Good evening to everyone. My name is Van Hubbard and I'm with the Division of Digestive Diseases and Nutrition of the National Institute of Diabetes and Digestive and Kidney Diseases. And I'd like to welcome everybody to our initial lecture and our second year of providing a clinical nutrition and obesity lecture series. As we have done in the series last year, we have made arrangements through the cooperation of the nutrition department of the Clinical Center for Dietitians to receive CEUs for attendance at these lectures. And there is a sign-up sheet in the back of the room for those that want CEUs from the ADA. In addition, through the Foundation for Advancements of Education and Sciences within the NIH, there will be provision to receive CME credits for physicians. And to do so, there is an evaluation form and a page where you can sign up and provide your name and other information and indicate that you do want CME credits as a physician. In addition, I would appreciate any others of you that would like to fill out any evaluation form to do so and we will try to take your comments into consideration as we design future series of this sort. This evening, we are pleased to have Dr. James Hill, who is currently Associate Professor for Pediatrics and Medicine and Associate Director for the Research Center for Human Nutrition at the University of Colorado Health Sciences Center. He is a member of our National Task Force for the Prevention and Treatment of Obesity and also has the unique experience of heading off this lecture series last year and due to popular demand as well as trying to get him to do it again and improve on his past performance, we have invited him back this year. And it is also particularly significant that he was one of the co-organizers and co-chairmen of a workshop that was held on the NIH campus last December on physical activity and obesity and he will also include an update related to the outcome of that conference during part of the presentation. And so I welcome Jim to again initiate this series of lectures. The titles for all the lectures in the series and the dates are also provided on the back of the auditorium. Van told me I had to keep doing it until I get it right, so hopefully tonight I can do it right and I won't have to come back and do it again next time. It's a real pleasure to be here. I'm always amazed to get this sort of crowd at this time of the evening. I hope we can talk about some things that are interesting to you in the area of obesity. The title of the talk tonight is Physical Activity, Diet, Composition and Obesity. And I want to start out by presenting a model which represents my current thinking about obesity. It may not represent anyone else's in the area, but it's a model that's sort of guiding the research we're doing. I'm going to talk a little bit about how that model may be affected by physical activity and by diet composition and throughout the talk trying to relate these factors both to treatment of obesity and prevention of obesity. Do I do the lights here? I think of body weight, the level of body weight maintained as a settling point. This is a concept introduced years ago by Wirt Schafter and Davis. It's different from a set point. A settling point is the point that results from a number of other systems, all of which are regulated. The key concept here is that body weight, body composition, body fat may not itself have to be regulated per se. It may be the result of many other systems. If we start at the top, I think no one would dispute that we have genetic and non-genetic influences on body weight. And this determines what I'll call the characteristics of the organism. Now, I think it's useful to divide those into sort of a behavioral phenotype and a metabolic phenotype, both of which, again, are influenced by genetic and non-genetic factors. The sum of these behavioral and metabolic phenotypes would be the functional phenotype of the individual. And it's through the functional phenotype that a situation of energy balance is reached, where intake equals expenditure, body weight and body composition are stable. We've been very interested in looking at the metabolic phenotype, particularly looking at individual differences in the metabolic phenotype and ways in which environmental factors can influence the metabolic phenotype. The more I study metabolism, the more convinced I am that behavior is ultimately important in this. So at the end of the talk, even though we're going to concentrate a good bit on metabolism, we're going to come back to behavior. And I think you can see that you'll be able to see that you really have to consider these in combination to really understand how an individual reaches a settling point of body weight and body composition. Now, the factors, diet composition and exercise that I'm going to talk about today, can influence each aspect of the energy balance equation. And the point here is that by manipulating physical activity and diet composition, you can reach a new settling point. This isn't resetting the set point. This is just changing the system so that it reequilibrates at a different settling point and a different body composition. And we'll come back and talk some more about this at the end. So the two non-genetic factors likely to influence obesity development are diet and physical activity in a very broad sense. And here we're going to look at diet composition. Here we're going to look at physical activity. And there's a prevailing feeling today that obesity can be prevented or treated by a low-fat diet and high levels of physical activity. The popular press tells you this. Sort of the man on the street believes that a low-fat diet and high levels of physical activity is the thing we should be doing if we want to treat obesity or prevent it. And by and large, I think both these things can have a very positive outcome on treating obesity or preventing obesity. There aren't any long-term trials in which we've really looked at the effectiveness of a low-fat diet and high levels of exercise on either treating or preventing obesity. There's a lot of experimental data which suggests this should be a good prevention or treatment strategy. However, I don't think it's the only answer. I think there are going to be some people who will be affected a great deal by such a regimen and others which won't. I approach body weight regulation from an energy balance viewpoint. If we take a person whose weight's stable, then they have to be in a situation where the energy intake equals the energy expenditure. This produces a stable body weight and a stable body composition. So in one simple level, it looks like all we have to do is measure energy intake, measure energy expenditure, and measure body composition, and we can really understand what's going on. But I guess there's some question as to whether we can measure any of these accurately enough. So it's a major challenge really to do this all in one study. In addition to balancing energy, an individual whose weight's stable and has a stable body composition is also in balance for each of the macronutrients. This has to be the case. The intake of fat has to equal the oxidation of fat, intake of carbohydrate equals oxidation, etc. If this isn't the case, then you accumulate or you lose stored energy from one of these compartments. So it's important to realize that the outset, if we start out with a person who is an energy balance, there's an equality of energy and there's a quality of nutrients. When we talk toward the end of the talk about diet composition, you'll begin to see why it's important not just to look at the total energy in and out, but the composition of energy in and out because the relationship between the intake and oxidation of fat is different than the relationship between the intake and oxidation of either carbohydrate or protein. Let me spend just a minute on telling you in my laboratory how we deal with measurements of these issues because the kinds of studies that we're going to do is to manipulate exercise or manipulate diet composition and look at the effects on energy balance and on nutrient balance. In general, most of our strategy has been since we can't measure this very well to fix intake. So this is the variable that we control, the amount of energy intake and the composition. We measure energy expenditure in a way I'll show you in a minute. We measure body composition, usually with underwater weighing, although we do a number of other techniques. So this is the one we're controlling. We're measuring here here and we're measuring here, this we know from what goes in. To turn for a minute to the energy expenditure side, let's look at the components that we may be dealing with when we measure daily energy expenditure. The height of the bar would be an individual's total daily energy expenditure. Lots of people break it down into different components. Some people disagree about the exact components, but this is a typical way that we might break up 24-hour energy expenditure. The lowest energy expenditure occurs during sleep, we'll call it sleeping metabolic rate. If you have a whole room calorimeter like we do, you can measure this reproducibly. It's the most reproducible measure within an individual. If an individual is lying quietly awake at rest, energy expenditure is a little bit higher, so resting metabolic rate is higher than sleeping metabolic rate. This varies from about 5% to 15%. We'll call it arousal, but we really don't understand the reasons for this difference. Resting metabolic rate is the most frequently measured component of energy expenditure. Probably about 99% of the literature measuring energy expenditure measures this component, usually about a 5- to 30-minute measurement and sometimes extrapolating for longer periods of time. When you eat a meal, energy expenditure goes up. This is called the thermic effect of food. It may be some 8% to 10% of total energy expenditure. The remainder that I call the energy expenditure in activity is the most variable and the most difficult component of energy expenditure to measure. I will show you some data a little later on to try to convince you that understanding this component, the reasons for within and between subject variation, may be very important to the understanding of obesity. This is the way we measure energy expenditure. This is a live-in whole room calorimeter, which the person stays in for 24 hours or longer. We've done studies up to 10 days in duration. You can see that it's pretty similar to a room at the Hyatt Regency. TV, toilet, you can even look outside and watch the traffic go by. The advantages to the room calorimeter are many. There are some limitations, but there are some advantages. Because we control the environment so carefully, we can measure energy expenditure with a high degree of accuracy, about a 1% error as compared to many other systems which have 8% to 10% error. This is a very accurate way of measuring energy expenditure. We can measure continuously over the day or over several days. We actually make our measurements over one minute time period, so we get a very quick response and we get this throughout the day. The limitations are that probably not many of you would undergo your normal level of physical activity if I put you inside this room for 24 hours. By putting someone in and expecting that we're going to measure their usual daily energy expenditure is erroneous. We have to deal with that. The number one use of the calorimeter really is to look at how the system responds so that when we vary exercise or vary physical activity, we can look at how energy expenditure responds. We're actually doing some studies in which we try to assess daily energy expenditure and reproduce it in the calorimeter. We're getting closer, but it's still difficult to do that. We have high accuracy. We can do long-term measurements, but we aren't measuring in naturalistic conditions. We call them semi-naturalistic conditions. Let me show you one of the things that makes our room calorimeter unique. We have a force platform inside. It's not visible in this picture. This was taken before the force platform was put in. The force platform covers the living area. It's on force transducers. It measures the amount of work delivered by the person to the floor. This is very useful because it allows us to really quantify the energy expended in physical activity. You can see obviously the calculations are straightforward. Just kidding. Here's the kind of output we get in the way that we would use our floor. This measurement here is a measure of work performed measured by our force platform. And here's a blow-up down here. We associate that