 to the third year of these lecture series on clinical nutrition and obesity. Again, we this year we're starting a little bit later than we have in the last two years but we hope that this will be an exciting series and in the back of the room on the back table I have left a poster type of program for the whole lecture series that will be taking place this spring. There are only four lectures this year with the next one being on April 13th and entitled nutritional findings and interventions in the age patient by Donald Kotler. However this evening in order to launch the series we have brought Dr. Judith Stern from the University of California at Davis and she has been associated with one of our NIDDK funded clinical nutrition research units there. She's been instrumental in developing an animal models core for the study of obesity there and has been very active in numerous societies in promoting both nutrition and education, both research and education. As an example of some of her past accomplishments she is the immediate past president of the North American Association for the Study of Obesity and she is currently chair of a National Academy of Sciences committee dealing with evaluation of outcome criteria for obesity weight loss programs and has just recently heard that she will be becoming vice president-elect of the American Society of Clinical Nutrition and so we all hope welcome her this evening and let her begin her talk and telling us about physical activity metabolism and weight control or in her words if the new word is weight management. Thank you. Thanks very much fan. I really feel privileged to be asked here to NIH to not only give a research lecture this afternoon but to talk a little bit about obesity with respect to physical activity and metabolism and diet and before I start this lecture I want to thank a few people. Linda Hubbard do you ever stand up in an audience? Could you stand up just for a minute? We had a wonderful dinner at the Hubbard's house and I think I had my five a day for dinner and it was just special and it feels very good to do that and I want to give you I think what's a take home message that I'd like for you to go away with from this lecture and that's obesity and I'm sure you've heard this from many other people is a very complex disorder. It's more than just eating too much or being less active and that it has very firm biological bases and it's when the individual albeit a human or a genetically obese rodent comes in contact with perhaps diet that's high in fat or a plentiful food supply or in activity that in fact some of these underlying characteristics can actually blossom so to speak and being chair of this committee for IOM has been a challenge and I think that well I can't talk about the report because it is embargoed I think there is consensus among the community that we really fundamentally don't understand why some individuals become obese and some don't and we think it's very important for example that that institutions like the NIH continue to forge ahead in trying to find out the basics for what chromosome genes are what genes are involved in body weight and obesity but at the same time we as practitioners have the obligation to our patients and clients to provide the best that we can provide for them and so the reason why I talk about weight management it shouldn't only just be loss of body weight but we're trying to think in terms of physical fitness better and nutritional practices probably feeling better about yourself and try or the client feeling better about him or herself we're trying to get that message across whenever we can so that was the two-minute commercial and now let's talk a little bit about obesity I'm not going to give you the standard slides that obesity is harmful to health I'm sure you know about increased morbidity and mortality in the obese I do have just a few preliminary slides one of which is from the work of Dr. David Williamson where he's just looking at incidents of 10-year major weight gain meaning an increase in five basal meaning body mass indices units among men and women and men are shown in the open bars and women in the closed bars and it comes probably not as a surprise to many of us women that from the ages of 25 even to 74 women gain more weight than men do and that it isn't just the amount of weight you gain or your body weight or even how fat you are but in fact it depends in part where the fat is distributed and we're talking about a waist-hip ratio to clinically get at that and for example if an individual has an elevated waist-hip ratio he or she is at greater risk for diseases associated with obesity such as diabetes hypertension and the hyperlipidemias and here we're looking at age and on the y-axis we're looking at waist-hip ratio and let's just focus on men that you can see as men in the very high-risk category have elevated waist-hip ratios same thing with women only women normally have don't have an upper body fat distribution and again as waist-hip ratio increases one is increasing the risk associated with obesity and the final point or two that I'd like to make before going on to some data slides is something that we all know either personally or professionally is that once an individual takes weight off it's extremely difficult to keep it off permanently and here is this woman saying I lost 2,000 pounds and that wasn't because she weighed 2,200 pounds but because she lost weight and gained and lost and gained weight and the next slide just presents the data in terms of diet success rate and I must say that I object to sort of the heading we're talking about weight loss now if we look at the statistics the end of therapy after one year after five years it really doesn't matter what treatment you're you're looking at whether it's diet alone behavior therapy or any combination the point that we all know who treat obesity is that at the end of five years probably even at the end of nine years that the vast majority of people who lose weight regain the weight back and again I take that to mean that there are strong biological bases and it isn't because and I'm a rat doctor that you're either a bad rat if you don't lose weight or you're a good rat and this was from a greeting card I just felt that I had to show it to you or and it isn't because you eat snack food that you're fat and I hope to present what I think are some compelling data using animal models and also showing you some data from the human from studies of humans so the first thing that I'd like to talk about using data from animal models and humans is the effect of diet then exercise ending up with genes and not Calvin Klein okay so let's focus now on changes in the American diet and if we look at the proportion of energy from carbohydrate fat or protein and we compare 1910 to 1980 clearly the amount of fat of the proportion of fat has increased in the diet and meeting with Barbara Moore this afternoon she told me that and Haynes 3 has told us it tells us now that we've gone down from about 38% of calories from fat to about 35 or 34% of calories from fat and that's encouraging however she also told me that people are eating a little bit more and people are fatter than they were even six years ago and as a health care professional I am concerned that some of the guidelines that we've set out for healthy people 2000 and reducing obesity in adults and in kids simply won't be met and either we have to reevaluate the healthy people 2000 goals or we have to do a great midcourse correction I just don't think they're very realistic or obtainable or even perhaps desirable given now what we know about obesity and in the question period I'd be happy to talk more about that if you like well this is a slide from the work of Dr. Elliott Danforth and what this shows is he's looking at the amount of weight gain by overfeeding a mixed diet for seven months or a diet very high in fat for three months and what you can see is for the same amount of weight gain you gain fat or weight more easily on a lower caloric excess and so in fact that probably underlies some of the basis for telling the American public to cut back on fat now we've taken the approach to study these biological differences in a number of different animal models of obesity and one of the rats that we use is the Sprague dolly rat it's just the good old normally lean white rat and what we do with this animal is we feed it a very palatable diet on the equivalent of a high fat high sucrose diet and low and behold what we did was we fed these Sprague dolly rats this high fat high sucrose diet for a period of about three months and what was remarkable was that some animals increased everybody increased their percent body fat the leanest animals were about 20% body fat but we had a small but significant number of these fatty