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Jeffrey Friedman, head of the Laboratory of Molecular Genetics at Rockefeller University in New York and a Howard Hughes Medical Institute investigator, has devoted much of his career to the study of obesity at the microscopic level. Most notably, his studies in mice during the early 1990s led to the identification of the adipose hormone leptin, which plays a crucial role in regulating food intake and weight gain. Friedman's current research focuses on learning about the genetic bases of obesity in humans, and in forthcoming studies he hopes to explore leptin's effects on the human metabolism. He also plans to collaborate with other researchers to concoct a more potent version of the hormone. |
Jeffrey Friedman answered selected viewer questions about leptin, obesity, and weight-loss research in October 2006. Please note we are no longer accepting questions, but please see our links and books section for additional information on these subjects. Q: I noticed on the program that leptin would not help a person lose weight but could possibly help one keep it off after losing it. I find that more hopeful than just about anything I've heard. When do you estimate it will be available for such a purpose? A: Good question. The available evidence indicates that leptin will reduce weight in a fraction of obese individuals but that it does not reduce weight in the majority of patients. There are also some recent reports that leptin used in combination with other drugs induces substantial weight loss. There are also reports studying a small number of patients suggesting that leptin could also prevent weight regain if given after weight has been lost. However, this finding has not been confirmed, and this conclusion will require additional experimentation which is likely to take several years. Q: Will finding out that my receptors may be malformed play a significant role in a weight-loss scheme (exercise, eating healthy, etc.), or is it only just information? If significant, how do I find out if my receptors are malformed? A: Good question. Leptin receptor mutations (your word was "malformed," which is essentially the same thing, meaning a defective gene) are rare but when present result in massive obesity. Thus, it is not likely that an obese individual would carry a mutation in the leptin receptor. At present an abnormality of the leptin receptor would be a research finding that would not influence treatment. Much research is being done to find ways of mimicking leptin's activity by changing neural activity downstream of the leptin receptor. It often takes a long time for research of this kind to be translated into new medicines. Q: Specifically, where is leptin produced in the body? Is there a "normal" level? And lastly, for those who would be judged to have a "high" level, is anyone close to creating a drug to block the leptin receptor? A: This is a good question, and the answer is a bit complicated. Leptin is made in fat tissue in proportion to the amount of fat tissue an individual has, meaning more fat more leptin, less fat less leptin. In general, lean people have less than 10 nanograms (10-9 grams) of leptin per milliliter of blood, which is roughly the same amount as other hormones such as insulin. Obese individuals have more fat and higher levels of leptin, typically ranging between 10 and 100 nanograms per milliliter. The amount of leptin that is made is to a large extent a result of how sensitive a given individual is to their own leptin. For example, if an individual was less sensitive to their own leptin, the thinking is that there would be a less potent effect of the hormone to keep weight down. This individual would then gain fat and make more leptin in an effort to overcome this "block" in leptin action. For this reason, in obese people my view is that in general there is no such thing as a "normal" leptin level. Rather there is a leptin level that is normal for that person based on their own biology. There are medical conditions that develop when someone makes too little leptin such as in patients with mutations in the leptin gene, in patients with a condition known as lipodystrophy (the absence of fat), or in extremely thin women, ballet dancers, gymnasts, or long-distance runners. These conditions can include diabetes, a failure to enter puberty or menstruate in women, bone abnormalities or even reduced immune function. These other abnormalities can develop when leptin levels are less than five nanograms per milliliter, though again it would depend on how sensitive someone is to their own leptin. Q: Can you try using larger doses of leptin? A: Giving larger doses of leptin does not appear to be any more effective than lower doses in people who do not respond to the hormone. A key issue for future research is to understand the reason why some people do not respond to large doses of the hormone at all. There are many possibilities. There could be alterations in the neural circuits in the brain that respond to leptin. There could be defects