black men are at greater risk of diabetes than overweight black women. There are also differences in asian and other ethnic groups but I will not be able to touch upon this.

Based on the work of the national institute of aging, we know that weight loss is not necessarily beneficial. Fat loss is. Aging is associated with cytopenia, and loss of muscle especially at the level of the quadriceps is associated with increased insulin resistance.

In order to answer the question why do we eat more, it is important to understand the relationship between chronic stress and obesity. This is a cartoon from the work of my two former mentors at nih as they described this stress system which had has two main components. These components have integrated metabolic affects that are complex. They relate to insulin sensitivity and secretion and the glucocorticoid intake form and compartmentalization of energy. Why do we eat more? Is there such a thing as comfort food? High glucocorticoid levels increase intake of palatable food. Fat and sugar act on the brain to activate pleasurable responses. These nutrients are able to modulate the intensity of this stress response. This is a slide from a group in San Francisco showing when rats are allowed to eat highly palatable food prior to exposure to acute or chronic stress they exhibit a reduced response. Stress causes a dramatic rapid increase in CTH and this increase is almost abolished in animals that are treated with comfort food. Centrally messenger rna levels rises less if the animals are pretreated with palatable food. In the lower panel, after 240 minutes of immobilization, CRH levels in animals pretreated with comfort food is about half of the levels in the animals that receive the standard diet. This is the case both in the hyptohalumas where CRH controls CTH secretion and in the nucleus where CRH modulates control. Neuropeptide y is a 36 amino acid peptide found in the brain and is an important appetite stimulant in the nervous system. During stress, NPY is secreted. As shown in this slide, NPY excreted in the adipose tissue causes angiogenesis. Abdominal obesity may result. We have been told that energy balance is regulated by homeostatic mechanism at the hypothalamic level. This is still true but there is increasing understanding that the nonhomeostatic levels may be as important. This has been elucidated mostly by others. The mesolimbic system is part of the reward system. Leptin receptors are present in blue in the hypothalamus where it's a appetite stimulus. Leptin stimulates the ventral area the abuse of palatable food. In obese subjects, insulin decreases liking of palatable food mostly via opioid mechanism. Leptin affects the wanting of food via dopaminergic tone. Increasing leptin and insulin may progressively negate the pleasure associated with food. This vicous circle leads to more food intake with less and less reward.

Excessive food in take is still a controversial topic but is regarded by some as an addiction similar to drug abuse. We should develop effective ways to clinically identify subjects that may be prone to food addiction.

Why do we move less? Do we become obese because we move less or do we move less because we are obese? Non exercise thermogenesis indicates the energy extended through all activities of living when voluntary exercise is taken away.

"Neat" is an important determinant of total energy expenditure accounting for anywhere between 100-700 kilocalories a day. To understand whether this large individual ability is related to the obese status, the mayo clinic did the following experiment. Activity was measured for 10 days, with lean individuals in the white box and then moderateley obese individuals. There were also sedentary alpha females and alpha males. At baseline, the obese individual spent more time sitting than the lean individual and they moved much less. Then all subjects lost weight under controlled conditions. And under these new conditions, the post obese subjects still moved less than the lean subjects. When the subjects gained back the weight, they still maintained the same posture. This indicates that neat is an established feature of each individual and that lack of propensity to move characteristics of any given individual.

What are the biological determinants of neat? As suggested by the work of kathy in minneapolis, neat is controlled by several neuropeptides. We already mentioned rx and a. Neuropeptide y, others. Elevated signaling of these pathways may protect from obesity.

In summary, the amount of physical activity is a crucial determinant of body weight. Physical activity is not a pure nutritional phenomenon but has a strong biological component which is genetically determined.

The word pandemic indicates a phenomenon of large scale. There is also the idea that obesity may be transmissible. So is it contagious? Two new lines of research seem to suggest that that may be the case. One is in the microbiotic and the other is the social network.