rats there were over 50% aha had over 50% of the body weight in terms of carcass lipid and this is as fat as any genetically obese animal so you can look at the final distribution of body weights these animals started they were pretty much homogeneous and if you look at carcass lipid there are a number of animals that are quite fat and also there is a distribution in lean weight and the question would be is if there's a way to predict this individual variability that could be a bonus and let's not and what this shows is is that the animals that were more efficient in terms of food intake gain more weight and that shouldn't be surprising and basically that in fact these show the differences in quartiles final body weight and carcass composition and let me tell you how we divided the final body these into quartiles before the animals were exposed to this wonderful rat diet we took a little bit of adipose tissue a little bit of fat from one of the subcutaneous areas and we put it in a test tube and we stimulated it with epinephrine and we just measured the amount of fat that was that the amount of glycerol that was released and free fatty acids that were released from the triglyceride and they were a group of rats that were quite resistant to epinephrine induced lipolysis and we said that maybe these might be the obesity prone they would tend to resist mobilizing fat and then there were a group of rats that really quite readily responded to epinephrine and what we found out was that the low responders meaning the low response to epinephrine had much more lipid at the end after we fed them than the animals that were the high responders and that also their carcass lean body weight was a little bit higher and certainly their final body weight but there appeared to be a pretty robust effect in terms of body fat and Dr. Barry Levin has an even easier measure to predict and he just looks at 24-hour urinary catecholamines and gets very robust correlations of about 0.9 before these animals become obese so that might be potentially a biological marker that one could use to predict which animals or individuals might get fat when exposed to a high fat high sugar diet so to speak. Now the next thing that I'd like to talk about is troublesome in the sense that I don't think that we have the final word on it and the question is is gaining weight and losing weight and gaining weight deleterious weight cycling and about five years ago I'd say definitely it's deleterious because we had done a series of studies to show and this was along with Kelly Brownell and Judy Rodin and Marcy Greenwood this is the imperial we so to speak looking at some of the framing ham data to show that that men whose weight changed the most had the highest morbidity mortality we did some studies with rats to show that animals that went through two or three weight cycles seem to get a bit fatter or eat more and we also did a study with exercise to show that when animals basically were weight cycled and then allowed to refeed the animals that didn't exercise selected very little carbohydrate in their diet but if they exercised along with weight cycling in fact they selected a fair bit of carbohydrate compared to the normal animal and the good news that we were very excited about was fat selection was elevated in weight cycling animals but decreased in animals that not only weight cycled but were exercised but the results were in fact very controversial most people didn't find this and there there is an NIH consensus document now about weight cycling that says basically and I'll be reading it tomorrow that really weight cycling isn't deleterious to health and I was already to tell you this and three days ago I picked up my newspaper which often is how I get some of the science the latest breaking science to read that Steve Blair at the Cooper Institute at University of Texas reported at an American Heart Association meeting that men whose weight fluctuated multiple times as little as 10 pounds had higher incidences of coronary heart disease so I guess I would say that it's hard for me to resolve this instantly here but there may be individuals that are more susceptible to weight loss and regain and I guess that and I really have to read the Blair paper I've been unable to get in touch with it but the final word may not be in on weight cycling but independent of that I don't think that we should use a possible hypothesis and it's only a hypothesis that weight cycling might be deleterious to health to preventing individuals who want to improve metabolic fitness who want to try and lose weight and maintain it from trying it once again I wanted now to talk a little bit about exercise because based on some of the data we've obtained both in experimental animals and humans and the data that I that I see in the scientific literature I am really convinced that exercise is one of the key factors that makes a difference between maintaining a weight loss or putting weight back on and it's still not clear whether it's a metabolic effect it might be a psychological effect I know that I have great discussions with my psychology colleagues that claim well individuals that exercise and were determined they're able to maintain they're able to to have a stabilized regime and reduce stress and then I speak to my other colleagues who come from the area of metabolism and they say it's clear that individuals who exercise have lower insulin levels and so on they burn up more energy but nonetheless what we can report is individuals that do exercise regularly do tend to maintain body weight lost weight better than those that don't and it doesn't mean that all obese individuals are inactive but certainly if we were to survey the obese population and compare them with a lean population they tend to be less active this is a study that was published way back in the 1960s I like to say before I was born by Dr. Mickey Stunker this was before he went to University of Pennsylvania and what Mickey did was he just logged in the average daily miles a non obese man walked an obese man walked and then he did the same thing for women and he had them wear pedometers you know he just had them wear it on their waist they would walk and at the end of the day they'd measure it and on the average non obese man walked about six miles a day an obese man walked less about three point seven miles a day and women walked even less non obese women walked about four point nine miles a day and obese women walked two miles a day and the way I've used this in the clinic is to try and get people to have some sort of measure of physical activity and I think pedometers are as good as any measure and so that if an individual a woman let's say is only walking two miles a day or even two and a half or three we can have her set a goal and gradually increase her goal and increase her activity so for some individuals this may be a good way of monitoring physical activity it's also a way of trying to see if the individual person that you treat is active or inactive it doesn't work with swimming however it's hard to wear a pedometer while you swim but nonetheless there's also evidence some of some of the old work by John Maier that when individuals spend time in physical activity if they're obese they can be they are typically less active than their normal weight counterparts this again was a study done quite a number of years ago where Dr. Maier with a late Dr. Maier observed obese and non obese adolescent girls at a summer camp and there you have periods of physical activity and he videotaped them swimming playing volleyball and tennis and what we see on the y-axis is the percent of girls that were relatively inactive or the spent percent of time basically that the girls were inactive during the period and and what I just want you to take away from this this talk is that whether they were swimming playing volleyball or tennis on the average the obese girls were less active than the lean girls they were less active than the lean girls and less active than lean girls and so again even if you have patients or clients that say they play tennis for an hour a day they may be watching the ball go by and chasing it less so it the effort is important to look at well we have we also looked at the psychological aspects of exercise in obese individuals and we studied and this is an old study that I did with Dr. Joel Grinker in it must have been 1980 or so and we look we went to a summer camp or actually our graduate student went to a summer camp and she spent time with obese boys and they had an intensive physical activity program and it was a seven-week program and during this program the average boy who weighed a hundred and seventy seven pounds after seven weeks weighed a hundred and forty eight pounds and that's a huge weight loss for a kid the percentile