in the ability of leptin to cross the blood-brain barrier and reach the brain. There are also other theoretical explanations. For now the answer is unknown in humans. Q: You said in your interview [on the October 3rd broadcast of NOVA scienceNOW] that reduced leptin levels are what cause the body to want to regain lost weight. If, however, one were to maintain one's weight at the reduced level (by exercising/creating calorie deficit) for long periods of time, does the body get used to the lower levels of leptin and decide that this is the new "natural" body weight? A: Good question. The available evidence suggests that the body does not reset its sensitivity to leptin after weight is lost by dieting. This is consistent with the fact that most people who lose substantial weight by dieting report that they have to continually battle the urge to eat more long after the weight has been lost. Q: I think it's wonderful that there is serious research out there about obesity. I'm curious to know if leptin would help those who compulsively overeat. Not necessarily as a weight-loss miracle drug, but as a way for those types of people to understand what is normal in terms of portion size/meal size/food choices, etc. A: Thanks. It is possible that leptin could prevent overeating in some individuals. It certainly did in the leptin-deficient children in England and might act similarly in additional people. The available evidence indicates that leptin will reduce food intake and body weight in a fraction of obese individuals but that it does not reduce weight in the majority of patients. There are also some recent reports that leptin used in combination with other drugs induces substantial weight loss. Q: My daughter has always been a healthy eater and very active, but when she was five she gained a significant amount of weight and has had a weight problem ever since. At that time she developed asthma and was given several different medications. Could a medication cause a leptin receptor defect? A: There is no evidence to suggest that any medications can cause abnormalities in the leptin receptor. Some drugs can cause weight gain, including drugs for some psychiatric disorders. Some people receive steroids for asthma, and this can cause weight gain of a specific type, though this is almost certainly not a result of effect on the leptin receptor. Q: According to the NOVA scienceNOW presentation, people who have the disorder with the M4 receptor always feel as though they are starving. I have heard that after a few days of going without food the feelings of starvation leave. Why doesn't the same effect occur? A: I am not sure that the feelings of hunger leave after a few days without food, though I have no basis in personal experience for saying so. My sense would be that the feeling of hunger would grow more intense after days without food rather than less. What is the information source for your statement that hunger grows less intense over time? I should know about this. [Editor's note: Send to NOVA at wgbh.org and we'll forward to Dr. Friedman.] Q: I'm crying—it's hard to see the screen. I maxed off my doctor's scale; I'm over 350. I've been 200+ since I was 14. My father died when I was 5 of diabetes. I am diabetic, as is my son, 27. I shoot around 200 units of insulin a day, which contributes to my weight—around 120 of Novolog and 90 of Lantus. I am very insulin-resistant—one slice of bread, around 15 carbs, equals 30 units of insulin. I beat myself up because I'm so fat. I will occasionally eat a bag of popcorn and pay for it later with two shots. I eat a lot of vegetables and salad, watch the dressing. It takes SO MUCH ENERGY to move. I find myself finding reasons not to leave the house. It is hard to fit inside my car now. I WANT TO LIVE! Is there a test I can take, out here away from the "big city" that could help me understand and forgive myself for being this size? What can I do, with no medical insurance, to save myself? A: I do not believe that it is your fault that you are overweight. I believe that everyone's biology is different and that to a very large extent some people's genes ordain them to be fat while other people's genes lead them to be thin. My advice would be to accept who you are and do what you can to improve your health. This would include starting an exercise program, eating a heart-healthy diet to minimize cardiac risk, and trying your best to lose a small amount of weight (on the order of 10-20 pounds) instead of trying to lose much more weight than that, which for most people is not realistic. It is absolutely clear that even modest weight loss of 10-20 pounds can have a significant health benefit, especially for diabetic control. Q: Why are some obese individuals able to maintain weight loss? Are they resistant to the effects of decreased leptin levels? A: Good question. It appears that roughly 5 to 10 percent of extremely obese subjects can maintain substantial weight loss with diet and exercise over long periods of time. While there are ongoing studies of these people, it is not