Microbes have the amount to extract energy from otherwise indigestible polysaccharides. This figure depicts the phylogenetic diversity from the microbiota of  31 identical female twins and 35 fraternal female twins. Obese twins in the trial had reduced bacterial diversity and ultimate metabolic pathways. In these subjects microbiota where it reached with the phosphotransferase enzymes involved processing of car bow hydrate.

Longitudinal data suggested obesity may spread from person to person. Individuals were identified in this network and they extended up to one degree of separation. If one spouse became obese, the likelihood the other spouse became obese increased by 37%. In summary, obesity appears to spread through social factors. Promising research still in infancy suggest the built-in environment can be obesegenic, more in terms of physical activity and diet.

Are we missing something? This comes from the work of a scientist in birmingham. Epigenetic. Children born from a post obese mother that have gone through biotic surgery have a lower risk for obesity than their siblings born from the same mother before weight loss.

Maternal age as women enter the workforce, there has been increase in maternal age. Each 5 year increment is associated with increased odds of developing obesity 14%. The mechanisms are unclear.

Obese mothers tend to have both underweight and overweight children. Underweight children are exposed to starvation because of decreased vascularization and maintain metabolism through the thrifty genotype. Infants are also more likely to become obese. 65% of the variability in mice genetically determined. Obese people tend to have children with obese people. This affect seems to go beyond the shared environment as it is more evidence in the first years of cohabitation.

Endocrine disrupters, chemicals derived by plastics, pesticides and other agents that are widespread and very stable in the environment may interact in the estrogen receptor and affect the amount of white adipose tissue. Medications commonly prescribed medications such as psychotropics, beta blockers and antidiabetics are associated with small but significant increase in weight. Olanzipine, an antipsychotic drug of new generation causes weight gain which is very severe and very fast. It could be as early as 5 weeks. It could go up to 15 kilos or more.

I will now expand a little bit on the question of whether chronic sleep deprivation causes weight gain because that is part of my research.

Recently a growth in self reported sleep deprivation has been observed. Sleep has gone from 9 hours at the beginning of the 1900s to approximately 7 hours. And you can see here how the prevalence of obesesity has gone from 13% in the 60's to the current 33%. For children, they need more sleep and the decline in sleep has been worse. Given the data, it has been suggested that chronic sleep deprivation may be linked. Their epidemiology parallel each other. Obesity is more common in those with lower social economic status and in women. There is experimental clinical and epidemiological evidence that suggests that there is a strong association if not a causal link.

Experimental evidence in 1997 involved a group having been cloned the clock gene. Mice homozygous for the clock mutation sleep less. They had severe hyperphagia and developed obesity. They gained more weight both on a regular diet than on a fat diet. Clinical evidence. Sleep deprivation is a stressor and the stressor causes increasing endocrine growth hormone. Leptin and add pi static signal is diminished by 50% and appetite stimulant is decries by a similar amount. Pro-inflammatory cytokines are also increased. These endocrine and immune changes together increase appetite and rapidly affect insulin sensitivity. Just it takes one week to become insulin intolerant.

Epidemiological evidence, this is my own data. Sleep deprivation is on the horizontal axis, bmi is on the vertical axis. This is the relationship. The first reports were in 2004, since then there have been more than 50 epidemiological reports. Mostly cross sectional and showning an association between the lack of sleep and obesity.

Based on a recent metanalysis of all the status, short sleep is associated with obesity. 1.9 in children. 1.5 in adults. To address this question from a causative point of view, i'm conducting a randomized control trial. We have already enrolled 109 patients, the total is 150.