above desirable weight and here we were using the 1959 metropolitan life insurance tables forty four and it went down to about nineteen percent percent body fat and we were measuring by using skin full thickness went from thirty nine percent to twenty seven and a half they were still above the average but clearly there was quite a drop and there was no change in lean body mass and that's because in fact literally these kids were physically active for about six hours a day they were eating about fourteen hundred kilo calories a day but they were extremely active and there was a fitness index where they were looking at the minutes to walk around a mile and a half and it went from a little over twenty one minutes to seventeen minutes well we had the hypothesis that basically that obese kids if they were physically active that they would improve an index of what we call locus of control and they would also basically what we looked at with locus of control and it's a standard inventory in terms of if a child or any individual was more internally controlled they basically believe that their own effort leads to rewards and if they were externally controlled and they would have a higher score on this no wiki Strickland locus of control inventory they would believe that luck or chance leads to rewards and the reason why we were interested in studying this is because LOC is supposed to be very stable it's not supposed to change with weight loss and our hypothesis was was that if weight loss was achieved with exercise we wouldn't see we'd see a movement towards a more in internal locus of control inventory and some example of the sample items that were asked on this test was do you believe wishing can make good things happen and if you answered yes then you'd get a higher score under external control do you think it's better to be smart than lucky I think it's better to be both but they didn't give that option if you answered yes to this then it would be a more internal means of control and the bottom line and unfortunately we did this without a control group and I would criticize my colleagues if they did it without a control group the control group would be obese boys losing weight without exercise but in such a short period of time one it's hard to find it would be extremely difficult to find but basically what we saw was a movement towards a lower score or a movement towards more internal control and the study was never followed up on but the thought would be that if you are more internally controlled that you might have better success with taking control of weight management issues the other thing that we looked at but I'm not showing the data for we looked at some estimates of body size and the way the reason why we were interested in body size because if you were to do this determination in adults before and after weight loss and if the adults became obese as adolescents and they lost weight they would continue to see themselves as fat even after they lost the weight however typically adults that become obese as adults after that key period when self-image is being determined with weight loss they tend to see themselves just the way they are and what we found out with these obese adolescent boys and they ranged in age from about 11 to about 16 was with weight loss they saw themselves just the way they were so that we never followed up on this but I think that it would be an interesting thing to look at to see if indeed we could move locus of control inventory for kids that are very externally controlled by using physical fitness well I'm now going to change the tone a little bit of the talk and talk a little bit about metabolism and basically these are data from Karen Siegel studies and she does extremely elegant work with humans where she where she studies obese and lean men women etc and here we're looking at lean women we're looking at obese women and basically we're looking at the thermic effect of food at each at each level of activity and what Karen is showing what dr. Siegel is showing is is that as one increases basically the level of activity one increases the thermic effect of food in lean but not in obese and so that the obese individual in some ways has the deck stacked against her or him when it comes to some of these effects well our approach to studying physical activity we took a developmental approach and we studied rats because we found that they obey instructions a little bit better than patients in some cases and this is a picture of a genetically obese and lean in quotes zooker rat it's called a zooker rat because Lois Zooker and her husband spontaneously found this mutant in their colony of rats and what we have here is we have actually a running wheel almost like a hamster running wheel typically you see a caged attached to the running wheel and the mouse I mean the rat excuse me can just stay in that cage and eat or it can go through the little opening and run in the running wheel and at the end of the day we actually count on this counter how many revolutions this animal has run at 16 days of age when these zooker rats just open their eyes and they're still suckling we put them in this cage the stationary cage for several hours a day and then we wean them at 21 days and they were housed totally in this cage and our hypothesis was that certainly the obese animals would be less active than the lean but we didn't know when the onset would be would the onset of it be after they become considerably obese and then there are problems with movement or would it be early on and as seen in the next slide and we didn't expect this prior to weaning and the lean animals as shown by the solid white line and the obese animal by the dash yellow line there basically is no difference in activity but we wean them in this particular study at 24 days of age there was an increase in activity probably reflecting deprivation rodents when you deprive them from food they run more but immediately thereafter the obese animals became considerably less active when we change the onset of weaning when we moved it to 21 days the onset of inactivity moved to 21 days when we let them stay in the cage with their mom she spontaneously weans them at around 30 to 35 days because their little teeth are not conducive I think to weaning to continued suckling and so then we saw an onset of inactivity that was sort of around 35 days of age again we didn't pursue this but clearly at least inherent in this obese animal before it becomes obese is some degree of inactivity and it may just be that they're spending more time eating and less time running and so then what we did in a follow-up study we fed the obese animal precisely what the lean animal ate and it became actually no we restricted them to 50% of their normal food intake was which was less than a lean animal we got them to be comparably active and they were somewhat less fat than their ad libitum fed and inactive lean obese counterparts that they were still very obese in terms of body fat so from our zooka rats you can decrease food intake lower than normal they can be comparably active and they still in fact are not made normal by by these procedures so there has to be something biological some basis for this obesity now the sad news about this study was is that we took all our rats at eight weeks of age and we let them we stopped them from exercising and we looked at them when they were six months of age and the said let's would I just present the data from the lean animals and if we look at the grams of fat in the lean animal that never exercised it was about 20 grams but in what we call this formally active athlete in fact it was fatter at six months of age then it would have been if it never exercised for about six weeks and this intrigued us and we went to do a series of studies looking at what we call the retired athlete albeit a rat and we looked at several ways of exercising it in a first study we were looking at swimming and this is a study that Janet Wolberg did when she was a graduate student or in our lab and what she did which she had the animals swim for eight weeks and then she stopped them from running and we had several groups we had lean animals that swam and didn't swim and then they became inactive they wasn't much of an effect here we had obese animals that basically were pair fed to the lean animals and kept active here we just allowed them to become inactive and look body weight is shooting up even though they're eating what the lean animal is eating and this is the animal that just swims it weighs a little bit less and then when we stop it from being active it it begins to approach the the other animal now we had problems in doing the study though it's really hard to get an equivalent degree of exercise if you swim an animal that's pretty buoyant that's fatter they tend to float