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Obesity is an epidemic. Obesity is intimately involved in the pathophysiology of type II diabetes by increasing insulin resistance and moving people from a state of compensated insulin resistance to uncompensated insulin resistance with diabetes mellitus. Obesity is not just being overweight. Obesity is an excess of adipose tissue. Body builders may actually be heavy but they don’t carry the same risk by having increased muscle mass as patients with increased adipose mass have. Like diabetes, obesity is really a heterogenous group of disorders. There’s no clear molecular pathophysiology and there’s no ability to discriminate the etiology by the phenotype. You can’t tell, in an individual who comes in, who is 40 or 50 pounds overweight or 30 or 40% above ideal body weight, what caused them to be that way. The bigger problem is that in the overwhelming majority of those individuals, there is no clear appreciation - based on our ability to do a history and to do a physical exam - about unraveling the initial causes. However, what we do know, is that from a medical perspective obesity is linked to both excess morbidity and excess mortality obesity, overweight, fat, obecity.
There is increasing evidence that obesity has a strong genetic component. But like type II diabetes we don’t yet understand what those genes are. The genetic contribution has been estimated to be 30 -70% of the cause of increased weight gain. This comes from twin studies, adoption studies, family studies. But again, we don’t know what genes are at fault. We do know that there are ethnic predilections to the development of obesity. Such things as basal metabolic rate actually differ between races and may predispose certain races - particularly African-American, or
As a medical problem, obesity is prevalent - roughly 30% of the U.S. population - and importantly, it is increasing in prevalence, both worldwide and in the United States. Worldwide this is an issue because of improving economic status and quite frankly, the development of the internal combustion engine. People no longer have to walk or run for their food supplies or have to walk or run to their other family members. They are
Now what about the problems coming from obesity? These are the actual risk figures on mortality. We are not talking about morbidity, we are talking about mortality. They come from two different cohorts of individuals. The first is actually from the nurses health study they ran at Harvard School of Public Health, which looks at the adjusted relative risk for mortality, one being baseline, for body mass index for women who have never smoked. To smoking is not a risk factor here. You can see that as their BMI increases so too does your mortality when you get to a BMI of above
Now if you look at obese men and you look at excess mortality, look at the increased risk that obesity brings to the male who is 25-34 years of age. Very dramatic. Over tenfold increase in mortality in that population. That risk actually declines with older ages. Other risk factors begin to play a role. So obesity can be a lethal condition or predispose to other lethal conditions.
We’ve learned over the last couple of decades that one fat cell is not equivalent to another fat cell and it depends where it is located. There seems to be an increased risk associated with what we call android obesity. Android obesity refers to the "apple". That is the weight residing around the middle. "Pear-like" obesity is increased weight settling around the hips and buttocks. The android obesity is really associated with abdominal fat. Visceral fat. And that is associated with increased risk of coronary heart disease and diabetes, compared with excess subcutaneous fat on the hops and flanks. So android obesity is associated with insulin resistance, type II diabetes, hypertension and hyperlipidemia. While we don't understand the underlying the mechanism, there is increasing evidence that free fatty acids increase splanchnic concentrations of free fatty acids that derive from increased splanchnic visceral fat, may be causative at least in the insulin resistant syndrome and perhaps in type II diabetes.
What are some of the consequences of obesity? We talked about the mortality, obviously, but what about specific consequences? Well, diabetes mellitus you’ve already heard about. Hypertension, I’ve already mentioned. Cardiovascular disease, coronary artery disease, stroke, congestive heart failure, all are increased in obese individuals. Pulmonary disease, sleep apnea clearly increase with obesity. As is the work of breathing. So if you have somebody who has underlying restrictive lung disease, chronic bronchitis or emphysema, obesity adds to that burden. There is a six-fold
The higher the lean body mass, the higher the energy expenditure. We are now talking about basal energy expenditure. There is obviously a huge range here that depends on genetic backgrounds but these tend to be parallel to this. What happens during weight gain or weight loss is the following: during periods of weight gain people move off the curve. Energy expenditure actually increases. We believe this is one of the homeostatic mechanisms to try to maintain a weight even when increased energy availability is present. The bigger part of the problem is that with weight loss energy expenditure falls off the curve, so that again, there is a greater tendency to gain weight or limit the weight loss, if you will. This is one of the things that happens when patients who go on a low calorie diet, lose weight, suddenly plateau on that same diet within several weeks or a month thereafter. Because their energy expenditure is decreasing due to this compensatory mechanism. This has led to the so-called "set-point" theory of body weight control and we are beginning to figure out what some of the signals are in this homeostatic process. First, it’s now very clear that there is a signal that is proportional to fat stores and that signal happens to be the protein leptin. Secondly, there is a sensor that detects fat stores. Those sensors happen to be in hypothalamic nuclei, work at least in part through the leptin receptor. Although other neuropeptides may also be involved. There is a site of action for control of energy homeostasis, both for appetite control and energy expenditure. That also is a hypothalamic nuclei but we are just beginning to scratch the surface of understanding what this complex activation model is. And there are consequences. There can be satiety or hunger, alterations in energy expenditure, and activation of the sympathetic nervous system. The combination of these different systems and actions is in fact of what adds to the complexity of our understanding of obesity and our difficulty in interceding effectively.