Will we ever find an effective treatment for obesity? This is a frequently asked but ill formulated question. The issue for any drug, especially for obesity, is a balance between safety and efficacy. And in a historical example of an appetite suppressant from review article at the fda, in 1947 adjunct management for obesity was approved. By 1960 there were 5 such drugs. In 1962, substantial evidence was shown effectiveness for the drug. An expert panel concluded that amphetamines failed to meet standards mostly because of the short duration of the studies. In this day, the fda considered the drug effective if it was statistically superior to the placebo. The clinical relevance was considered match later in 1995 when at a time of the decks application when the fda stated that first of all, studies of obesity have to be placebo controlled long at least one year, 12-1500 patients. Obesity drug to be considered effective has to have one of these two criteria. There is a difference at the end of 5% between the placebo and the drug group, and/or the proportion of losers subjects who lost more than 5%, is greater in the intervention than in the comparison. Why 5%? Because in those days, there were large clinical trials starting to accumulate evidence that 5% relatively small weight loss is sufficient to increase insulin sensitivity to decrease blood pressure and may possibly diminish the number of cardiovascular events. Safety became known only much later. And when fen-phen was approved there were 80,000 prescriptions per week. Later on, as you probably all remember, it was pulled from the market for left side valvular degeneration, a risk that no one saw coming.

Medical consequences of obesity are many. I'll just mention there are more than 100,000 deaths per year. I would like to comment on the potential association between obesity in mid life and increased risk later in life and cognitive decline, because it's a relatively new concept. Obesity in mid life seems to predict increased risk of alzheimers. You have years of fall out and then you have accumulative incidents alzheimers.

This is a prospective study published two week ago. The highest of leptin is 6 specific levels associated with the greater risk of assignment. Mechanisms are unclear. Acquired resistance with neuroprotective effects of leptin in the level of hippocampus may play a role. Current medical treatment is an appetite suppressant. Cybutromin is a centrally acting, norepinephrine inhibitor. It has increased blood pressure. It was withdrawn from the market in Italy because of deaths. It is going for fda review for cardiovascular events right now. In another drug, arlistat the association with weight loss is modest and side effects are not dangerous and self limiting. They include incontinence.

Another drug is a selective inhibitor antagonist and mostly appetite suppressant. Interesting story. In june 2006 it was approved in europe for obesity. In the u.s. it did receive all the approvable letters but in 2007, an fda advisory committee voted against the recommendation of approval. It was later withdrawn by the European Union for manufacture because of psychiatric problems which were dose related and including suicide. In summary, so far no medical treatment has shown a favorable efficacy and safety in my opinion.

But as to surgery in 2002, in the U.S. there were 171,000 surgical procedures for obesity. 10 times more than in 1994. From the more invasive procedure, we turn to less invasive strategies but surgery is recommended for individuals not greater than 40 or not greater than 35 if there are co-morbidities. Efficacy of the weight loss is dramatic, 30-50 kilo grams. Surgical risk, there are minor if experiencing any. Again, long term safety is a different issue. Prospective data are being accumulated. These procedures are expensive. Statistics on cost effectiveness are needed.

Some of the rapid improvement in glucose metab lin seems not to be caused by weight loss but changes in gastrophysiology we need to understand better. It is somber to note, and it is my personal conclusion that the true effective intervention for obesity that we can offer right now is a series of surgical procedures that have the ultimate goal of impairing the effectiveness of the gastrointestinal track as it had developed over evolutionary time.

Over the course of this talk, i mentioned the work of many distinguished colleagues. I started a new series of lectures, the brain and obesity lecture. Since 2007 we have had 15 scientists that have come to for work that was sent in involving this idea. The colleagues listed here as i would like to thank them again.

The obesity epidemic has developed for over more than a generation. This problem will not resolve within a generation. We need the courage and intellectual honesty to acknowledge that although something can be done at the patient level, we may be be losing the battle at an individual societal level. To win the war on obesity will take more than eating a little less exercising a little more. It will take dramatic structural changes at the societal level.

This is last week's commentary in Jamma. The apparent energy imbalance for the u.s. population is 5-10 fold greater than eating an extra cookie a day, far more than the amount of most individuals to address at the personal level. We shouldn't rely solely on the willpower of the isolated individual, although each one of us will always bear the possibility to be as happy as possible.