with energy expenditure, and we get a quick response time. For this individual doing walk tests or step tests, we have the amount of work performed, the amount of energy expenditure associated with that, so that we can do efficiencies. How much work is delivered per amount of energy expended? That's one of the aspects that makes our calorimeter unique, is that we can measure these kinds of things. Here's a typical 24-hour recording of an individual in the room calorimeter. This is energy expenditure in Kcals per minute measured over the daytime. We generally put people in the morning. At night, it goes down. This is, it's usually pretty stable. This is just not our best subject, but not our worst. When the person wakes up in the morning, you can see it comes up again. This is respiratory quotient. We use it to determine the composition of the fuel burned, and this is our measure of work. A couple more slides just to show you here. This would be energy expenditure in a typical sedentary person. This is someone we put in the room for 24 hours without any instructions to exercise, and they were fairly sedentary. I'm going to show you on the next slide, an individual who went in with some specified work to show you the difference in energy expenditure. You can see here are the periods where we had the person do planned exercise. I always show this slide to demonstrate the enormous impact that physical activity can have on energy expenditure. The other thing that we can do with our room calorimeter, we can get an energy balance, because we know the amount of energy going in. The dieticians on the clinical research center tell us that. We know the expenditure, so we can get the height of these bars, and we can determine if a person is in zero, negative, or positive energy balance. Additionally, we can do nutrient balance studies. We know the composition of food that we deliver to the person, and from the results of the calorimeter, we can actually divide that into fat oxidation, carbohydrate oxidation, and protein oxidation. It's possible to do both energy balance studies and nutrient balance studies. When we vary physical activity or vary diet composition, we're interested in both the effects on overall energy balance, and the effects on balance of fat, carbohydrate, and protein. This is one of the real advantages to having a room calorimeter. It's one of the few tools in which you can get both energy balance and nutrient balance information. Now, let's turn to exercise, and let's start out with this hypothesis that I'm pretty convinced is true. Exercise must produce negative energy and nutrient balance unless there's compensation. How can compensation occur via food intake? In other words, you increase your food intake to match the energy you expend in exercise, and here we're talking about increasing both the amount of food equal to the energy expended in exercise, and the composition of that increase has to be equal to the composition of the excess fuel you burn during exercise. Unless that occurs, then you're going to produce some negative energy and nutrient balance. The other way that compensation can occur is via reductions in spontaneous physical activity. So if I were to put someone on an exercise program and have them walk three times a week, they might become more sedentary in the rest of their life. There's really no evidence that this occurs, although we don't have very good techniques to look at it. So we have to raise this as a possibility, but I'm pretty skeptical that there's this sort of compensation for planned physical activity. Now in order to adequately evaluate effects of exercise and obesity treatment, the expected effects of exercise must be considered. There's almost certainly some compensation in food intake when we add exercise. So if you're doing a study, for example, you want to look at the effects of exercise and obesity, you plan very carefully how much energy is going to be expended in the exercise, and then you plan for people to lose that amount of weight equal to that energy, it isn't going to happen because there's going to be some compensation via food intake. So you have to be realistic in the overall amount of negative energy balance that you produce. It will be less than the energy expended in the activity, and the amount will be determined by how much compensation occurs, and this is an area where we desperately need additional research to look at how people compensate for exercise. Who does, who doesn't, what's the composition of the compensation, etc. How does exercise affect energy expenditure? Well, it's been hypothesized to affect every single aspect of daily energy expenditure. I don't want to spend a lot of time on the data regarding the acute and chronic effects of exercise on these components. I'll go through it quickly and give you my summary of the interpretation of the data. A lot of people think that, well clearly after exercise, energy expenditure doesn't come down to resting. So if this is resting metabolic rate, your energy expenditure goes up during exercise. It doesn't immediately come down. There's some post-exercise energy expenditure. There may be some extra fat oxidation during this period. It clearly occurs what is debated as the magnitude of this increase and the importance for overall energy balance. And most data now shows that it's pretty insignificant unless you're talking about very, very heavy exercise of long duration of the kind that only highly fit individuals could do. So for obese people, this is likely to be pretty trivial and to be down to baseline in a few minutes. One of the other debated areas is the effect of chronic exercise on resting metabolic rates. So you'll see some controversy in the literature concerning whether trained athletes have a higher resting metabolic rate over and above changes in body composition than non-trained. And I'm presenting one slide from a study we did recently in which we did a cross-sectional study of 78 men and women varying in fitness levels. And we studied them in a room calorimeter. We wanted to see a fitness level was related to resting metabolic rate independently of body composition. We know that fat-free mass is a major predictor of energy expenditure. So all components of energy expenditure we measured whole day and then we divided into sleeping, resting, thermic effect of food, energy expenditure and physical activity. All of them were significantly correlated with fat-free mass. However, four of them were significantly correlated with VO2 max. This is independent regression analysis. However, when we did multiple regression analysis, once we accounted for fat-free mass, then VO2 max wasn't significant in any case. So we interpreted this to mean that, yes, athletes have higher resting metabolic rate, but it's totally due to differences in body composition. So we don't believe there are any direct effects of chronic exercise on resting metabolic rate. Those effects are indirect and mediated via body composition. Doesn't mean exercise isn't important. It still has positive effects because it has positive effects on body composition. If you look at the effects of exercise, either acute or chronic on the thermic effect of food, you can find virtually any answer you want from the literature. You can find increases, decreases, no effects. I've concluded it's pretty impossible from the current data to really conclude anything here. And I think there's some real problems with the way we measure the thermic effect of food and what we're measuring. So right now, be aware of this, but there's no consistent data suggesting that physical activity has a consistent effect on the thermic effect of food. The final component is the energy expended in physical activity. And I think of that as consisting of two components. The amount of physical activity or work you perform, and that's probably the thing that's quite variable. How active are you? How much do you exercise? How much work do you perform? That's a big determinant of this component. The other one is the energy cost of physical activity or the efficiency of exercise. And we know, we really know very little about both of these because we don't have good methods of measuring how active a person is. And we don't, until our force platform, didn't have good measures of looking at the efficiency of physical activity. So we're real interested in this component. Let me tell you why I think it's particularly important. Three pieces of data to suggest that this is a component of energy expenditure that's much more variable than the other components. Here's a study Livingstone in which they used activity questionnaires. A pretty crude way of determining energy expenditure of activity. But just by the questionnaires, they found the range to be 1.44 to 2.57 times BMR. You know, if someone has a BMR of 1800 calories, this is a huge range of daily variation in this component. Analyzing studies that we've done in our room calorimeter in which we just put people in with no instructions to exercise, no bicycle, no treadmill. Analyzing how much energy they expend and it varies considerably. A low of 200 and a high of a thousand calories a day. Here's a person that's expending a thousand calories a day in physical activity in that small room that I showed you earlier. Here's another one. This person, you know, probably only got up from the couch one time during the day. Very low levels of physical activity. This kind of variation inside a small room. Imagine how wide this variation would be in real life. Eric Ravison in his calorimeter finds a surprisingly similar range in the same kinds of studies, 100 to 800 calories. We obviously had one subject who was very active in there. But the point is we look for small differences in resting metabolic rates, small differences in the thermic effect of food as potentially important in the energy balance equation. Here's a component where we don't even have to look for small differences. We can look for large differences between subjects in energy expenditure. So I would maintain that this is an area we really need to know more about. We need to know more about why some people are active, why some people aren't. What are the determinants of amount of physical activity? And then we're quite interested in the efficiency. Are there some people who are more efficient exercises than others? So we've demonstrated that exercise increases energy expenditure because if nothing else it increases it during the bout of exercise itself. It may have a small effect on resting rate, may have a small effect on the thermic effect of food. So again you're going to have an overall negative energy deficit unless you get this compensation on energy intake. Well what do we know about that? From the few studies that have been done it's quite variable. There are some studies for example which show lean people are better compensators for exercise than obese people. It may depend on the amount and type of exercise and on other characteristics of the subjects. Some recent work presented at a recent workshop on physical activity suggests that a number of psychological factors may be markers of who's going to increase food intake in response to exercise. This is an area that we really need to learn more about because the total energy deficit is going to be dependent on how much compensation there is in response to exercise. Now exercise also affects fuel oxidation, particularly lipid oxidation, although it depends a little bit on the type of exercise. And here when we're using exercise to treat or prevent obesity is the goal to create negative energy balance or negative fat balance. If it's negative fat balance there are some types of exercise that are much better at oxidizing fat than others so we need to consider the type of exercise used. It's the best exercise program for body weight control the same as the best program for cardiovascular health where we're told to go out and exercise three times a week for 20 minutes at 70 percent VO2 max is that that will clearly improve cardiovascular health. Are there better exercise programs for obesity? Should we be exercising lower intensity, longer duration? It's an important question. Does the type of exercise program used for weight control depend on the characteristics of the subject? Should we be trying to match the type of exercise to the subject? We can only talk about this theoretically now. I don't think we have very much basis to do this. And what we're really after is what's the best exercise program for the prevention of obesity or the treatment of obesity? And I'm always asked by people wanting to lose weight what the best exercise program is and I think we can talk about the benefits of one type versus the other one but before we get to that I think the first decision is whether to exercise or not. That's the most important one is to do something. Once you've begun to exercise chronically once you've changed your behavior then I think we can talk about one type being better than the other type but the real decision is whether to do it or not and the most important thing you can do is to begin to exercise. And then I think we need to look at what do we measure to answer these questions? Are we really interested in energy expenditure, respiratory quotient, energy balance, fat balance? And I think one of the things that we have to be aware of is fat balance. Obesity is a problem of excess fat and we can measure energy expenditure but what we're really after is positive or negative fat balance. So to summarize on exercise and energy expenditure I think the greatest effect is during the exercise itself. There may be minor effects on other components but this is enough enough of effect to really make a difference.  