Here is the leptin story. Leptin is a protein made by fat cells, which circulates in the blood to the brain - specifically hypothalamic nuclei where specific receptors are present - and that leptin when it binds to the receptor sends a cascade, or develops a cascade of biologic effects which include a sense of satiety, and increase in thermogenesis and an increase in insulin sensitivity. This molecule was discovered genetically in a mouse model of obesity. This mouse is defective in leptin. Give it back leptin, lo and behold they lose weight and a lot of abnormalities that they have correct. There is another mouse model called the DBDB mouse. This is not a talk on mouse genetics, but the DBDB mouse was actually found to have a defect in the leptin receptor. Didn’t have a natural leptin receptor. So we have two mouse models that suggest that a single hormone or protein, leptin, acting through the very specific receptor can alter body weight, homeostasis and energy balance, either by having the defective protein - absence of leptin - or a defective signaling system and abnormal leptin receptor.
Now, how does that relate to humans? Well we really don’t know the answer to that question very well yet. However, it is now quite clear that there is a human model of OBOB mouse. That a couple of individuals, and I do mean a couple of individuals - actually two siblings in the United Kingdom - were identified who had absent leptin, so they couldn’t demonstrate or couldn’t generate a signal from adipose tissue to tell the brain to stop eating. And these two kids, as you might expect, were characterized by morbid obesity. I mean, there was a three-year-old who weighed 95 pounds at age three and who ate insatiably. When treated with leptin, the older of the two children - older than three-years-old - actually began to actively lose weight and to stop eating to the same degree as before. So the model exists. Is this the cause of human obesity? Garden variety human obesity? The answer to that is clearly no. Leptin levels are increased, not decreased in human obesity and in fact leptin is an accurate reflection of fat stores. The more fat the more leptin in circulation.
The second part of the paradigm, if you will, the defective receptor for adipositis also has been described. So there are defects in the leptin receptor in a couple of other kids - actually in Germany. It is postulated that there are post-leptin receptor abnormalities and these are being aggressively pursued. There are also individuals who have abnormalities of hormone processing enzymes that result in obesity. I’m not going to go into the complexity of that. But the bottom line is that we now know that there are single gene defects that can explain a minute percent of the population of the patients with obesity, but these are proof of concept kind of things that really support the pathophysiology or the physiology’s we are beginning to understand.
Drug treatment for obesity is a bit problematic at the moment. One of the problems of course is that there is lack of long term efficacy with other interventions. Behavior modification, diet and exercise just don’t tend to work for the long term in those patients. There are also issued of initial weight loss versus maintenance of weight loss, in part due to recidivism - that is patients slipping back into bad habits, and also the decreased metabolic rate that occurs. There are issues of weight loss per se versus reduction of risk from the obesity, in the fact that obesity is a chronic disease. Now for drug treatment, we have three basic approaches. One is to reduce energy intake. That is the use of anorexics. A second is to increase energy expenditure. While we don’t really have good agents currently, there is active development in the pharmaceutical industry to try to develop agents that either act as so-called Beta-3 adrenergic receptors located on fat cells more specifically than on other tissues. And then when activated increases fat metabolism and energy expenditure, or drugs that activate a series of proteins called uncoupling proteins. Or finally, an approach to inducing decrease in energy absorption. Not looking at appetite control, but actually decreasing the actual number of calories that are absorbed, and there is a new agent currently out there called Xenical or orlistat which does that, a lipase inhibitor.
What are the issues in drug therapy for obesity? Benefits obviously weight loss, weight loss maintenance, prevention of weight gain and improvement in co-morbidity, including diabetes, hypertension and arthritis and immobility. When do you turn to these agents? Again, if the BMI is greater than 30 or greater than 27, if additional risk factors are present, such as diabetes or hypertension. If there has been a prior failure of all other modalities short of surgery and if there are no contraindications; Pregnancy, uncontrolled hypertension, depression, substance abuse and again, I want to stress the need for a team approach in conjunction with diet and exercise and consistent follow-up to screen for toxicity.