they do float and and so we thought well we'll swim them with lean animals so we'd swim them for about six animals actually in a garbage can you know those 32 gallon garbage cans we regulated the temperature of the water we made sure the water didn't get too close to the top because they'll jump out and we found some other things that if the obese animal didn't swim and it floated which is basically what it did the lean animals would use it as a stepping stone to hop out of the garbage and and so that I'm just sort of sharing with you some of the the thing you have to be somehow inventive so the Janet came up with the idea well we'll give them weights because when you look at not weight training we'll give them weights when you look at the position of a lean rat in our swimming pool at UC Davis their body is at an angle when you looked at their b-sanals they were floating so she had one interchange where and my graduate students have to be inventive she went to a fabric store and bought Velcro and she was gonna make little belts for the rats and put little weights on it and she remembers the sales lady saying saying to her dear what are you going to make that's a lot of Velcro and Janet said belts for my rats and that seemed to conclude the conversation so that we then decided perhaps and swimming they can inhale the water it's really very traumatic not only for the rat quite possibly because it's the swim or sink approach with a sink or swim approach but also the graduate student so then we move to exercising rats using treadmills and finally what we did we wanted to look at the very rapid response to what we called no exercise or detraining so what we did and these are just normal rats these are Osborne Mendel rats typically in this study we would feed them a high-fat diet but we didn't have to feed a high-fat diet and for those of you who read runners world the student who did this study is Dr. Liz Applegate and she has a monthly column in runners world so when you read it then the next time you can think of Liz doing the study so what she would do she would exercise her rats for six weeks for about 20 meters a minute which isn't very fast for a rat for 50 minutes a day six days a week for six weeks and then suddenly they would stop exercising and then 24 48 60 72 and 84 hours after they stopped exercising she studied them and what I found quite remarkable was the effect on food intake we had previously observed that when animals in quotes detrain their food intake is elevated two weeks after this happens and now it the slide is a little bit confusing because rats eat in the dark and they don't eat in the light so that's why we have a zigzag picture but let's focus on the sedentary animals they're shown by the solid line let's focus on the animals who up until now were exercised this is 24 hours after the last bout this is 48 hours and 60 hours after the last exercise about they were already eating significantly more than their sedentary controls they were already eating significantly more than the sedentary controls and actually the first thing that we measured was up that was up was insulin at 48 hours and animals that typically exercise insulin levels are low and they had returned to normal and there was a slight overshoot at 48 hours we also measured or should I say Liz also measured the activity of an enzyme lipoprotein lipase now lipoprotein lipase or LPL is considered a gatekeeper enzyme for adipose tissue that's that enzyme allows the triglycerides to be hydrolyzed to enter the fat cell and then to be stored as triglyceride this is the sedentary animal this is the animal that exercised just the day before 24 hours and you can see that with what we called in quotes detraining there was an increase in LPL activity or return to normal over the 72 hours of the study what was really even I think more impressive that when we studied them in the dark cycle and this is basically in the fed state that by 60 hours LPL and by 84 hours LPL was significantly elevated over and beyond what one saw even in the sedentary animals and you might say this probably has no relationship to people well it may and this was a study done by Robert Holly published in 1986 and it was done with people who basically competed in the Iron Man competition in Hawaii now I think that you have to be a little bit crazy to stop me if it's swim 10 miles you bike for I'm is it a hundred miles a lot of miles maybe 110 and then you run a marathon so clearly people who enter this race have to be in very excellent physical shape and they train a lot and in fact one of the experimental subjects and he was part of a group was Dave Scott who that year won the Iron Man competition and we were just looking at serum triglycerides or dr. Holly was looking at serum triglycerides in these triathletes and initially they clearly are very low on race day they are very low but five days post race day where they've been exercising considerably less we see a rise in triglyceride levels now albeit this is a very artificial situation I don't really feel that that many people encounter this type of paradigm but there are some conditions in humans where sudden cessation of exercise or a sudden increase of exercise does change metabolic rate and these data are from a study that we did at Davis with female athletes and they volunteered for a period of three days to stop exercise so that one month prior to the period when they stopped exercising when we could control for the menstrual cycle we measured the resting metabolic rate and that's the zero and then we measured it one two and three days after they stopped exercising and we found small but significant decreases in rmr with cessation of exercise and that's certainly could if it was extended lead to weight gain or weight regain if food intake was not altered we also did a study that I still think is controversial and I'll admit the controversy because a colleague of mine dr. Steve Finney finds the opposite and we're at the same campus we exchange data and ideas all the time but what we did in this study the hypothesis was we knew that resting metabolic rate expressed per body weight to the two-thirds power drops within about 10 to 14 days when individuals are put on very low energy diets and for this particular study I think they were eating about they were eating food and I'm taking in about five or 600 kilocalories a day and our hypothesis was that two weeks into this weight reduction program if we could get them to exercise we thought that we could prevent or reverse this drop in metabolic rate and the exercise was at least a half an hour a day at 60% of vo2 max and they had to do this exercise at least 12 hours prior to the measurement of resting metabolic rate which indeed they did themselves at home what we're seeing here is we're looking at individuals on this 500 kilocalorie a day diet over this two week period we're showing a drop of resting metabolic rate and we're expressing it as percent of their control metabolic rate and actually it's better to look at the bottom slide because it's expressing it in a mass independent fashion and that's body weight to the two-thirds power so by the end of two weeks there essentially was quite a significant drop in resting metabolic rate these individuals did not exercise and the drop in metabolic rate remain low these individuals exercise for that period of time and humans are not like rats in some ways and as I referred to they don't always follow instructions and we found that if there was a day when an individual didn't exercise that metabolic rate returned to this low level and our hypothesis was we think that the reason why metabolic rate is up was due to an activation in the sympathetic nervous system but again not everybody finds these effects when they study the effect of exercise on metabolism well nonetheless I hope that I presented some interesting amusing and also some convincing data for getting individuals who want to control their weight to try and become physically more active I don't think there's any really splendid data showing that it aids in weight loss in the sense that it it significantly increases the rate of weight loss especially in women but it certainly helps in the maintenance of body weight now for the next few minutes actually 15 I'm going to talk a little bit about genetics and why I'm convinced one the first there's a strong genetic component to human obesity and two to present some data that have been obtained obtained in our laboratories showing that at least in genetically obese rodents that there is a metabolic events that occur early on that certainly don't reflect what their mother does to them the mother isn't overfeeding them so to speak and here we're now just looking at parental fatness and obesity in children and these are the data from Garn