Some forms may be better at this than other forms. There's no evidence for exercise compensation. I don't think we can say that people who begin to exercise program become more sedentary in daily life and I think this post exercise energy expenditure is probably small and insignificant at least for the obese individual. Now we've talked about the theoretical effects of exercise on energy intake and energy expenditure in body composition. What do the studies show? Is exercise an effective treatment for obesity? Well if you look at the available studies you would have to conclude that with exercise alone the loss of body fat is modest in the available studies. In general men lose more than women. That might be expected. Men have higher caloric requirements. They expend more energy in the same kinds of exercise because they have a higher body mass. Fatter subjects lose more body fat. The more you exercise the greater the fat loss. We know very little about type of exercise. We've always used aerobic. We're beginning to look at anaerobic exercise. But the real problem here, the reason that this is fairly modest is because we're really doing short-term studies. We're looking at the effects of exercise on weight loss over a few weeks. If you look at the energetics exercise isn't going to produce the same sort of caloric deficit that diet is. It's inappropriate to compare exercise over a 12 or 20-week program and say that you got far less weight than you got from a low-calorie diet. Exercise is if it produces a negative energy balance it's going to be modest and it's going to be necessary to evaluate that over long periods of time. Now there are problems with that because obese people don't want to enter a program in which they're going to have success three, four, five years later. They want success three, four, five weeks later. So part of the challenge is going to be if we're going to successfully use exercise to get people to have realistic expectations about the effects of exercise. I tell people who want to lose weight with just exercise not to do any sort of measurements for at least six months and really a year before you're really going to be able to see very many measurable changes. So again the short-term studies, less than 20 weeks, find the effects of exercise either alone or with food restriction on weight loss, body composition, energy expenditure, very modest. This is pretty depressing. However then you go out to the long-term studies and by long term I mean studies which have brought people back a year after weight loss. They haven't followed them this whole period. They've gone out a year later, looked at people who were successful and people who weren't successful and here now exerciser is the best predictor of success. So you take the people, follow them for 20 weeks, exercise doesn't seem to really make any differences. Then you go out a year or two years later you look at who's successful and who's not and whether or not they're exercising is a good predictor of success. So it really suggests that if we're going to understand the effects of exercise we have to get rid of the 20 week studies not nearly long enough and we have to do the long-term studies. Now these are difficult to do. They require lots of NIH funding Jay. So but these are the kinds of studies that I think are needed and really in order to understand exercise. If we're using exercise as a treatment for obesity one of the important points that came out of the workshop I think is that we may have to consider these two separately. Inactivity is a very attractive behavior in this country. So we may have to decrease inactivity that may be a different sort of target that increasing activity. Decreasing inactivity in other words getting a person to be more active just in their lifestyle not even planned exercise could have tremendous impact upon energy balance and that may take a different strategy than trying to increase activity per se. Let's switch gears a little bit for the remainder of the talk and talk about diet composition and this is back to the idea that energy balance isn't enough. If we really want to understand body weight regulation the development or the not development of obesity we have to look at a nutrient balance model rather than energy balance model. The reason is it's very clear now that when we manipulate intake of protein and carbohydrate oxidation is changed in the same direction very quickly even a single meal. We add carbohydrate to a single meal we're going to see an increase in carbohydrate oxidation immediately. So the body is adjusting protein and carbohydrate to the intake.  If we were to add the same number of calories as fat that we did as carbohydrate we're going to see no change in fat oxidation. In other words those calories aren't compensated for they're stored. So you can see that adding adding fat to the diet when fat's in excess it's stored virtually intact 100% efficiency really about 98% efficiency. When carbohydrates added to the diet you get an increase in carbohydrate oxidation it may not be complete immediately but the net effect is that you don't get 100% of the extra calories available for storage. So it becomes real important then to look at the fat to carbohydrate ratio in the diet and how body weight and body fat are responding to that. Now over time if you were to add fat to the diet and keep that fat at a certain level what's going to happen is you're going to keep storing it as fat. Eventually fat oxidation is going to increase but this seems to be subsequent to an increase in fat mass.  So the the fat balance becomes real important in the whole equation and there's been a great deal of work to look at why that's the case why is fat calorie for calorie more obesity producing than carbohydrate and I believe it is.  Now there's a lot of evidence that fat intake does not acutely promote its own oxidation a number of studies using single meals feeding fat over a single day and I'll show you later we fed it over a two-week period where these changes in dietary fat have virtually no effect on fat oxidation so the excess fat is simply going into storage. Carbohydrate intake does promote its own oxidation one study here by Atchison now there are a couple of other studies that show single meals single days week two weeks of carbohydrate overfeeding produce big increases in carbohydrate oxidation. Now what about the chronic effects of diet is there evidence that carbohydrate and fat have different effects on nutrient balance or body composition over time well there hasn't been a lot of direct data here we're extrapolating from the acute studies we're showing that fat has no effect on fat oxidation carbohydrate does have an effect on carbohydrate oxidation so we're predicting that over time fat should should make you fatter than carbohydrate there are a number of rat studies in which this has been demonstrated nicely calorie for calorie over long periods of time rats get fatter on high fat than high carbohydrate diet and then we've relied on correlational data in humans I'm going to show you a study we did to begin to look at the effects of of carbohydrate and fat fed over longer periods of time but sort of to build up to this we've systematically looked at the influence of diet composition in relation to the overall level of energy balance if you look at the influence of diet composition in a food restricted situation the influence is negligible if you're fixing food intake the individual has no behavioral adjustment in other words you can't modify your food intake the metabolic adjustment is slight the composition of the diet has a very small effect almost an unmeasurable effect on energy expenditure when you're eating less food than you require for your your maintenance energy requirements so in a food restricted situation that composition has a negligible effect we did a study in which we fixed energy at maintenance and varied the fat to carbohydrate ratio in the diet the the calories were fixed so we didn't allow any behavioral adjustment we found here the metabolic adjustment was very slight a a insignificant difference in energy expenditure between the high fat and high carbohydrate diet so here again it's negligible now in ad libitum situation we begin to see some interesting results because now there's a higher intake on the high fat diet so you get an effect on the behavioral adjustment you also get an effect on the metabolic adjustment when we put individuals on ad libitum high fat versus high carbohydrate diet what you see is that fat oxidation is it increased by the high fat diet carbohydrate oxidation is increased by the high carbohydrate diet so now you're getting a behavioral adjustment and a metabolic adjustment so you have a high influence of diet composition and then the study that we just completed is sort of the sledge hammer effect when we really wanted to flood the system with excess carbohydrate or excess fat to look at how the system responded to that and what I'm going to show you is the effects of diet composition under this kind of overfeeding situation are very high that even though we're not allowing a behavioral adjustment when there's a great deal of excess available the metabolic adjustment is high enough to have a significant effect of diet composition and one way I think of the response to overfeeding is there's a problem in fuel partitioning and obesity may be a problem in fuel partitioning if you look at energy coming in the body has to do something with that as the first step you can petition it between storage and oxidation you can find in the literature a lot of the the older studies that show you feed individuals excess calories and they expend a lot of it as heat it's been called luscious consumption and dietary induced thermogenesis I'll show you in our data there's very little evidence for that but there is some differences in partitioning excess between oxidation and storage if if you have energy available for storage it can be stored in different tissues it can be stored in fat or other tissues so there's a petitioning between fat and fat free mass if you store it as fat you partition where you store it intra-abdominal adipose depots subcutaneous depots so one of the ways that one could approach obesity is that it's a problem in fuel partitioning tending to partition energy toward storage and toward fat so in the time that's remaining I want to show you some results of a study that we just completed I think it will illustrate both our methods in terms of measuring energy and nutrient balance it will illustrate the effects of diet composition on body weight gain and present an intriguing hypothesis at the end that it may not just be dietary fat that's important so we set out to use our whole room calorimeter to assess the effects of overfeeding fat and carbohydrate on any energy and nutrient balance we're really interested in fat and carbohydrate we did it in lean and obese and I'm just going to concentrate on the first part this is I'll run you through the study design real quick what we do in these kinds of conditions is we take great pains to understand what people are eating and their exercise pattern we they wear accelerometers to measure their movement we do weight food diaries once we get a pretty good indication of what they're eating we bring them in the CRC and put them on a food selected diet to verify really what they're eating so we take great pains to during baseline to show that we can assess the energy balance of these individuals and for the study that I'm going to show you we were very effective at doing that we were the average