Thanks.

[APPLAUSE]

QUESTION: As we get older we find we are less able to exercise, and we have pscyopenia. How do we handle this?

CIZZA: Unfortunately from a pharmacological point of view there are no good agents to treat that. There are lifestyle modifications and intervention based on exercise because people don't exercise they lose muscle mass. It should start when people are still middle age.

CHEN: Thank you for the opportunity to speak with you. The doctor laid out the groundwork and I'm not going to go through the details of the cause of obesity. I'm going to concentrate on the measurement issue. My disclosure is that I'm an engineer. So a lot of the things i talk about are in numbers. And I'm not going to disclose my bmi at all.

So I want to acknowledge the people that helped me along, particularly as Dr. Gallin mentioned, I was recruited from Vanderbilt 3 years ago. What a grateful way to recruit an engineer to run the clinical core. And all the investigators that use the metabolic core, which I'll tell you more about and we can't do anything without the nurses. So I must recognize all the nurses. Some of them probably are here. And my lab is including Dr. Bricta, who I took from Vanderbilt, they are still crying about him leaving. And Lynn, who was my nurse practitioner. These are my students. Here is the postdoc who left recently and here are the previous students all recognized for their work. Of course we have a larger core, Dr. Smith is the clinical psychologist on the floor. As Dr. Cizza submissioned, there are a lot of things going on. We are looking at obesity from a multifactorial perspective. The dieticians and techs as well as other support staff.

So my outlines are very simple for the next two hours. No, 20 minutes. We're talking about what is energy balance on an individual level? And how do we measure these things? That's the only thing I know. How to measure these things. Particularly in energy expenditure, because dietary intake is difficult to measure very accurately. So, where would we apply these measurements? Hopefully you will generate thoughts and use these things in your research. And what is the metabolic clinical research unit?

So the major components of energy balance despite what genetic factors or other factors, my understanding is a simplistic way. I look at it as energy in and energy out. We don't produce calories. We don't absorb it through the sun. We take it in from cherry pie or whatever that we eat. From carbohydrate, protein and fat. This is a major component that we take in, the calories. On the other side, to balance that is energy expenditure which was mentioned about. You can sub divide into basal metabolism maintain your body temp chemical balances as well as maintain your breathing and brain functions. This composes about 60, sometimes 80% of your total energy expenditure. There are small components involving digestion, 8-10% and the nonexercise activity, and some people think it's about 7 or about 20%. And the last part, although pretty important part is physical activity. Not necessarily exercise. And just walking, most people don't think it's an exercise. It doesn't have to involve heavy sweating. This physical activity can tribute to quite a bit of the energy expenditure.

Most people believe that the imbalance over time if you have more you take in than you burn, the result is fat storage or eventually obesity. And so it's arguable whether this 100 kilocalories per day is sufficient to cause this obesity epidemic. It's debatable.

How to measure it. Well, so if you talk about the energy expenditure or heat, there is a direct way to measure. It's direct calorimetry. And it's measuring the heat through water or air or by metal materials. And the advantage of the direct calorimetry is that it measures the thermal regulation directly. I'm using too many directs here. But it doesn't get you this information about which fuel does it come from. Carbohydrate or fat? And roughly they have a fairly low response rate means especially if you use the water to measure the heat because of the capacity of water to absorb heat, it takes 30 minutes or longer to get you any data points. Fortunately we have now used the indirect calorimetry, essentially measuring the oxygen consumption and CO2 production. You can actually resolve and substrate oxidation. I'll show you how we do that. It's a fast response. So the old direct calorimeter is not used anymore in this field. This was a calorie meter built in 1892 over 100 years ago in Connecticut in the basement of a building. This is what the chamber, the name chamber comes from. This is a very dark, small room. Because this measure heats and lights everything it needs to be precisely controlled. A very tiny light up here and fluorescent light. This is the chair. It's a metal room because it's the circulate with water and this is a heating element. And to measure the heat exchange. This is the bed by the way. This is the chair. This is outside to measure the heat exchange and everything else, the control. So the metabolic chamber as Dr. Gallon says, it's scary. That name stuck.