and what I want you to focus on is is that basically that for children who have two obese parents this is the percent of children that are obese that if we have look at children that have two lean parents the height of the green bar is the percent of children that are lean versus obese and this is taken to mean that there is certainly a genetic but perhaps environmental component but one can always look at and I think pictures are worth a thousand words these are slides of fraternal twins and you can see that for some of the twins there's quite a difference in body shape probably body weight body fatness certainly here's a dramatic illustration and the next slide just looks at identical twins and here body weight body fatness body shape is more identical you don't see the variation well for those of you that are interested in looking or reading more about the models of genetic obesity that I'm going to talk about I co-authored a chapter on animal models of obesity that appeared in annual reviews of nutrition in 1991 it also talks about some of the genetics some of the proposed gene defects and you might find this instructive if you're interested in knowing more about it well these are our genetically obese so far at again and thanks to the people to the group at Rockefeller University we know that the reason why one of these animals will become obese and the other will be lean is because there is a defect on chromosome 5 inheritance of this trait is autosomal recessive and also the fatty gene has been moved to different backgrounds and depending on the background of the animal you can get it these animals when they become obese are not diabetic but in fact if it's on a wister Kyoto background that's just another strain of rat these animals the males will become spontaneously diabetic and had developed and IDDM with glycated hemoglobins at three months of age approaching 13 where normal for their control rat counterpart might be six and a half so I think they offer a wonderful way to look at how disease might develop and or be prevented in genetic obesity now if we were to look at some of the metabolic characteristics of this obesity rat they clearly have elevated insulin levels and this afternoon I talked about what I think contributes to increased insulin secretion in this animal they are insulin resistant they're marginally hyperglycemic but not in a clinical sense they have impaired protein deposition their hypothermic they don't generate heat to cold they have elevated fat cell size and number and they have elevated activity of adipose tissue lipoprotein lipase which even after weight reduction is still elevated and in fact obese humans also have elevated adipose tissue LPL activity now this is just a slide to illustrate that even if you undefeed the fat rat prior to weaning it still develops more fat cells but let's first look at the lean animal this is the lean animal and we're looking at total fat cell number in the lean animal that's just being fed eight pups to a rat mom this is a lean animal that's being fed 22 pups to a rat mom and this is a lean animal there where the mom only has two or three pups and they're fed this way and at weaning they're allowed to eat ad libitum and then they're studied at six months of age and you can see undefeating leads to a permanent decrease in fat cell size and overfeeding in increases fats that's all number excuse me decreases fat cell number increases fat cell number now the bad news is is that in the obese rat that's overfed prior to weaning there's a permanent increase in fat cell number but in the rats that are underfed prior to weaning there is no permanent decrease and in fact in these fat animals they continue to make fat cells long after the lean animal stops now this is a slide that was generated from a former graduate student of Dr. Barbara Horowitz in fact Vanessa do I see you back Vanessa Ruth I see Vanessa and her husband Mike in the audience and she was looking at some of the neuromodulator changes in the central nervous system in the Zooker fatty and lean rat and she also in this particular side identified that the rat as early as two days of age before they become obviously obese have blunted thermogenesis and I'll show you a slide illustrating that in a minute they have larger fat cells by seven days of age and Vanessa was able to show that they are hyperinsulinemic by 14 days of age prior to her study we felt that this didn't occur until about 21 days of age and they increase their food intake their hyperphasic by about 18 days of age and that's at a point where they have access to solid food the next slide just in a cartoon slide I had to bring it because this appeared in the Washington Post illustrated what we mean by blunted thermogenesis what I what we mean is that if we were to put these rats in the cold sort of like what you had in January when I visited about actually it was lower than five degrees centigrade that the lean rat would appropriately increase heat production maintain body temperature the obese animal would not and also would begin to shiver and at some point in some of these obese rats body temperature might drop low enough and they might die in fact of hypothermia the next slide just illustrates this in a more graphic form and this is a slide taken from data generated by Dr. Barbara Moore who is now working with Dr. Van Hubbard in the nutrition program at NIH and what Barbara looked at was in the genetically lean animal the animal that we didn't know the heterozygous fatty animal that isn't fiat typically fat and then the homozygous fatty animal and what she was able to show that it thermonutrality and for a little baby puppet two days of age that would be about 36 degrees 37 degrees centigrade that there was a drop in heat production at thermal neutrality and just sort of remember that these are mills of oxygen consumption express in a mass independent fashion and what we're seeing here is about 3.5 for this lean animal then what Barbara did was she placed them in the cold 26 degrees centigrade which by the way is quite pleasant for us for adults and in fact heat production or oxygen consumption increased in the lean animal from 3.5 to over 6 and basically in this fatty animal while heat production or oxygen consumption increase the increase was not as great as one saw in the lean animal and this is really one of the very earliest things that go awry in this genetically obese animal and this just shows data that that doctor Ruth collected when she was a graduate student where she did look at hyperinsulinemia and she did look at 12-day-old Zooker pups and here because we were not able to tell who was fat and who wasn't we basically looked at we compared them to pups that we knew were homozygous lean because they had a lean mom and a lean dad and those are the high those are the red bars and that's the lower body fat the blue bars look at all the offsprings from the mating of fatty males and phenotypically lean but heterozygous females and what Dr. Ruth did was she declared that all these animals that had a percent body fat greater than this this lean which clearly was an outlier basically were deemed fatties and she looked at percent body fat and in fact by definition body fat was higher because that's how she defined it but she also measured insulin levels and I think that this is stunning in the 12-day-old animal that plasma insulin levels are elevated now since Dr. Ruth left Davis campus we now can do these studies in a special animal model a Zooker brown Norway hybrid where we can identify the animal that's obese by doing an RFLP analysis and so that we don't Vanessa would have been happy if this were available when she did her studies she also went on to look at some aspects of monoamines in the central nervous system and one of the things she found was an alteration in serotonin metabolism in these pups as early as 12 days of age another thing that we've studied in these genetically obese animals is insulin secretion and in fact that's a major focus of our laboratory and here we were perfusing the pancreas in situ and we even had preparation where the pancreas was innovated by Paris sympathetic and sympathetic nervous system and in the non-intervated pancreas Amy Cupford who was a graduate student a number of years ago showed that at glucose levels as low as 75 milligrams per decilita the pancreas from obese animals really secreted quite a bit more insulin than in lean animals and in fact they were hyper responsive to glucose and Ed blondes another grad former graduate student of mine who is also writing a syndicated column now I don't know what it is I drive them out of research and into what that's only two of them though he was perfusing the pancreas at two weeks of age and again what he found was that there were some animals that hyper secreted