was zero energy balance in which we where we put people in the calorimeter at the end of baseline so here we bring them in on a self-selected diet at the end of that diet they go in the calorimeter and what we're looking for here is to demonstrate that we have them in zero energy balance that we're feeding them just the amount of energy they need while they're in the calorimeter they wear the accelerometers and we have a programmed activity pattern for them so we're matching their activity to their usual activity and the fact that we get zero energy balance I think means that we did a pretty good job of that then they go through two fourteen day overfeeding periods and one of these they're given fifty percent excess calories in the form of carbohydrate and the other one fifty percent excess calories in the form of fat this is major overfeeding for some of our obese individuals we were giving them seven thousand calories a day so again the sledgehammer effect they were in the calorimeter on days one seven and fourteen they were outpatients the rest of the time one of the advantages of overfeeding is you don't have so much concern about them going out and eating food that you don't know about they were hard pressed to eat all we gave them each time in the calorimeter their activity was carefully met so what we're able to do is look over time at what happened to the excess energy we knew how much energy we gave them using results from our calorimeter we could partition that between storage and heat and then partition it between fat balance and carbohydrate balance but a one month washout between these were all men and the results I'm going to show you are based on I think six lean and six obese men so twelve subjects if you look at what happened to energy expenditure this shows day zero with the open bars carbohydrate feeding the slanted bars fat overfeeding if you look at day one seven and fourteen energy expenditure tended to increase not very much and highly variable not a big effect over 14 days I plotted it down here just as change from day one so that you can see in general the carbohydrate produced a greater energy expenditure than did the fat but it was highly variable suggesting that the increase in energy expenditure was variable from subject to subject now we knew how much of the excess was expended as heat so we assume the rest was stored okay so this would show the energy storage in other words the the excess energy which wasn't expended as heat with the fat overfeeding we found a very high efficiency of storage throughout they were storing virtually 95% of the excess energy that they were storing in other words they expended the increase in energy expenditure was was less than 5% with the carbohydrate we found on day one that storage was high and this fits with the ideal that they're storing a lot of carbohydrate as glycogen however on day seven and fourteen excess energy storage was much lower so with the carbohydrate overfeeding they're partitioning more energy into expenditure and less into storage so one difference between diets right there now from our balanced data from our fat carbohydrate and protein balanced data we could predict what was happening in terms of storing excess energy the top slide shows proportion of excess energy stored as carbohydrate during the high carbohydrate diet and during the high fat diet and basically pretty low storage throughout high carbohydrate storage on day one this is the most interesting result I think because this is our best estimate of the proportion of excess energy stored as fat with the fat overfeeding it was very high all the way through they were storing better than 80% of the excess energy as fat very little evidence of increased energy expenditure with the carbohydrate overfeeding we expected a difference between carbohydrate and fat what was a little bit surprising is the time course they were storing only about 50% of the excess fat on day one about 60 on day seven by day 14 they were storing just as much of the excess energy as fat as were the ones that got fat overfeeding okay so to me this raises some very interesting questions about how obesity arises if we can project that these two would be the same out here we really don't know let's assume for a minute that they would it would suggest that the effects of diet composition would be less the longer the overfeeding so if people get fat by overfeeding for sustained periods of time the composition of the diet may not be important however if people get overweight by overeating a meal here and there overeating over Thanksgiving over Christmas then this is the point at which diet composition can have its maximal effects so if body storage occurs from acute periods of positive energy balance then the composition of the diet may be very important now one of the beauties of the calorimeter is in the next two slides I'm going to show you why this occurred and when I show this data the first response here is that well you've given them a lot of excess carbohydrate and now they're making fat from carbohydrate we didn't see any indication of that this is the carbohydrate overfeeding the top panel is carbohydrate oxidation what we predicted is that carbohydrate oxidation would go up with the excess carbohydrate it did a major increase in carbohydrate oxidation over time just as expected but look at what happened to fat oxidation this is the baseline level of fat oxidation what happened is the carbohydrate in the diet turned off fat oxidation and one way to look at it is there was plenty of carbohydrate available for fuel that's what they preferred to oxidize and they didn't oxidize fat so fat oxidation went down the reason they were storing fat is because now the carbohydrate has turned off fat oxidation so an amount of fat which was their usual intake at baseline is now in excess and they're storing body fat this is what happens during fat overfeeding basically nothing 14 days of fat overfeeding no significant effect on carbohydrate oxidation a tiny insignificant effect on fat oxidation so what's happening with fat is that it's not changing anything the body isn't doing anything to compensate for the excess that the excess fat is simply going into storage in a highly efficient manner so I think this illustrates the important differences in the composition of calories available and the effects on body weight gain fat is more obesity producing calorie for calorie here than it's carbohydrate now how do we reconcile that with some epidemiology data available it suggests that only a weak relationship between diet composition and body mass index so I think we're left with the idea that a high fat diet probably can explain all of obesity not everyone is obese because of eating a high fat diet and I think that's true not all obese people are eating a high fat diet we're very interested in individual differences in response to diet composition differences in the metabolic phenotype I just wanted to show you this is some data we have where we just looked at average daily intake this is self-report and body fat percent a weak positive relationship so I think the idea that all obesity is due to a high fat diet is probably naive and we went back and looked at our data on an individual basis okay here we have the fat overfeeding the carbohydrate overfeeding this is a proportion of excess energy stored look at how tight the numbers are with fat overfeeding very little individual variation with fat overfeeding essentially everybody's responding to fat the same way they're storing most of it now look at carbohydrate overfeeding you're really beginning to get some wide differences here's 50% here's virtually 100% wide individual differences in proportion of energy stored if we look at a proportion of excess energy stored as fat again here's fat with the exception of this one subject who was very interesting again everybody's storing excess fat very efficiently from fat but look at carbohydrate overfeeding now here's where we're beginning to see the individual differences and when we started the study out we were hypothesizing that individual differences in the amount of fat stored on the high fat diet may be very important now we've sort of changed our thinking on this and now what we think is very important is whether or not carbohydrate turns off fat oxidation and that here's where the individual differences are going to be that everybody's going to get fat if given a high fat diet if given a diet which is high in fat also high in carbohydrate then some people are going to be more effective at turning off the fat oxidation and using the carbohydrate than our other people so really what we're thinking about now is that the high fat diet is interesting I think clearly linked to obesity but there are some people which are going to be susceptible to obesity on a diet which is moderately high in fat and high in carbohydrate or possibly a moderately fat diet in which they overeat carbohydrate so I think we can't just look at fat we've got to look at some individuals who may be susceptible to preferentially burning carbohydrate and turning off fat oxidation so to conclude reducing dietary fat and increasing physical activity should reduce body fat content in everyone I think this is a good strategy for treating and preventing obesity and I think we need some long-term trials to demonstrate this the factors which determine the extent of this reduction have not been identified I think some people are going to respond very well to this other people are going to lose a little bit of fat and a little bit of weight a low fat diet and increased physical activity may be an effective strategy to prevent or treat obesity in some subjects I think what we need are we need good markers of which subjects are really going to respond to this type of diet which types of subjects may not be responsive when we talk about preventing obesity I think it would be a mistake to go out and try a low fat diet for everyone because we may get the wrong answer we may need to identify those individuals which may be particularly responsive to a low fat diet and then assess whether this is a useful prevention strategy in that group I think we have a great need to identify subjects who will respond to a low fat diet and exercise and let me go back to the model because what I've talked about are some individual differences in metabolic phenotype and how exercise and diet composition may play a role here but what I want to emphasize is we haven't looked at the behavior but the behavior is very important and the overfeeding for example so what if you store excess fat very efficiently well behaviorally if you never get in a situation where excess energy is available you're not going to have any problems however you may be someone again who when excess carbohydrates available you turn off fat oxidation if excess carbohydrate isn't available then it's not going to be turned off so we can look at the metabolic phenotype and here's how the system will respond under specific conditions the importance over here is whether or not the individual gets into those situations and I've tried to illustrate that schematically here and looking at the interaction between behavioral and metabolic phenotypes you may have a metabolic propensity to obesity and by that I mean you may tend to store excess energy efficiently you may tend to store most of that excess energy as fat that's going to produce a little bit of increased susceptibility to obesity but it also depends on the behavioral propensity if you're an individual who has a high metabolic propensity to store energy well and behaviorally you tend to put yourself in situations where excess energy is available then your degree of obesity is going to be up here so we have to look at both phenotypes either one gives you an increased susceptibility to obesity but it's really both together that leads to this real high degree of obesity and I think by separating them out what we need to do is identify markers for differences here markers for differences here and then when we talk about treating or preventing obesity we have to use these markers to determine which type of treatment is appropriate for which individual thank you very much questions yes yeah the second one first that's a real problem that's a problem for our studies and what we've done is we've gone to a group of foods that are very low in fiber content for our studies because fiber gives us lots of problems and really determining the intake side of it but it is a problem regarding the second one it's a very interesting question you know for years we equated exercise with aerobic exercise as studies are coming out with