clear why they can achieve weight loss while the majority cannot. The ability to maintain weight loss is a result of a battle of sorts between one's level of conscious motivation and the biologic (unconscious) drive to eat more and regain the lost weight encoded by leptin. Leptin levels fall after weight loss, and low leptin levels provide a powerful stimulus to feel hungry. Clearly the power of this biologic drive and the power of conscious motivation will differ among people. However, the power of the biologic drive is underestimated by most people, and for most individuals biology trumps motivation, at least over the long term. Ultimately, we would like to understand where the neural circuitry controlling conscious motivation is located and how this circuitry interacts with the unconscious neural circuits that encode the drive to eat. Q: Are you aware of any research being done in the area of leptin and its role in anorexia nervosa? A: Patients with anorexia nervosa have very little fat and as a consequence have low leptin levels. In recent years it has been learned that several medical conditions develop when someone makes too little leptin, such as in patients with mutations in the leptin gene, in patients with a condition known as lipodystrophy (the absence of fat), or in extremely thin women, ballet dancers, gymnasts, or long-distance runners. The same is also true with anorexia nervosa. The conditions that develop with very low leptin levels can include diabetes, a failure to enter puberty or menstruate in women, bone abnormalities, or even reduced immune function. It has been shown that leptin treatment can improve these other abnormalities, though in the case of anorexia nervosa giving extra leptin could lead to further weight loss, which would be undesirable. Q: Have you ever compared leptin levels to ghrelin levels? Is it hard to tease out what functions related to food regulation are controlled by ghrelin as opposed to leptin? Also, the hardest thing about weight loss/maintenance for me is how it affects my sleep. Recently there have been studies linking ghrelin to sleep cycles, which might explain some of my struggle. Have you looked at leptin levels and sleep patterns specifically? A: Regarding your first questions, ghrelin levels appear to increase before meals, and it has been suggested that ghrelin plays a role in stimulating hunger before the onset of a meal. Leptin is a longer-term signal that controls the amount of fat an individual carries. The two molecules have opposite effects on food intake and also have been shown to have opposite effects on the activity of key neurons in the brain that regulate food intake. As for your second question, there is research investigating whether leptin plays a role in sleep and whether, for example, it is relevant for sleep apnea. But the answer to this question is not known, at least by me. Q: Are there any foods that help to stimulate leptin in your body, but are not "fatty" type foods? That is, have you found any natural substances that help the body product leptin, but do not add fat? A: I am not aware of any evidence that different nutrients influence the amount of leptin that is made. Leptin levels are most closely correlated with the total amount of fat that an individual carries in their adipose tissue. Q: You said that each person has a set-point range that is determined by their genes. I'm just curious: roughly how wide would this range be? Five pounds? Twenty pounds? A: There is no precise answer to this question, but my sense is that the range is 15 to 20 pounds. This is not to say that one cannot move outside this range. Rather it means that the further away one moves from this range, the greater the strength of the biologic forces that resist it. Q: I have been on a 700- to 1,000-calorie/day diet and working out three to five times a week for an hour each time. My weight goes down a couple of pounds and then comes back. I am 5'7" and 180 pounds. I have been doing this for three months or so. I got tested for thyroids and everything came back normal. Could I be disposed to staying at this weight? I don't think I can do anything more and am thinking something is wrong with my genes. I would appreciate any feedback. Thank you so much. A: There are powerful biologic forces that resist weight loss. For example, it has been shown that when people lose weight, they not only feel hungry but that they also burn fewer calories than a person who is lean. This is part of a complex biologic response that seeks to return an individual's weight to the starting point. Q: What are your thoughts on the current prescription weight-loss aids, i.e., Meridia, Phentermine, Xenical? A: These drugs have been shown to be effective for inducing relatively modest weight loss. Each, however, also has side effects in some people, as do almost all drugs, and this together with the fact that they do not induce weight loss to the same extent as most people aspire to has limited their use. My view is that use of drugs for the treatment of obesity should be limited