insulin some animals that didn't and it did relate to their body fat again when Ed did his studies we could really not determine early on who was obese and who was lean but it was related to body fat Julie Lee another student in a lab went on to look at some aspects of the central nervous system of neural input to the pancreas and in particular she was interested in muscarinic receptors and she used the agonist but the botanical to see if in the genetically obese zucca rat that muscarinic receptors were involved in the production of this hyperinsulinemia and in fact she found that they were and let me walk you through this slide the this is insulin secretion with glucose only with botanical and these are various concentrations of glucose 75 125 and 200 milligrams per decilita and at minute 21 we add she added botanical into the preparation and what you can see is at very low level of glucose in the obese animals that basically there was an enhancement of insulin secretion when she added botanical in fact it was quite striking that this is the insulin secretion of the animal without botanical added to the system so it was a greater than three-fold elevation when she looked at the lean animal she had to go up and there was no effect at 70 milligrams per decilita and basically in order to achieve the level of insulin secretion that she saw at 75 milligrams per decilita she not only had to increase the glucose to 200 milligrams per decilita but she also had to use botanical and Julie concluded that in fact she felt that muscarinic receptors that in fact the beta cells of these zucca obese rats are hypersensitive to muscarinic neural receptors stimulation at very low glucose levels and and the hypercholinergic neural activity was based on another study we have now gone on to look at the effect of nutrients on insulin secretion and that's the the study that I put the studies that I presented this afternoon and we really feel that the fatty acid arachidonic acid may play a role or probably plays a role in hypersecretion of insulin in islets isolated from genetically obese zucca rats the question is what can you take away from this to the clinic you know this research is hopefully has provided some basic data so that we can find out more about obesity in genetic obesity but what can you offer your patients and I still think based on a study that we published in the American Journal of Clinical Nutrition in 1990 where we looked at women who actually were able to lose 20 pounds and keep it off for at least two years women who never had a weight problem and women who took 20 pounds off and regain it this is what emerged from the study one women who kept the weight off or who were successful maintainers selected a lower fat diet they also individualized the weight reduction program the weight loss program meaning didn't mean that they didn't go to the Weight Watchers or the Dren Jenny Craigs or whatever but they took the best from these programs and they adapted it to their needs they had regular exercise and I can't tell you what regular exercise meant we just asked them do you exercise regularly and almost 90% of the women who kept the weight off said that they did less than 35% of the women who put it back on said that they exercise regularly they also had better problem-solving skills and I'll give you an example of problem solving skills women who regain weight tended to practice what we call escape avoidance behavior and I'll give you an example of escape avoidance behavior versus attack problems directly as the good maintainers did that basically both the regainers and the maintainers had similar life crises but in fact the maintainers had better problem-solving skills for example if something would come up at work and there was a crisis or something at home the regainers would say oh I'll reach for something to eat oh maybe I'll get a little more sleep and when I wake up it'll go away but the individuals who were successfully able to maintain the weight loss attack the problems directly and they also had an excellent social support network where they had three or more people that they can turn to for help where the regainers didn't they had one or fewer people that could help them in their life events so I think that based on this study there and other studies as well they give give us some indication as to where we what we can do to try and optimize individual weight maintenance programs or weight control programs until the time when Jules Hirsch and Rudy Leibel at Rockefeller discovered the gene for obesity in zucca rats and the genes for obesity on Claude Bouchard and Canada is looking at that as well Mickey Stunker to Penn and so on that are associated with weight gain in individuals and then it might be easier for us to predict who becomes obese or lean now the reason why I have this up here is because I think it's really important to pick put everything in perspective that food is something that should be enjoyed it's one of life's pleasures and that there are ways that we can teach obese individuals and individuals who want to maintain a lower weight to try and deal with this and I actually was really serious when in a Vogue column that I had in 1985 I said emotionally I think chocolate should be declared an honorary vitamin because certainly in my life chocolate is one of the pleasurable foods and I just want to thank you for being so patient but before you answer question ask me questions Barbara more do you quickly want to tell everybody about this blended program that you and Van Hubbard are showing to the White House or Van do you want to say something about it you're showing to the White House tomorrow that we got a chance to see the CD run program for children 5 to 10 and this is the nutrition education person in me I don't miss an opportunity to give you a tip that that you may really enjoy Barbara basically the the dole food company and the Society for Nutrition Education have put together a nutrition education program for children between the ages of 5 and 10 and it is a CD-ROM based program and it does require equipment which is rather expensive I mean it took us several days of searching and NIH to find a computer that could run it however it is available from the from the dole food company for free to schools that have the equipment that can run this program they will supply it to those schools for for free any school in the United States can contact the dole food company and get a copy of this program in any rate it's a very interactive program and we have learned today we we actually played with it today and we learned that it has elements to it that will teach children geography as well as nutrition and physical some basics in physiology and it really is a marvelous program and I think it's this is the kind of thing that we need to to look very carefully at is what are children eating and how are they behaving and is there any way that we can get them to learn how to build a healthier diet more effectively because we're not doing such a great job at the at the moment and I guess I'd just like to add that I'm very encouraged by this and I think that hopefully at some point they'll make program for adults too and I told Barbara in van that I definitely would not come in seeing the song the broccoli did because my voice isn't as good as the rap singer on the CD wrong but it's really quite wonderful at this point I'd like to open up the the time for questions and for those of you that are asking questions I would ask that we you come down and use the microphone in the past year some of the questions have not been heard by the audience so we have put up microphones this year so that everybody can hear the questions as they are asked thanks and yes please there's not really a question it's a comment on one of the things you said at the beginning of your talk you mentioned the N. Haynes data that shows and it's been published pretty widely of the press that shows that the percent of fat has gone down I think there's been a misinterpretation of this data good thanks for the comment fat intake has not gone down that data shows that fat intake has gone up I think the data shows that between N. Haynes to was 36 percent of calories from fat but there were 1969 calories on average which comes out to 708 fat calories and it's now 34 percent of calories but calories have gone up to 2200 that makes 748 calories so between N. Haynes 2 and N. Haynes 3 fat intake has gone from 708 to 748 on average you can't look you can't compare percentages of intake when the base that the percent refers to is changing well we could get possibly into a discussion that I'd be happy for other people to participate let's say we actually believe that these data were absolute and there was no wiggle in the collection of the data which I don't believe