resistance exercise some quite interesting findings in general the loss of body fat with the resistance training seems to be just as much as with aerobic and you have the additional benefit that you either preserve or increase muscle mass so from the acute studies that are coming out there's some indication that resistant exercise may be useful for obesity it may you know get rid of fat just as much as the aerobic and maintain lean body mass and since lean body mass is a determinant of energy expenditure you know that could have some long-term benefits we don't have any long-term studies with resistance training other questions some of the discussion that occurred at the conference last December on maintenance of level of lean body mass with resistance training versus aerobic training and the frequency of exercise and then the other question would be are you aware of studies actually looking at the degree of energy expenditure with periods of aerobic exercise versus periods of resistance type of exercise yeah the first one when resistance training is added to a weight loss program it seems to be very effective at maintaining lean body mass and if a goal is to maintain lean body mass during obesity treatment then resistant exercise may be important there and another major issue that came up was how much exercise does it take to get a positive metabolic effect and then how much does it take to sustain that and one of the things that we know about exercise if you quit exercising you lose the positive effects very quickly so one of the ideas is once you achieve whatever positive metabolic effects you want with exercise sort of what's the minimum then that you can do to maintain those effects and that's something that's quite interesting but there's no data on it regarding the effects of energy expenditure during the aerobic and the resistance training it really depends on a lot of factors on intensity intensity related factors and subject characteristics the major difference one of the major differences is the fuel utilized because the resistance training tends to utilize carbohydrate tends to be intense utilizing glycogen stores and the aerobic the longer the duration the more that it should depend on fat oxidation so that's a little surprising given the results coming out that suggest the resistance training is having just as much effect on loss of body fat than is aerobic yes that's two tough questions the question is how do we know what's the appropriate body weight and what we've done in the past is to try to relate body weight or more recently body mass index to mortality and there's the typical sort of J-shaped relationship where at the low body mass index there may be a little increased mortality and at the high end it goes up with body mass index and we take sort of the steady state as saying well this is the lowest mortality so this is sort of the appropriate weight and body fat for an individual it's an issue which is which is hotly debated how do you define that we know for example that it's not just the amount of body fat you have it's where it is so if you're you know if you're a woman with the body fat in the you know subcutaneous lower body fat which isn't strongly linked with negative metabolic effects should we be evaluating your weight differently than if you're a man with intra-abdominal fat which is known to be linked to that so that's not an easy question this the second one is is obesity necessarily bad and again I think we have to look at the the distribution of body fat we know that intra-abdominal body fat is strongly linked to diabetes cardiovascular disease etc I think where it's not quite so clear is where you have an overweight female with lower body fat in which the the risk of those diseases may be very similar to a lean man and the question is there should we be treating that obesity that's an issue that has come up at all of the obesity meetings over the last few years and has generated a great deal of discussion and at this point there are individuals who are adamant on one side or the other but there's certainly no consensus I think if we link it to mortality there certainly is a question that can be raised about the the woman with the lower body fat issue at risk for for for bad things and if not should we do something it's really an open question yes yeah it's a good question right yeah we've done a great deal of work in that area with the rat model and I can tell you in the rat that the only type of fat we've found so far that makes a difference is a diet high in omega three fish oil in that case the animals with comparable fat in the diet don't get as fat they maintain insulin sensitivity if we look at saturated versus unsaturated we find some interesting differences in the way the obesity develops but in the long run they're equally obese and pretty minor differences between say corn oil and and lard is a fat source whereas if you go to something like fish oil it is very different but this is a diet containing fairly high amounts of fish oil yes Barbara that is the increased the exercise food intake increase and body weight stayed stable except for the extremes that is when the exercise was so much yeah right right yeah so you're so the the sedentary people and the real ultra athletes and if you look at the ultra athletes and we've studied some of these and I think their problem is getting enough calories in their their energy expenditure is so high I mean you can only spend so many hours in the day eating and their calorie demands are so high and they typically consume a high carbohydrate diet I think you're right and I I think the key maybe getting people in the middle or at least getting the sedentary people in the middle if you look at our hypothesis about sort of reductions in in lipid oxidation really being predictive of obesity development exercises is the most obvious thing that can influence that because just whatever form of exercise you do your total lipid oxidation is going to increase particularly if you do aerobic types of exercise consistently this is a way to get your lipid oxidation up so if you're someone who tends to when you eat carbohydrate suppress lipid oxidation one of the best things you can do to to get around that is is to have a high level of oxidation of exercise that keeps your lipid oxidation high so I think yes get getting people into that at least the moderate exercise range maybe very important getting back to your previous comment about the omega-3 fatty acids I'm sure you're aware of the controversy in that area with regard to human studies in your discussions with other investigators have you come to any resolution how do you interpret your observations versus the slight but distinct worsening of glucose homeostasis in humans that are fed high omega-3 diets yeah I don't know it may be a dose effect because the humans don't get nearly so much but we find with the rats that as the you know in a year of feeding the omega-3s they they really maintain a very high level of insulin sensitivity but these are diets containing 40 percent of calories from fat and and most of that from omega-3 so I don't know it may be a dose effect it may be a rat human difference you know I think we we need to learn a lot more about the omega-3s before we start promoting omega-3s as as sort of anti-obesity fats because I think there may be some drawbacks to those and in the rat studies we're we're particularly interested in looking at the mechanisms whereby the are really looking at where the omega-3 fatty acids are going when we put it in the diet so I think it's too soon to say that this is the fat that should be included in large quantities in the diet yes there are people that argue for the set point one of the problems that I have with the set point is is I guess I was taught that a that a good theory should you should be able to disprove it and and you really can't with the set point if you do a manipulation and everything stays the same well they say well you know set point works if it changes they say well you change the set point so you know I don't in concept the set point and the settling point aren't very different that the difference in the settling point is that it's not that you're regulating anything per se body weight and body composition sort of are the result of a lot of other regulated systems and when you change any of those systems the system is going to reequilibrate reach a new settling point dose effect because the humans don't get get nearly so much but we find with the rats that there are people that argue for the set point one of the problems that I have with the set point is I guess I was taught that a good theory should you should be able to disprove it and you really can't with the set point if you do a manipulation and everything stays the same well they say well you know set point works if it changes they say well you change the set point so you know I don't in concept the set point and the settling point aren't very different that the difference in the settling point is that it's not that you're regulating body weight and body composition sort of are the result of a lot of other regulated systems and when you change any of those systems the system is going to reequilibrate reach a new settling point so right yeah it's easier to gain weight than lose weight and the question is is that a metabolic phenomenon or is that really a behavioral phenomenon and I don't know I think probably everybody in this room would agree it's easier to gain weight than lose it but I don't know that that argues necessarily for a set point in the set point theory we really don't know the people that are arguing for the set point it's not clear what it is that's regulated is it body fat is it body weight is body temperature there are a lot of things that could be regulated and yes the system responds as if there were a set point but things like exercise for example seem to if you add exercise chronically to a rat or to a human you're going to change the level of body weight and level of body fat is that changing the set point or is that just the system responding to other kinds of conditions I think largely we're talking semantics here I think everybody realizes that there are lots of things like activity and diet composition that can cause you to end up with a different body weight and body composition then I think it's interesting to look at the mechanisms there do those mechanisms respond more like a temperature control system or is the system just responding to the end result of other regulated systems yes good question both what seems to happen is it depends a little bit on stage of life there are some stages in life where it's sort of a critical period for developing fat cell number but in general the first response is for the fat cells to get bigger so you have excess fat that needs to be stored somewhere you have a lot of fat cells first thing that happens is they get bigger at some point then they recruit new fat cells and the factors regulating this are an area of great interest we need to learn more about why does one fat cell possibly send out a signal which recruits new fat cells so in every form of obesity you're going to find increased cell size you may or may not find increased cell number in some models you do some models you don't if we overfeed and the other thing is that increase in cell number can occur anytime in life we used to think it was only occurred if you you know got fat early in life but we can take adult rats feed them high fat diets and we can produce increase in cell number at any time in life yeah unfortunately we haven't found anything that can get rid of cells you can change their size and make them small but if you have a lot of them you're still going to have a lot of small cells yeah that's a good question and you know a couple of things come to mind and this is just speculation I think it'd be real interesting to look at what happens to to fuel oxidation after the resistance training so you may get increased carbohydrate during the exercise itself what's it doing to fuel metabolism later in that day in the next day and so forth so I'd like to see some longer term studies there I guess one hypothesis is that a calorie deficit it's a calorie deficit if you expend the same number of calories even if it's from carbohydrate that it's having the same effect on fat loss I have trouble accepting that so I'm looking for other kinds of explanations but these studies are really short term a few weeks 10 weeks, 12 weeks I think it's important to follow that out and see if the if the loss of fat ultimately is the same in the two conditions in terms of the lean subjects you know if you