So the principals of indirect calorimeter now. If you remember biochemistry, when you breakdown carbohydrates you use oxygen and produce CO2 and calories. One gram of glucose produces roughly 4 kilocalories. And with fats, you do the same. But the difference noted is that it generates more heat and has a different ratio of CO2. If you measure the oxygen and CO2 and measure the nitrogen excretion, it's essentially solving 3 equations with 3 numbers. So essentially that by measuring these components, you can calculate energy expenditure very accurately. And the risk-free quotient, the ratio between the carbon dioxide production and oxygen consumption level at point 7 level it represents all fat oxidation whereas at 1, it's a all carbohydrate oxidation and most of us burn in between that.

This is a human energy expenditure study. Essentially we had one 60 years ago. Or 50 years ago. Don't know where it is now. I put these names in a global and can't find them anymore. But if anybody knows any history of this metabolic chamber, I would love to hear more about it. But eerily there are a lot of similarities between the chamber, when they published in 1960. This is a laboratory. There is a control unit and thesis are tubes to measure oxygen consumption which is not in the room oxygen consumption. This is a treadmill. And this is an environmental room. So this was on campus. So, this was the subject. They essentially put him in a metabolic hood and they called it an elephant trunk because you can see he is taking a nice milk shake without leaking air and through this, there is a tube that measures oxygen consumption. You see the subject was minimally dressed because the room is controlled at 78 degrees fahrenheit. Essentially that was thought to be a thermoneutral temp if you're not wearing clothes. And you can alter that by experiment reported to reduce that temp to 50 degrees fahrenheit. Imagine the conditions. So in fact, over time, you can't see that very clearly.

They did a couple of sleep studies at 50 degrees versus 78. This was recorded at July 27, august 4, 1959. So, again remind ourselves that we are not the first one to do this. We are just repaving the road over and over again. Perhaps with modern technology. And this is with the technology looks like these days.

So this as was mentioned, one of the 3 metabolic chambers we built in the last 3 years in the southern southwest unit. This is a picture, slightly bigger room, not as scary. Some of you probably stayed in that room. A nice cushioned bed. 550 pound capacity. We had our subject a couple months ago weighing roughly that. Treadmill, a window facing south. Very important in the afternoon. The sunshine in. So psychologically they are not so stressed out. This is open circuit system meaning we always tell our patients we pull air out and we measure the CO2 and concentration difference between that and an outside room. And this is the outside room which supplies the room constantly with fresh air. So essentially it's not all the 30,000 litres of air. It's all have you for the 24 hours. Essentially we refresh it. And the elephant trunk is repleased by a nice sophisticated computer and tv. We say it has better cable than I have at home. This is the blood port from where they can have visual contact with the nurses as well as the blood draws for our endocrine dynamic tests that we can do. We draw blood and then simultaneously study the energy expenditure in the substrate oxidation. This is where we pass food in and specimens pass out from this event. Here are the blood tubes that reference for the nurses. That's what the instruments we use.

These operate the number 2 and number 3 chambers. These are neuroimages. This is one set up and this is the other. So we have 3 independent metabolic chambers we run simultaneously. This is the CO2 analyzer and all the equipment to make it work. I won't go through the super details with you since there are only a few people that know how to operate it. But I will show you some data. I believe our subject is also in this room. This was a postdoc extraordinair that we did an early study to find the reproducibility of our metabolic chamber. So he spent two days in the metabolic chamber shown in minute by minute fashion and for two separate days did exact same activities. Including resting. This is sleeping period. This is exercise running about 10 miles per hour on a treadmill for 30 minutes both in the morning and afternoon. I was a little bit upset at first because he missed 5 minutes during the second day but then it was very good to show so people don't think that i super impose the same days of data. So very reproducible. The total difference between the two days was less than 1%. Our cue respiratory quotient, is also very reproducible with reasonable amount of noise or artifact. This is about as good as we can get. You can see the breakfast and lunch and supper. You have an increase in here suggesting he was shifting between a fat oxidation at night or fasting condition to a more carbohydrate metabolism in the fed condition.