that I think that it's not only the total amount of fat but it is sort of that it is the distribution of the macronutrients because in fact if you were on a 500 kilocalorie a day diet and you had 80 percent of your calories from fat you would lose weight I think the data I think you know if you're gonna believe the end if N. Haynes is gonna publish the data and draw conclusions from it then I think they have to draw the right conclusions if they if the data isn't accurate then let's throw it out and let's not talk about it but in fact there is a difference between 700 and 750 calories of fat it's gone up I mean if you're it's like anything else I mean if you had several sources of income and you know one source went down that percentage wise it could still go up in absolute amounts the what would be really important to you is the number of dollars you got from that source of income not the percent that it represents and I think I think N. Haynes has to look at this data they've been misleading the public and you know a lot of very smart people have been jumping through hoops trying to explain why people are getting fatter and percent fat intake is going down when fat intake is going up and it's consistent with the data they don't have to jump through any hoops okay I'd like to just like to make a quick comment on that and that mean the data that is being reported currently is preliminary data it has not been presented in full form meaning for to allow for full interpretation the dietary assessments have been done using different methodologies in previous surveys so they aren't readily comparable in terms of how the data was collected and I know that the N. Haynes people are going back to see how they should best interpret the data and they have not come out with a final answer there well if you do talk to them please tell them that their own data that they're publishing or disseminating shows fat intake going up and not down period you didn't say anything about people who have a compulsion to eat or overeat way beyond satiety and I just wonder if you think that the idea of a chocoholic or a foodaholic or a compulsive eater or some kind of addictive behavior can explain any of what you observe or none of it well again I think in the Zooker obese rats it doesn't explain it but clearly there is a subset of obese individuals or individuals that have trouble control with weight maintenance that binge eat that do have classical eating disorders and again if we can diagnosis and identify it we we would treat them differently or we can treat them differently would you like to comment about that I mean what what do you believe well speaking personally I think there is such a thing well no I we know there's such a though personally right I mean people do obviously eat way beyond satiety the question is why they know they're full what they're still eating just for the taste at that point I think well you know some of the data that Barbara Rolls has collected she's now at Penn State I think a really some compelling data she basically talks about sensory induced satiety I translate that into the Thanksgiving dinner effect why after you have this wonderful Thanksgiving dinner and your stomach and upper GI and CCK and everything is signaling that you've had too much and the apple or pumpkin pie comes out you have pie and Barbara would say that variety of good tasting foods leads to increased consumption I'm in women too you showed a number of examples of number of results where obese individuals were compared with lean individuals and say for example the obese individuals were exercising less but with such cross-sectional data of course you cannot establish causality and so I was wondering to what extent there are results from randomized intervention trials where different groups of people are put on different levels of exercise and then followed for weight gain well there are certainly numerous studies I would say that the study that I like to quote I think it was done in 19 third published in 1939 by by Green and he was a surgeon and he looked at change in weight gain or increase in weight gain with forced inactivity patients that would come in and they would have broken bones or something and they would be forced to be inactive and I hope I'm quoting this right but about 40 percent of the individuals that had enforced inactivity really did gain a substantial amount of weight and some of the day I thought that if you go back to the the classic studies that Ethan Sims did with it are you familiar with the the prisoners that in quotes volunteer to overeat and gain about 20% of their body weight by the way we couldn't do these studies nowadays because prisoners are not allowed to give informed consent but nonetheless that for some of the prisoners weight gain was relatively easy but for others he not only they not only had to eat a huge amount but he had to force them to be quite inactive so that their individual variabilities and we've chosen primarily to study this in experimental animals where we can have an onset or not and then study it that way yes please question regarding eating eating is a reward system now has it have has your lab or any other lab looked at the aspect of increased tone in a dopaminergic system Vanessa Ruth could you please come down and talk about the dopaminergic system in terms of obesity and consistently we saw in the ventromedial nucleus and hypothalamus that either levels of the 5-HIA a major metabolite serotonin or the ratio was reduced in the obese animals this also occurred in a form of dietary obesity and we saw it in the genetically obese animals as early as 12 days of age and during the lectomy which tends to normalize to some extent some of the aspects of the obesity also raised serotonin Vanessa I thought that you got some changes with the dopaminergic system and I just can't remember which areas because you looked at so many brain regions we only saw in that first study in males in the paraventricular nucleus we saw decreased levels of dopac the major metabolite of dopamine I had another sort of fall question that now would there be since eating in some people is sort of a compulsive behavior could you treat that type of behavior with pharmacotherapy there's a there's a product out now it's been approved by the FDA for compulsive behavior can can we answer that question after your comment because I'd like to make a comment about pharmacotherapy for obesity in general and more specifically yes please I just wanted to address the question about the meso limbic dopamine system and feeding as a reward system I've been doing some work in that area and a man named Bart Hobel at Princeton University also has done a lot of work in that area as well as other investigators basically the take home story is there is some increases under some situations in meso limbic dopamine when feeding occurs there's also evidence that when animals are exposed to the stimuli associated with feeding that the dopamine goes up and the we're all still trying to figure out what's related to movement and what's related to the reward systems in feeding and that's a question that's still under investigation thanks for being a good sport just to comment about pharmacotherapy for obesity the North American Association for the study of obesity is trying to address this and come out with a paper that hopefully will be published within the next four months to six months in terms in obesity research and what we did was we got together a group of individuals members of naso and we invited people from FDA from NIH from nine or ten drug companies to join us to first observe us and in our deliberations and then in our second meeting which unfortunately occurred that day in Washington in January when the mayor closed down the city we had a second meeting and again everybody participated and I think that we are at the point of achieving consensus in this area and in that we think that it's appropriate to use drugs to treat obesity but only as an adjunct of a program that also focuses on improved eating habits increased physical activity in other words it shouldn't be used alone and we also think it's probably appropriate for a number of people that respond positively by lowering their body weight for them to be on it chronically and I must say the pair I've never understood this paradox if you had a patient with hypertension and you decided to put him or her on a blood pressure lowering drug and let's say blood pressure did respond by positivity meaning it lowered you wouldn't just say well now we can take the drug off because we've corrected your blood pressure because when you'd remove the drug what would happen blood pressure would go back up I've always found it curious in the obesity area that we put obese patients on drugs their body weight goes down