take a chronic exercising subjects that are in energy balance then you know you're going to see intake equal expenditure I guess the question is are people trained aerobically leaner than people trained sort of with resistance training and it's a mixed bag in a very general sense the the leanest are usually the the distance runners but you do find some resistance trainers that are pretty lean so I think it's impossible to just on the on the basis of looking at chronic athletes to sort out those effects but there are some resistance trained athletes that tend to be pretty lean weight lifters not so much but some of the other ones tend to be lean yeah in fact that's we're looking at insulin sensitivity as a key in the whole thing I think insulin sensitivity maybe one of the mechanisms that underlies fuel partitioning and determines what's going on it's a complicated sort of area to know exactly what's happening and one of the things about insulin sensitivity is you really have to define how you're measuring it there's whole body insulin sensitivity which is a reflection of a lot of different tissues then you can look at insulin sensitivity differently in the different tissues and one of the things that we're interested in is sort of the time courses we feed high fat diets what happens to the time course of development of insulin resistance in the different tissues and in general with high fat diets you see resistance at the liver first and resistance in the adipocyte comes much later so there may be these periods where you get differential insulin sensitivity in different tissues that may be influencing the partitioning of fuel from one tissue to another so I think the insulin insulin sensitivity really is a key player in that yes yeah well you know this is an area that I'm not up on and some other people may want to answer it but it seemed like when that first came out everybody was poo-pooing it and saying that you take them out and they grow right back and then it seems like I saw some interesting studies to suggest it wasn't quite that simple that there may actually be some some permanent effects at least that it doesn't come back in that particular depot so that's my only recollection of where the fuel stands I don't know van do you want to comment on that well information because I know that they are looking at the question in a preliminary way right now but again it has to be recognized that most of the fat cells that are removed during liposuction are subcutaneous and not the what we feel are the more metabolic like active at least with regard to the health risks of the visceral fat or intra-abdominal fat so it's influence on health risk we would expect like at the moment to not have a major impact but again we don't have studies to back that up Jay from the overall feeding studies are there any data to suggest that the diet composition causes different distribution of fast deposition? yeah there are no data but I think it's an interesting question and I you know I think in terms of individual differences in metabolic phenotype I think one of the places we could see important differences would be you know two people may store the excess with really the same degree of efficiency but if it goes intra-abdominally one and more subcutaneous than the other one that could be an important difference I know that Claude Bouchard has some data which suggests that twins respond similarly in terms of just the amount of fat versus lean mass that they put on during overfeeding but I don't know any data about the distribution per se they're that's right yeah yeah just to comment on one what's your reaction to okay if instead of talking about obesity what you're talking about has some interesting effect low fat diet has other positive health effects cardiographs right exercise has a lot some other approaches to diet such as very low calorie diet seem to promote more cycling and there is some very disturbing evidence that people that lose a lot of weight are worse off health-wise and it may be losing gradually which is probably going by somewhat reduction in the proportion of fat and exercise if you take all those together there should be a substantial gain on the health side from that strategy compared to other strategies I agree with your last statement that I think there may be some advantages there I think some of the data you're referring to on the potential negative effects of weight loss some of the epidemiological data and I think as that data is being re-analyzed separating out voluntary from involuntary weight loss it's the involuntary weight loss that has accounted for that so I don't know that we can use that as a reason per se but I've always been intrigued by the idea that the slow weight loss may be beneficial now there's very little data in support of that because most any kind of diet that has been used has been largely unsuccessful in the long run that you get weight regained after the moderate diets versus the very low calorie diets but it seemed to me that there may possibly be some advantages to this sort of slow weight loss but I think the objective data are a little... What does the verse say Well again, you're talking about a very controversial area and we've done a lot of cycling work primarily in the animal models and we've never found any of those effects so I'm skeptical of the effects at least in terms of body weight gain the idea being that you lose fat and lean and you gain back more fat than you do lean and ultimately this cycling is producing a more obese state I tend to be very skeptical of that and in looking at the data in the literature I don't think there's a lot of support for it but it's a highly controversial issue you'll find a lot of people that would stand up here and say that it is bad I don't think it is so I don't think that's the reason but I still think that a slow sort of weight loss whether you keep it off or not it's going to depend on if your behavior can match your new lower body weight if it can't you're going to go back up and the slower rate of weight loss may in some people give them a better chance to adjust their behavior so that ultimately they're going to keep the weight off Yeah, that's a good question if you look at the typical American diet which is now somewhere around I don't know 37, 38% of calories from fat the question is what's the optimum diet for weight loss American Heart Associations tells us to go down to 30 and eventually we would want to go down to 20 I think it really depends on the person I think that everybody is going to experience some weight loss from lowering dietary fat but I think it's going to be difficult to predict between and individuals because really what's going to happen is if you lower your dietary fat your fat oxidation for a while is going to be higher than your intake you're going to lose body fat mass the amount of fat mass you lose depends upon how long it takes you to reequilibrate how long does it take you to adjust your fat oxidation down and that's something that I don't think we have any way of predicting so that in some people I think switching from a 38 to a 30% fat diet would have a big effect other people switching a larger lowering of fat may have a lesser effect so I think it's going to depend on a lot of these individual differences in metabolic phenotype but I think in general the strategy is the lower the better now if we're talking about a 20% fat diet I think it's very difficult to eat a 20% fat diet and live a normal lifestyle so I don't think there would be anything wrong with that I think many of us would be better off if we could do it if you look at how much fat we really need to be healthy it's only a couple of percent of our calories for essential fatty acids so I don't think we have to worry about getting our fat down too low so I think sort of the lower the better but you've got to have a level that you can maintain you've got to be able to change your lifestyle so you can make a permanent reduction in that well if you're looking at sort of the relationship between dietary intake of these and energy metabolism I don't know of any data that's looked at that systematically you know relationship of the vitamins to to diet composition and energy expenditure energy metabolism I don't know of any you know that specifically looked at that well there there are a lot of studies about meal patterning and again the results aren't consistent at all but the idea is always intrigued me because we know there's a there's a pattern to metabolism during the day and I think it would make some sense that within an individual the pattern in which you you consume the food in relation to your pattern of metabolism may play a role from the reading of the literature there's no strong consensus that that's the case I think there are a lot of evidence a lot of them are rat studies in which fairly substantial alterations in meal patterning affected lipogenic enzymes etc which which could potentially play a role so I think at present it remains an intriguing hypothesis and I'm particularly pretty interested in that I think there are lots of reasons why it could make a difference but in terms of you know concrete advice that we ought to begin data in support of that right now yeah it's an interesting question and and and as far as I know I don't think resistance has ever been used in maintenance I don't know of any studies that have used anything there except aerobic hopefully those are going on now as people are are more aware that aerobic isn't the only kind of exercise but in terms of maintenance I don't I don't know yeah yeah it it you know this idea though think about it if you're saying that the obese individual which has more fat free mass to start with we know that these individuals have more now I'm not sure that we know it's beneficial to minimize that during weight reduction I think you can make that argument it relates to energy expenditure and so forth but are you really when you lose fat free mass with weight loss are you really just returning to a normal situation anyway so I think the first question is whether it's desirable to minimize fat free mass loss you certainly could argue it is and I'm not arguing it isn't but you know what's the composition fat free mass is a heterogeneous tissue everything except fat so what we don't know is what's the composition of that increased fat free mass that occurs when you get a bees and then when you go back down are you simply losing that extra that you put on yeah and in this particular study we used a lot of simple carbohydrates just because you know we had to get all this food in and we were we were limited in the kind that we could do I think that's a question that's unanswered I think it's an interesting question are carbohydrate overfeeding we used real foods we didn't want to use formula diet so we had the dietitians work with the individuals to the foods that they liked and that would eat and they tended in this study largely to be simple carbohydrates so we don't have any data on that but I think it's a very important question I want to again thank Jim and thank everybody for coming out this evening I also like to remind you that the next lecture in this series will be on Wednesday February 10th and entitled human studies on obesity it'll be presented by Dr. Jules Hirsch who's physician and chief at the Rockefeller University in New York City and we are also making this lecture a tribute to Dr. Henry Sabrell who is a former institute director of our institute and a former NIH director as well and who contributed significantly to the studies of obesity especially human obesity and he passed away this past fall and this will be a special tribute to him as well again, I remind you that for the dietitians there is a sign-up sheet in the back for CEU credits and anybody that wants to be placed on a mailing list that isn't already on the mailing list if they could leave their name on the sheet of paper in the back as well thank you all for coming out


Inflammation of central nervous system, CNS, is usually associated with trauma and infection. Neuro inflammation occurs in close relation to trauma, infection, and neurodegenerative diseases. Low-level neuro inflammation is considered to have beneficial effects whereas chronic neuro inflammation can be harmful. In an Indian system consisting of pattern recognition receptors, macrophages, and complement system plays a key role in CNS homeostasis following injury and infection. Here, we discuss how innate immune components can also contribute to neuro inflammation and neuro degeneration. This article was authored by Apishak Shostri, Domenico Marco Bonafati, and Uday Kishore.