So we did 10 subjects and I show you the data all together. In this fashion subtracting the day one verses day two. Compared between the 10 individuals compared with the average of the two days. You'll see that day one was a little bit more than day two. Essentially 50 kilocalories. What I attribute this to is more like a hotel affect. If you go to a hotel first night, you find out where you put the luggage and toothbrushes and where the TV remote is. So this is a little more active than day two. But the impressive thing is the reproducibility, essential is the conference interval and gives you about 50 kilocalories, one standard deviation. So we use those for designing experiments. And our cue is also very reproducible.

And this was the subject that I showed you and this is another subject on the other extreme. Very sedentariy and low energy expenditure. And fairly standard cue. This is the subject that with no activity you'll see the energy expenditure on top of each other. Our cue as well. So we are pretty happy with the basic functions of these metabolic chambers.

If you do these studies cross sectionally long enough and this was a study group that we finished at Vanderbilt before I came here. 145 heterogeneous population of various age and body composition group. If you compare the resting energy expenditure with fat free mass measured by under water weight, you see a nice linear correlation, suggesting that the fat free mass including muscle mass organizes tissue mass and explains about 70% of individual variabilities in resting energy expenditure. After you control for fat free mass, the measure component, this is also correlated with the fat free mass, for the fat mass, confirming that that fat mass itself is an endocrine ornament and regulates basal metabolism. And this is the multiple regression analysis. So we did that with 145 individuals. Our phoenix colleagues have been doing this longer than we have. They have done a study with almost 1,000 people. They can essentially have similar correlations between fat free mass and fat mass. Male gender is shown in this study to have a slightly higher metabolic rate and the last question is shown with age you reduce your metabolic Rate after all your corrections of fat free mass and fat mass. And furthermore, there is a slight difference of waist to thigh ratio and the insulin in tolerance to glucose tolerance or impaired glucose tolerance. With all these factors with the larger population, you can essentially study the role of basal metabolism.

I'm going to show you a few other cases of how you can apply to clinical research.

So we did a small study about 12 per group of chronic renal failure patients versus patients going through dialysis. Same correlation with resting expenditure and fat free mass. The solid lines are chronic renal failure patients. And the dialysis patients you will see with given fat free mass. They have about 300 kilocalories higher basal metabolism suggesting the treatment process increases the metabolic rate. And if you process them as a group, it represents about 15% higher basal memetabolism. So the treatment process does increase or in some of them probably decrease their metabolism.

What about certain medications? We did a small clinical study to look at what ephedrine has in terms of its metabolic affect. so we measured in 10 lean individuals, fairly lean individuals, energy expenditure in a metabolic chamber at Vanderbilt -- so we showed between day one and day two there is a slight difference, and this in study we had a placebo day or baseline day and the placebo day, and then the third day we actually had ephedrine at 50 milligrams 3 times a day. Without going through super details, you'll see about 35 kilocalories difference between the baseline placebo and the hotel affect. On ephedrine day which increased the metabolic rate by 3.6% or about another 60 k calls or so. And this is statistically significant.

This particularly is the case at night because we saw 9 out of 10 patients had sleep disturbances. So furthermore, we did express the data in individuals. These are 10 individuals. You see all individuals increase their energy expenditure except one. So there are individual variabilities. We also looked at since this was associated with a sympathetic group, we looked at epinephrine and norepinephrine and the urinary excretion seen with the ephedrine, they have a reduced excretion of catecholamine. We also did a binding study and further isolated the ephedrine binding to beta 1 and beta 2 adrenal receptors but not so much in beta 3.