to those instances in which a person's health can be shown to improve, such as in better glucose control in diabetics, lowered blood pressure, or reduced risk of cardiovascular disease. I also believe that this same caveat should apply to future medications that are made available to the public. Q: What do you think is the role of additives and preservatives in obesity? Can they downregulate specific receptors in the brain responsible for sensing satiety information? A: While it is theoretically possible that nutrients or additives could modulate neural circuitry in the brain, there are no specific examples in which this is known to be the case. Q: I was fascinated by last night's NOVA scienceNOW segment about obesity, particularly the part about the brain in obese people not having the receptor sites for leptin. This helps explain a situation in my own life. You see, I am a formerly obese woman who stayed between 210 and 240 lbs for about 15 years. I took off 100 lbs over 14 months beginning in spring 2003, and I have had some difficulty in maintaining it. I used a 12-step program for food addiction to do it, eating nothing with flour or sugar and by weighing and measuring my food. It is a very rigorous program. I have had several lapses since then, and—now, getting to my question—I have noticed that whatever that part of me was that used to signify that I was full seems totally gone now. If I start binging, I can't seem to get back to a place where I know myself to be full or satiated. It's like the satiety center in my brain is totally broken, unlike before I lost the weight. Is this because I may have lost more receptor sites, or because I now permanently have less leptin in my system? I have gradually put on almost 30 lbs in the past year and am more convinced than ever that what the folks in the 12-step program for food addiction say is right—that I will need to continue to rely on a food scale instead of my own idea of "enough" in order to maintain a healthy weight. What are your thoughts on this? A: Regarding your first question, leptin levels fall after weight loss, and low leptin levels provide a powerful stimulus to feel hungry. It is highly likely that it is reduction in leptin that contributes significantly to the hunger you describe. While it is also possible that weight loss could also alter receptor amounts or function, this has not been shown. Regarding your second point, conscious control of food intake can lead to weight loss, but over the long term this is not effective for most people. The ability to maintain weight loss is a result of a battle of sorts between one's level of conscious motivation and the biologic (unconscious) drive to eat more and regain the lost weight encoded by leptin. Leptin levels fall after weight loss, and low leptin levels provide a powerful stimulus to feel hungry. Clearly the power of this biologic drive and the power of conscious motivation will differ among people. However, the power of the biologic drive is underestimated by most people, and for most individuals biology trumps motivation at least over the long term. Ultimately, we would like to understand where the neural circuitry controlling conscious motivation is located and how this circuitry interacts with the unconscious neural circuits that encode the drive to eat. Q: Do you know of any research that links anosmia (no sense of smell) with obesity? I was born with no sense of smell and have often wondered if this affects how long it takes me to feel satisfied by a meal. (Yes, I have a sense of taste.) A: This is a good question. It would be interesting to know if the incidence of obesity is different in anosmic people versus people who smell normally. It would also be interesting to know if obesity rates are different in people who have defects in taste. I do not know the answer to this question, but please let me know if you find out. Q: Can people who share a cultural, ancestral diet (such as Native Americans or people of Japan, for example) experience extreme weight gains when they change to a diet that includes foods that come from outside of their diet "heritage"? If so, is this because of a change in fat content or starches and sugars, or simply a matter of calorie increases? A: This is an important yet open question that is the subject of intense debate. Some people believe that a calorie of lipid is the same as a calorie of fat, etc. (i.e., a calorie is a calorie, whatever its source). Others believe that the source of the calories is very important. For example, the Atkins Diet posits that too much carbohydrate predisposes to obesity, while others posit that it is fat that has a disproportionate effect. There is no clear evidence favoring one hypothesis over the other, though my bias is that a calorie is a calorie and that the source of the calories is not as important. That said, there is a lot of individual variation, and it may be that some individuals or populations respond differentially to some nutrients and others do not.
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