I'm American, so I went out to my relative's cabin on July 3rd and watched the fireworks out on the lake. It was a grand old time. But on July 4th is when we actually celebrate. So instead of doing fireworks again, I opted to stay home for the night, hunker down with the wife and watch a great film on Netflix, but then decided to watch The Ice Road instead. Before I really dive into this one, I have to first apologize to some of you viewers out there for my review of the Tomorrow War. Had I known that the quality of films coming out in 2021 were the Ice Road, shit, the Tomorrow War is a 10 out of 10. I take everything back. It's a flawless film in comparison. Because dear god have things fallen. Where to begin? You know, that's kind of the question here, isn't it? It stars Liam Neeson and Lawrence Fishburne. I don't blame these two for taking on the roles, you know, they have to eat at the end of the day.  I mean, come on, they're American heroes here. The plot is simple and straightforward.  In order to keep these guys alive until there's time to dig them out, they need to replace some sort of a coupling or piping that's going to give them breathable air. The problem is twofold. They're up in Northern Canada, it's hard to gain access to that place easily. And two, the part that is required weighs 25 tons. How are they possibly going to pull this off? They're going to call up the Ice Road Truckers. I believe this movie was inspired by the reality TV show, the Ice Road Truckers. My father-in-law watched it religiously. I saw maybe 20 minutes of it.  So that was already enticing enough to get me to watch the movie. Now, as I'm not the target audience, I did make sure to call up my father-in-law before I put this review out to see what he had to say.  He didn't like this movie at all. So my criticisms are just here. They're fair and they speak to an all-encompassing audience, to Ice Road enthusiasts and cinephiles alike. Speaking of moviemaking, this is a first for the director who has previously written films like Armageddon, but never really been behind the lens of a camera. And you can tell. It looks awful. Cards on the table. I watched this movie as a joke. I knew it was going to be bad. I saw the title. That was all I needed. Didn't watch a trailer. There's always a part of me, though, that is hoping I'm going to be impressed and blown away by a movie.  Well, we just blew your mind. This is amazing. One of the positives I'll give this movie right out of the gates is it truly makes me appreciate a good filmmaker. There are so many shots in this that are just done so against the books of how you're supposed to set up a shot. Like for instance, when we're first introduced to Lawrence Fishburne's character, he's underneath of his rig with the flashlight kind of just checking things out, you know, doing his spot checks and whatnot. And he talks to one of his subordinates who comes over and tells him the mission they need to go on. And the camera just jumps between two static shots. One is looking down on Fishburne and the other is looking up at this other guy. Now a competent director would look at this scene and they would say, Fishburne is the dominant player here. He's the boss. The framing of the camera should be in a stoic way or in a way that lets the audience know that he's an intimidating character. He's a character that we should respect and listen to. And it should also show that he is in charge of this situation. But instead, we're looking down on him the whole time. So we feel like we're empowered here. We're better than this guy. And this guy is cowering to the dude above. Like, it's just so horribly set up. And that's just one instance. The whole movie has this very, very cheap kind of high school college filmmaking thing going on.  And I had two cameras. So I would just, you know, like do the one static shot and the other one I would kind of be flexible with and move around. And I look back on those movies and they're very similar to how this was set up. I'm not complimenting myself here. I'm putting down this director because he's filming the same way I did when I was 16. Who cares about the filmmaking, Adam? We're here to see big rigs drive across ice and get in scary situations. I don't know what the term is for a guy that appreciates semi trucks. I'm not discrediting you in the slightest. Everybody has their hobbies.   Because anytime an event takes place in the film, it's really, really bad CG work going on and really bad camera shots. So you don't get the good filmmaking. You don't get the semi porn. How's the acting? Oh, it's bad. It's bad. Liam Neeson is just putting in the bare minimum here. Fishburne has so little to do.  And the actress, no idea who she is, a new up and comer, horrible. Just horrible. And I don't totally blame her. The dialogue she's given is insulting at best. The scene direction is so comically bad. There's a point in the film where one of the characters dies. Spoiler, someone dies in this. There's a whole cliche scene where he's getting pulled into the water and he's like, just let me go. Just let me go. Because there's just no way for him to get out at this moment. And it's over so fast. You don't even have a second to process it. And he's never mentioned again. No one talks about this guy. And they don't even shed a tear or really even any sort of remorse. And he was a good dude. They're just like, eh. This is what happens on the ice, baby. We're all emotionless because we know the job here. Oh, and if you weren't sure if this type of industry is dangerous, they make sure to tell you about 50 times in it. At one point, the semis flip over on their sides, each carrying 25 ton pieces of equipment. And I'm like, well, this is game over. How are they possibly going to get these things, you know, to the destination in time? They have 30 hours. They've already been driving for over a day. I mean, this is game over, man. No, not at all. Well, Liam Neeson grabs a couple chains and they just kind of pull the semi-trucks up. I really don't know how they did it. You have 25 tons each plus the weight of the semi-trucks. I don't know how you pull them up like this with a winch. That's going to pull that much weight. That seems very, very farfetched, especially on ice that was already cracking under the weight of one of these things. Now you have two of them. They said something about weight displacement. I don't think the science is sound in the slightest here. That scene was cool, though, where the ice was breaking. It's like behind them and you get these underwater shots looking up through the ice of the trucks. It looks so fakie. I loved it. It was so good because it was so bad. The Ice Road film has a lot to say, though. This isn't a film just about saving some minors or about corporate greed and bad guys. No, no, no, no, no. This tackles the opiate crisis. We have racism in this. We have PTSD. It's got every flavor under the sun for you to think about. This is a deep film. It's complex. Everything is on the Ice Road, baby. The music in this?  These guys could just be driving down the side of the road and the music is just all in. Liam Neeson is adjusting his mirror. They do a close-up shot of the gauge at 60 miles an hour. Their little dashboard bobbleheads are going. Easily, my favorite scene in the movie is when Liam Neeson and friends drop a bad guy off the side of a cliff in his truck. He rolls about a thousand times to the bottom. Of course, he's not dead. We know he's not dead. He's dead and out of that alive. Unscathed, as a matter of fact, zero scratches, zero bruises. He's perfectly fine. Not even a limp.  This causes an avalanche to come down the hill. Meanwhile, our crew down below sees this coming and Liam Neeson is like, we got to book it. We can outrun this thing.  We can outrun that. She was right. They start to book it. While the ugliest CG avalanche I've ever seen starts to unfold on them, it's amazing. And as I said, the girl was right because she gets taken out by the avalanche and there's like pieces of the tree thrower. Liam Neeson's just like, hang on, pulls it out. She's fine. She's perfectly fine. You know, come to think of it, this was the perfect 4th of July film to watch. These guys are about as American as it gets. At one point, Liam Neeson falls under the water, frigid ice, gets out. All it takes to heat him back up to room temp is to just throw on the heater. These semi-trucks are awesome. I was going to give this one out of 10 opiates, but now that I think about the context of everything, it being the 4th of July, having Liam Neeson and Lawrence Fish doing their best, I think this is easily a 12 out of 10 opiate. This movie is a touchstone cinematic classic that everybody should watch, and not me. And I definitely didn't have to fast forward the last 25 minutes of the film because I hated myself so much for wasting my life away on it. Hope you liked the review. Special shout out to Netflix for constantly ruining my afternoon. If you liked the video, make sure to hit the like button and subscribe to Adam Does Movies. I do a lot of these Adam Rantz videos along with my flagship show Movie Feuds that I've brought back recently. You can also find me on my second channel, Adam Olinger. You could throw a dollar or two on my Patreon at Patreon.com slash Adam Does Movies. I'm on Twitch at Adam Olinger. I'm on TikTok at Adam Does Movies. You see how I have this kind of back and forth thing going on. It's really quite something special. Join me.