So, various things we could do about it and I'm not going to go through super details of calorie restriction. We already mentioned a little bit about that and the fact that saying when you lose weight by-and-large, especially by diet alone, that youre basal metabolism also reduces. Due to time difference, I'm going to go through pretty quickly and talk about the pros and cons of a room calorie meter.

As you have seen, we can measure continuous energy expenditure allows are for dynamic tests on a resolution on minute by minute. We can do this over 24 hours and some of our studies that will probably prolong into two days. And we have the accuracy over 98% over 24 hours. We can partition out the sleeping, the resting, the effective food, the activity energy expenditure, spontaneous or exercise. We can look at macro nutrient oxidation rates. We can look at the fuel shift from carbohydrate to fats. And one of the limitations, it's a fairly small room. It's about 3 1/2 meters by 3 meters. Essentially it's a tight environment because we do need the sensitivity. So some activities cannot be performed. It is complex to maintain and expensive to construct.

What are the other alternatives? Other indirect calorie meters. These are just a few that we use for exercise or resting or basal metabolic rate. This is a portal unit. You can do an exercise in the mobile situation. And this is one of my favorite slides. I have to show in every presentation because we are not the only ones or the first ones to do it. This is 1906. A German investigator wearing a portable calorie meter. Very neat. It's controlled by fingers and this doohickey on the head it probably measures wind speed. But -- [laughter] very neat stuff.

But with the limitation, these are short-term measurements and this chamber is a 24 measurement. There are even long-term measurements. Let's push the fact that we have a mass spec core with which we can measure double labeled water. You may or may not know if you dose someone with a stabled isotope, it gets in your body water and you can measure the concentration over time and essentially after equivillation, they reach a plateau and with time, the tutorium loss is only into water whereas the 018 loses concentration both in water and CO2. So the difference of the two is a CO2 production. Essentially correlated with energy expenditure.

So this is a method that we do quite a bit with water that we measure the energy expenditure over 5-10 free living days. So you're not restricted in a room. You can take a drink of water and collect urine samples daily or every few days and then we'll get a overall energy expenditure over that period. But we don't have a lot of details in those periods, unfortunately. We and other groups have been working very hard to sort of close that gap, we have been developing and validated a lot of these portable activity monitors with technology nowadays. You probably heard of the biggest loser wearing arm bands. And that is one of the many techniques that we play with or test, that can measure activity energy expenditure over time. And this just shows you that one of our studies that compares 3 different waist worn accelerometers, and they are fairly good indicator of activity intensity so it can be modeled into energy expenditure. We so have done a lot of that work and it continues in my lab.

So as you can imagine, to be able to measure the energy expenditure as acurately as we can, applies to many research applications. Essentially with obesity, exercise physiology, nutrition and cancer. Different metabolic diseases that are unique to the clinical center. Growth and development and much more. And we built the unit in the last several years with a mission to provide these and other specialized state-of-the-art facilities for comprehensive and collaborative research. And this is our 5 Southwest unit. We have 10-inpatient beds. Very nice. And this is showing the inside of that room. Of course we can measure basal metabolic rate. We have eating and diet laboratory and, measure at leptin feeding as well as satiatey. We have exercise testing to look at the capacity for exercise and the do2 max. And we have the body composition lab. Which I don't have the time to show you a lot of the detailed information. This is the by pod most favorite of a lot of our visitors. This is dexa. And of course the metabolic suites. Those are located in 7 Southwest.

Just to give you a taste of what we are doing now, this is just a selective protocols. We and many others are interested in obesity phenotypes so we are studying a large natural history study looking at obesity also should put a plug in, I have a new protocol addressing the question why some people can eat all they want and don't exercise and don't gain weight. Very selective few. But if you are one of those kind, or know somebody, please refer them to us.