What about risks and side effects? Well, there are a number of agents but the adrenergic agents, including ephedrine, can produce tachycardia, accelerated hypertension and worsening of glycemia control. So these have to be used carefully. Phentermine, which is still available, then fenfluramine, dexfenfluramine redux which is no longer available. It had a variety of side effects. Most of these are CNS side effects that range from stimulation to sedation, to headache. There are also some cardiovascular and gastrointestinal side effects. You will recall that problems with mitral and tricuspid and aortic valvular disease with use of serotonin re-uptake inhibitors that fenfluramine, dexfenfluramine, that resulted in those drugs being removed from the market two years ago. Pulmonary hypertension was seen with the fenfluramine class of drugs, and of course the cardiac valvular disease which I’ve just mentioned. Dexfenfluramine is no longer available. The two relatively new drugs that are available are another centrally active agent, and anorexiant, sibutramine, which acts as both an inhibitor of the uptake of serotonin and norepinephrine in the CNS and has a side effect of hypertension. Like all of the drugs before that acted as central anorexiants, the drug Meridia produces about an 8 to 10 kilogram weight loss over time and thus be maintained if you are going to keep that weight loss off. Again, not magic. Does seem to work in some individuals but you have to choose the patients carefully because if they have hypertension that may get worse.
Orlistat is the lipase inhibitor. There are GI side effects associated with this drug. This drug blocks intestinal lipase activity. Not pancreatic lipase but intestinal lipase. Because of that allows more fat to flow through the GI tract and enter the colon and that results, can result, in loose greasy stools and some fecal incontinence. In high doses it may produce some fat-soluble vitamin deficiency, but this can be overcome by the use of multi-vitamins. This drug has 30% effect. Reduces fat absorption by approximately 30% and can result in a 200 kilo calorie deficit for individuals on a normal diet. One of the best reasons for using it however, is that is probably dissuades in an Antabuse-like effect, individuals from eating too much fat. Because if they do, they are going to pay for it.
There was huge excitement about leptin as protein made by fat cells as a therapeutic agent for the treatment of obesity. I’ve told you already that in a few concept studies, clearly effective in a child with general leptin deficiency and it’s been demonstrated to have marginal effect in routine obesity, again producing 6 to 8 kilogram deficit and 0.3 milligrams per kilogram, which is a rather large dose of protein, in patients with obesity. However I also told you that human obesity is characterized by leptin resistance and not leptin deficiency and it’s unclear how successful this agent will be as a drug.
So here we are with a plot of the drugs that are available and where they work and their mechanisms of action. Again, the over-the-counter dextrin-phenol-prolamine is an appetite suppressant, works on the central adrenergic mechanisms. It can increase heart rate, can increase hypertension, and can produce some jittery-ness. Phentermine affects appetite. It also may have some MAO inhibitor-like properties that may not be so good. Sibutramine, Meridia I’ve told you about. Again, a centrally active agent. Then the agents that have been removed from the marketplace. Then we have Orlistat, this lipase inhibitor, which affects caloric absorption, and ephedrine and caffeine which actually in combination have been found to both affect appetite and energy expenditure. Works primarily through adrenergic mechanisms.
Here are the results, just to show you the kinds of effects one sees in obesity studies. This happens to be with the combination of Phen-Fen, which is no longer available, but I show it to you because of the fact that one, there is always a placebo effect in weight loss studies; two, you can demonstrate the effectiveness of the active agent versus placebo when in fact it is active, but here we are talking about kilograms - 95 to about 77 kilos - about a 20% reduction in weight that was maintained for some weeks, but again, if the drug were to be stopped the line would go back up again.
There are issues in the use of anorexiants. Most patients will not reach ideal body weight. You are looking for 5 to 15% to reduce risk factors. You need comprehensive programs. There’s minimal response at the first pass particularly with the centrally active agents. They should be discontinued. Always this expected plateau weight will occur. This is not tolerance since weight gain will continue if the drug is discontinued. And the duration of therapy is not established. Obviously the complications we’ve seen with fenfluramine and dexfenfluramine raises concern about long term treatment with any of these centrally active agents.
Surgery in obesity? Again, indications for BMI greater than 40, for morbid obesity, 100 pound weight excess over ideal or 100% over ideal. You don’t go directly to surgery without trying other approaches first. It needs to be done with a team approach and long term follow-up is essential for success and for safety. There are two primary approaches now. The jejunal-ileal bypass is no longer performed and should not be performed because of complications, including electrolyte imbalance, gallstones, cirrhosis, arthritis and renal stones. The two current procedures are vertical banded gastroplasty and gastric bypass procedures. These can be done successfully and can be useful in the loss of significant amounts of weight in these morbidly obese individuals, with a reduction in their mortality and morbidity.
New approaches that you are going to be seeing coming down the line: still some active research on leptin, although it seems to be slowing a little bit. More activity trying to identify the agonist for the leptin receptor or other molecules involved in this malady. Central appetite regulators. There’s a whole host of neuropeptides and neuropeptide receptors that are now known to be involved in appetite control and energy expenditure, including neuropeptide Y. And agents that stimulate thermogenesis; beta pre-adrenergic agents and other stimulators on coupling proteins, UCP-2 and UCP-3, which are present in mitochondria, are involved in