So the curry comb is a good place to start and I'm going to start with his feet sort of in place. Maybe I work my way to the rear and then I'm going to step to the side just to get him to consider me just a little bit more. He's looking away but it's alright because he's allowed to be curious and he is considered of me. He's not looking away and forgetting that I'm there. But every once in a while I like to change it up. I like to brush and then I like to move their legs, move their hooves. And so it's sort of the same concept just different ways. So the barrel, we could roll that barrel and obviously he's looking at it really well. He's got his ears forward on it and now there's that little bit of a skeptical look. He's got to arc that barrel and so now he's got to track it but arc it. And then that right hind leg has to cross under like there, like there. See that? One of my main points to working with people starting young horses is when they're nervous about something, they first need to look at it, then they can bend and that bend can go through their body and then it would be really nice if he'd cross his hind legs and face up to something. And so we're teaching that with the barrel. We're teaching that even in our presentation when we're brushing. And then if I had a whip, it's not a weapon, it's a whip. So just like the barrel as well. So I lift it up, I draw him to it, I start to arc. Even right here he's slightly crossing the hind legs. So I start to arc around. Good, I turn, lower my posture and we settle. And then I'm going to pick it up again. Pick up, I'm lifting my posture, lifting the whip. I might even lift my lead rope there. And then I settle but this time I rub it on him. So lifting, movement, action. Settling, softening, and then in action. So we're getting him used to that whip. This right there he's just a little bit, a little bit goosey, nervous with it, sensitive with it. Good, lifting, moving, settling, stopping. Lifting, moving, but this time I took him in a slight arc around me, settle, halt. Always wanting to be able to come back to bringing that life down at any time and come back to a halt. So different objects and I think that not going at a horse but first having them track it, come forward, chase the danger, look at that point, you know, come to the thing that is interesting. Now see when I bring it under that can be really hard but I was far enough away. But see how when I bring that under or over, switching eyes. And so we're getting to where he's just tracking that. And then I start to cut more of a, sort of a, more of an angle. I tend to go more maybe past his side, more and more, until I go past his rump. And so in a sense it's sort of coming at him just a little bit more. But I don't want to present it in a way where he thinks that I'm directing it at him in a negative way. See I'm coming past his rump at more of an angle but then I follow up with bringing him to it. So I lift it, I'd come past that rump a little bit more, bring him to it. Now I come over the top, now maybe I touch him. And notice we'll wait here until maybe he blinks a little bit. I could even step him forward with it. That'd be better. If just because we can have him touch the, we can touch him with a flag, standing still doesn't mean he would touch it in motion. But if he could carry the flag in motion and walking, chances are he could handle the flag standing still.  And I realize he's still skeptical but he's learning, he's not getting into trouble with these things. Now here I was more direct. Put it on there, but watch I'll step to the rear slowly and then we'll just go off and I'll walk away. And then he has a chance to sort of relax a little bit and walk. When I stop, he stops. Good, coming over the top. Good. Good. That's fine. Now if he sort of decided to move his feet, which I think is actually a good choice because he didn't know where to go. So he said, I'll circle around you. And I think, you know, that would be all right with me. What I don't want to have a horse do is get there stuck, all four legs stop, be straight and get stuck. And this is how I set things up. If it's an arena ball or a bike, I've done bicycle, getting horses used to bike riders. I would do the same thing that I'm doing now. And you might say, that's the same presentation he used with the flag and the curry comb and the brush. And it is, it very much is. So the idea being that first we draw him too, then we arc. And why? Well, he looks, he draws, he can see it out of one eye, he can cross, he can bend and he can cross the hind legs. He can face it, he can turn and look at it. And then it gets to a point where he goes, well, just, I'd like to stand. And I say, okay, let me just put that pad on you. And you could, you could stand. And now I'm going to get lively, ready? Lifting. And I'm going to work the pad where my leg will be when I ride. And I bumped, put some motion in life in the pad and then I might stop. And we start. And this is what I do when I ride them. So I get this real, really good. Really, really, really good.


What I thought about today was just, it was awesome man, you know, just getting in the room with kids and, you know, they just got so much energy and they were so excited to be able to, you know, take Q and A's from them and the funny questions that they have but then sit and read with them and interact with them and then I always love to close the book and ask questions, follow a question just to see if they was paying attention. So what's the title of this book? Stevie. Stevie. All right, so what y'all think it's about? Stevie. Okay. What the Hartman Center is important for myself and my sister in the ways of our foundation because we just understand the importance of literacy and the importance of reading, you know, with our kids at a certain age, you know, we know that the foundation is built, you know, second, third grade and to be able to team up with Marquette to do that, I'm a place where I went to school, a place where my education, I'm a father, so important and so cool at the same time. So I'm just glad that we have a program in Marquette like the Hartman Center and I'm glad that Waze Road Foundation is able to come in and help to try to help, you know, our kids be better. I mean, you got to have the heart for, you got to just love, first you got to love kids and, you know, obviously in this greater, in this Milwaukee area, you know, to start at a young age, you know, will help, you know, the future and, you know, I think for myself, my job and my sister's job is just to leave our mark on this world, you know, while we're here and while we have the opportunity, while we have the blessings to do it. Or if you want to be a part of something, I think being a part of kids makes you feel great about, you know, what you're doing and come and check it out and I think you'll see for yourself.


All right guys, so I'm hanging out with the one and only the realest housewife, Miné. Hi, Miné. Hi, how are you, dear? I'm good. How are you? I'm easy.  Thank you. So, today is women's day and we're here to celebrate women in film.  Yes, I was nominated for Best Actress in a TV Drama. Best Actress in a TV Drama. We are rooting for you. Your outfit is gorgeous. Thank you so much. How long? Best by Afro Street and Native Woman. It's a collaboration between Kenyan designers, eyelabs supporting women and empowering women. So yeah, I look beautiful in red. So Queen of Shade. Queen of Shade.  How has the two weeks, the two weeks of the show has been running? How has that been for you? I think the show is very successful and you have seen the numbers and the ratings. I thank Nairobians for the love. I feel the love. One thing I said, even in the premiere of the show, is that I was the realest and you have seen that through and through. I'm real. I speak my Swahili language. I think it's beautiful. And I'm embracing who I am as an African woman and that's what people should take from it. You don't have to feel like you need to be Westernized or European. Just be you and be yourself. And I tell my true authentic self. I also actually bring, I bring people back to where it started all for me and it started here at K&T. And I'm happy that I'm back here and that I've been nominated. Mene, do you feel that you're the one carrying the show? The real housewives? Am I carrying the show? Guys are saying that I am carrying the show. I should take some insurance because hey, it's baddening me. But, well, I think we all brought it, but I just feel like I am the realest and people can actually relate to me, right? Kenyans can actually relate to my growth, my story and who I am. So I feel like it's just being me and just being real. And I feel like that's what Kenyans love. All right, Mene, I have a good feeling you're going to get this award. So we're going to be here interviewing you post the award. So, Kari Boussana. Thank you. I appreciate it. Thank you. Thank you. Bye. Bye. Bye. Bye. Bye. Bye. Bye. Bye. Bye.


The study investigates the effects of 36 naturally occurring flavonoids on nitric oxide, NO, production, in macrophages, exposed to an inflammatory stimulus. The results show that 8-flavons and related compounds inhibit INOS protein and mRNA expression, as well as NO production, by inhibiting the activation of nuclear factor B, NFB, and signal transducer and activator of transcription 1 and stat 1. These findings partially explain the pharmacological efficacy of flavonoids, as anti-inflammatory compounds. This article was authored by Marie Hamelainin, Brinana Minin, Piavoella, and others.