And Dr. Chely, probably in the audience, is very interested in looking at thermal regulation with myocode. We are not talking about 25 degrees drop in temperature, which not many people can tolerate. We are talking about 5 degrees, 5 to 10 in fahrenheit. And what are the mechanisms regulating those.

A lot of our unique populations or sickle-cell and other metabolic diseases are studying on the unit. Kevin Haul at NIDDK, is heading in the direction of selected under feeding or food restriction. Whether it's from carbs or fat.

And many other studies and aging studies and NHLBI and NICHD studies. So just a flavor of what we have and what we do.

So in summary, I hope I convinced you the energy expenditure and its components can be measured with accuracy and precision, and the technologies continue to improve, and we like to think we are at the forefront of those improvements and they are well suited for clinical applications and we are here to help. So I will leave this slide up and these are the rules I live by. I only talk about the things I can measure. I used to have a sign on my door that says in god we trust, all others bring data. You can't talk about things you can't measure. So with that, thank you very much.

QUESTION: I want to just challenge you on your statement how many lean people can eat anything they want and stay lean. I know a lot of lean people. Not one of them eats all they want. So I'd like to ask you whether it is common that lean people, whether they are athletes or not, that there are a lot of people around who eat a lot of food, of course it depends on you what eat, those lean people who eat all they want, they may be eating mushrooms and low calorie foods, they are not eating french fries. Can you fill in a little bit about that? I think most lean people don't eat so much.

CHEN: Absolutely i agree. I think but we all know somebody -- and I came up with this protocol several years ago. Generated by essentially anecdotal experience. Out of 7 or 8 subjects, they always come and say you need to study so and so. I hate him or her. They can eat all they want and they don't exercise. They may be the rare genotype or phenotype. But we like to find them if they exist.

QUESTION: (Unintelligible)

CHEN: How fast do you run? It depends on speed and intensity and generally –walking? To burn 3500 calories? That's about 100 minutes. I'm sorry, 1,000 minutes. 1,000 minutes if you walk about 3-4 miles per hour. 35 miles. Roughly.

QUESTION: You have done a large number of studies in the energy expenditure studies. So do you see any difference in the ethnicity? Do you see a lot of lean chinese and a lot of obese other individuals? Ethnicity and obesity?

CIZZA: There are differences which may depend mostly on muscle mass. There are genetic factors. We are not all the same.

QUESTION: But you have data.

CHEN: Yes. I know several groups that looked at this and particularly the group from university Alabama Birmingham they looked at that and they saw a difference particularly in African American women. But there are several other groups that did not find the difference. So it's a matter of how you sometimes how you measure the body composition. And sometimes it's how you do the analysis.

QUESTION: If you keep the temp low in the winter, does it increase metabolism? This will help me to tell my wife to keep the temp low.

CHEN: Are you around here? So address that to Dr. Chely. But i can tell you that -- is it classified? The information, is it classified? So when we reduce the temp from 74 degrees to 69 Fahrenheit, is that correct? We see a difference of about 6% increase in energy expenditure. But just put into perspective. You saw the ephedrine study. 3.6%. It is reported another drug increased energy expenditure roughly the same. Now we do not address the question whether reduced the temperature increased appetite. We didn't do that study. But it would be interesting.

ANNOUNCER: You've been listening to NIH Clinical Center Grand Rounds recorded January 20, 2010. On today's presentation, we heard from two tenure-track investigators from the Clinical Endocrinology Branch, NIDDK Division of Intramural Research as they addressed obesity research. Dr. Giovanni Cizza presented "Updates in Obesity Research." Dr. Kong Chen, who directs the Metabolic Research Core, discussed "Measuring Energy Expenditure in Humans: Tales for the Metabolic Chamber."You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link -- or by clicking the "View Videocast" link on the podcast homepage at www.cc.nih.gov/podcast. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America's Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I'm Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.