we take them off drugs the body weight goes back up and we say the drug has failed it's a bit curious don't you think so we're hoping that the climate the regulatory climate hopefully will change so that one FDA can begin approving drugs to treat obesity there hasn't been a new one in this country approved in the last I think it's 19 years also there are regulations in certain states that if physicians approve use drugs to treat obesity for longer than three months in California is one of those states they can lose their license so drugs are you're not allowed to treat patients long term with drugs they can be on a research protocol but right now it isn't appropriate so hopefully we'll be able to contribute to changing this climate because we're not giving the obese individual access to the full battery of things that we think that can help in weight management. I just wondered if maybe limiting access to certain foods encourage this bidden gene syndrome by creating forbidden food lists and our clinical patients I found in road studies if you limit access to preferred foods the rats eat tremendous amounts of this food in a very short amount of time almost mimics of binge like you might see in the clinic and when I was working clinically and the patients that had forbidden food lists and they self restricted access to these kinds of food through self-imposed limitations or an environmental situation where your favorite kind of ethnic food is not available and you have to drive long distances you eat a lot of it when you finally get there but maybe clinically one of the things that might help control these kinds of compulsive large amounts of intake that we see might be to get away from these forbidden food lists and encourage patients to build into their diets the foods that they fear the most. Well certainly that's been one of the approaches in behavioral therapy where you encourage the person to plan to eat some favorite foods to plan to eat them in limited quantities at a time when they're not very hungry. Comment? I wonder if you'd talk a minute about you mentioned exercise but about what type are terms of 100% of VO2 max. The implication of some of what you said is maybe daily is better what about weight training? Sure there there's been certainly studies that have been published to show that weight training can help if it's associated with an increase in lean body mass. Typically swimming isn't an exercise that's associated with improvement with decrease in body fat or dramatic decreases in body fat although cardiovascular fitness is one of the very positive benefits of swimming. In terms of the studies that we've done in terms of metabolic rate are talking about 60% or 65% of VO2 max but the study that I like to quote was a study by Dr. Gwinnup. He did it in Southern California and all he did over the course of a year was encourage his patients to walk and these were overweight patients and those who walked an average of 30 minutes or more a day lost a significant amount of pounds. I can't remember if it was eight or ten pounds in a given year those that didn't didn't lose weight. So I think that what I would say if I were in the clinic I would try and assess physical activity. If your patient is active that isn't an area in which you want to encourage further activity perhaps but if they're willing to make some changes maybe just using that pedometer would help. I know that if they there are studies that come out of the University of Wisconsin that if they have to rely on special places to go like health clubs if they're a distance away from where they work or live they tend not to do it. There was an interesting study done at the University of Wisconsin where they studied professors and they were enrolled in this physical activity and what came out of this study was professors whose offices were closer to the gym stuck with the program longer. Now I probably could have told them that but I guess it's important to find that out. So again it's important to individualize the programs and not and not to even maybe just focus on one activity and Dr. Rod Dishman out of University of Georgia has published some excellent things in this area. Since we have literally tens of millions of Americans trying this intervention of exercise and we should have some modest clinical trial type things about various variations you know like you know just 15 minutes how different types of updating of different stuff. We really have an enormous amount of people trying very hard spending a lot of money on this and not waiting for a drug or a genetic. Well I mean there are studies in the literature in terms of the amount and type and frequency in terms of physical activity. Gil? Well we haven't thought of obesity as being a disease and that's why we don't want to treat it with medicine. You think of hypertension as being a disorder or a disease and we're in allopathic medicine so we think well they've got a disease treated with medicine but obese people tell us and we tell them the normal they're healthy they don't have a disease why should we treat them with medicine that's where that reluctance comes from. Well I think it's just sort of I have a different approach to that I think that we describe I know we discriminate against obese people we call it a willful disease that if they only watched what they ate and they were physically active they wouldn't be any obesity and in fact I like the best solution to obesity. Vogue which I call vague what when I wrote for it certainly wasn't in touch with the real world although my columns were but but Grace Mirabella the editor of Vogue then said she had the cure for obesity you know what it was don't make any women's clothes greater than size eight. Now that to me symbolizes what we think about obesity physicians feel the same way and our genetically obese rats are obese they have an underlying disease and they die sooner than genetically lean rats we're doing some longevity studies Ruben you'll be interested to know so and I thought that NIH did declare obesity a disease but yet physicians under a lot of health plans cannot treat obesity. A lot of obese people don't want to say it's a disease you got to realize that and it's important the whole groups of women that get together they say we're healthy we love our fat big big birthers and I there's a new book coming out from California showing beautiful nude women that are for three four hundred pounds they think they're healthy and Gil I guess what I would say an answer to that is if we talk about weight management let's say they don't want to lose weight but maybe they can improve their metabolic fitness they can be more active they can cut back on fat in their diet they can do other things other than losing weight to improve their metabolic profile and what I would say is if their parents died of diseases premature heart disease had type 2 diabetes then I'd and if they had an increased waist-hip ratio I'd say boy you may be healthy now but this may foretell your future and when you want to do something about it we we will offer you something until then please feel good about yourself I know I noticed you talk quite a bit about the compulsion and not a lot about the obsession with people who consider themselves to be compulsory eaters and I am in that group and I just I had this question to ask does the amount of time a formerly obese person maintains normal weight have an impact on the decrease of fat cells and metabolic levels well for that's an excellent question the problem is you never lose a fat cell when you lose weight your fat cells get smaller and then when you regain it they just refill and you can actually get more fat cells but it's hard you don't get less and so one of the reasons why it was thought that obese individuals regain weight was that for individuals that have many more fat cells when they lose weight and maybe their body weight is normal their fat cells are very small and they may be more responsive or to refilling with fat so that you never really lose the fat cells and surgical procedures simply can't remove enough and we even have some evidence in rats that even if you remove fat cells they regrow we did liposuction on half of a side of a zucca rat thanks but no thanks right I guess what I'm with you thank you Judy and I did note that you didn't say anything about your favorite exercisers favorite sport baseball okay again I like to remind you that if you'd like to be placed on a mailing list for future lectures or other activities relating to the nutrition programs here please put your name on the pad it's a healthy kids pad I had in my briefcase so you can identify it in the back table I'm a pediatrician and then the next lecture will be April 13th again at 7 p.m. again on a Wednesday evening I hope to see you all there thank you