Genetics of Obesity – Bears do it–can we do it?

Lecture Presenter

Roger Orth, M.D.

Dr. Orth was born in Chicago, Illinois, and received his Bachelor of Science Degree at Illinois Institute of Technology. His Medical Degree is from Tulane University School of Medicine and he completed his internship and residency at the Univ…Full Profile

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“Hibercare” for obesity.” My original plan was to limit this lecture to issues evolving related to genetics of obesity. Though I plan to discuss some of the aspects of genetics that are recently described, I would like to also touch on several other parameters. It has become apparent that we are in a rapidly changing situation regarding the problem of obesity and overweight status in western cultures. I will touch on some of the apparent causes of this sudden increase in a process that has major morbidity and mortality ramifications. I would also like to discuss some of the issues related to other environmental factors besides food intake.

One interesting new factor would be that of infectobesity. The idea that an adenovirus might cause some people to become obese has recently been described and has some interesting potential spin offs. Methods of defining obesity will also be discussed, and the potential advent of the genechip will be briefly described. Some of the newer aspects of genetically-described pathways including those involving leptin will be of interest. Additionally, the process involving intracellular cortisol regeneration appears to be particularly interesting when applied to the visceral obesity which has the highest risk for cardiovascular and diabetic side effects of obesity. Aspects of drug treatment, current and future, will be described. The potential application of this new found information related to obesity and metabolism will be discussed including the possibility of mitochondrial uncoupling agents will be interesting. The possibility that the future treatment related to increased thermogenesis and the role of brown fat versus plain white fat will prove interesting. Lastly, a speculation that latent genes related to hibernation could be activated and allow an interesting approach–hibercare.

A. Hibernation Metabolism. I think it is interesting to actually start this discussion with a description of some of the remarkable aspects associated with bear physiology. During hibernation of a bear they do not eat, drink, or defecate. They use their internal metabolism to generate water and have a remarkable ability to absorb urea–a protein waste product–from their urinary bladder and reutilize the urea as a building block for amino acids. Alanine serine and even essential amino acids may well be generated with the reverse cycle that includes urea re-uptake in the bladder wall of the bear. This nitrogen reprocessing allows the bear to be a self contained metabolic factory–which is particularly important in the denning female bear–as she will generate enough protein to make a new cub. The cycle of urea plus glycerol to make amino acids is also performed by the male bear, and in fact the male makes enough protein in the form of blood proteins such as albumin to reflect the amount of protein that would also be needed to make a cub. This nitrogen shuttle plays a role in the fat metabolism that is quite remarkable in a bear as the additional albumin has a great deal of use in carrying fatty acids around the body for energy metabolism. A bear can lose 4000 calories a day while in hibernation, and the main shift is one of carbohydrate metabolism becoming inactive and fat metabolism becoming overactive. This activation of fat metabolism allows the bear to lose 40% of its weight, almost exclusively in fatty tissues, while preserving essentially all of its skeletal muscle and other proteins. At a meeting for the International Hibernation Society in December 2000 it was announced that two genes that are thought to trigger hibernation and allow enzymes to burn fat rather than carbohydrates had been described. One of these is pyruvate dehydrogenase kinase (PDK). This enzyme has a major effect on pyruvate metabolism and allows a modification of the pathways involving fatty acid production through acetyl co-A, and the tricarboxylic acid cycle to be markedly changed. Even the United States military is interested in how bears hibernate since it can affect ways to handle battlefield injury victims as well as organ donations. I think the most impressive component of the bear story is that of the polar bear. A polar bear can go into hibernation metabolism–but does not hibernate. Summer months are particularly difficult as the main source of food for a polar bear is the seal. When the ice is melted it is very difficult to catch a seal, and by activating their hibernation metabolism–without actually hibernating–they are able to maintain themselves during those difficult months when no seals are available. In the winter months, when seals are easy to catch as they come up between ice flows, they will eat one seal every 6-8 days and consume 50,000 calories of blubber at a time. It is interesting that a polar bear will not eat any of the meat product. In fact, if they are forced to eat meat their intake of water would have to be increased to meet the demands of excretion for urea. It is not possible for a polar bear to get fresh water without melting the ice and snow, and thermal regulation would be dramatically compromised if fresh water were a requirement of the bear’s metabolism. In that setting bears simply eat the fat from the seal and discard the rest. Consumption of ice and snow would cause a severe drain on fat stores and would not allow the bear to survive. Consumption of the fat releases carbon dioxide and water which can be excreted by respiration and nicely controlled. Having an animal that can turn on a hibernation mode while not actually sleeping may have particularly interesting ramifications to human physiology–especially human behavior which would like to have a way of losing weight while we sleep… It is particularly interesting if the central nervous pathways can be better defined in bears since the hibernating bear combines the difficult problems with starvation, pregnancy, and lactation all successfully done during the hibernation period. Whatever factors keep a bear from waking up from hibernation hungry as well as those factors that control pregnancy in a setting of not eating would be well worth studying. Interestingly, the bear represents an unusual variation in mammalian metabolism in that they produce the smallest cubs of any mammal when compared to the size of the mother. Also, the polar bear would appear to have the lowest intake of protein in grams per kilogram weight of any mammal. The idea of hibercare, therefore, may have a role if transcription activating processes could find the latent genes that are most likely actually present in the human genome but not active.

B. Will there be a pill for gastronomic promiscuity? There was a remarkable article summarizing the possibility of a pill that would let you eat what you want and stay thin in the new Scientist Magazine March 23, 2002. The writer, Geoff Watts, summarizes some of the aspects of recently described uncoupling proteins that allow mitochondria to be active but not generate a necessary stored energy as ATP–but rather generate energy as heat. He states, “We are on the verge of doing for eating what we have already done for sex: sever the link between the pleasure and its biological consequences.” “Forty years ago the advent of the Pill freed lovers from the fear of unwanted pregnancy. Why not a pill to free foodies from unwanted fat?” The idea of uncoupling proteins actually has historical background. 100 years ago when thyroid hormone was first described it was utilized–in fact it is still utilized inappropriately to turn on the metabolism and allow net weight loss. The problem with thyroid hormone is that it involves most of the cells in the body and results in net loss of skeletal muscle and other important building blocks. Thyroid hormone utilization for weight loss has almost no role in weight loss remedies–unless the patient is low in thyroid itself. In the aniline dye industry it was noted that many of the workers became quite thin. Dinitrophenol turned out to be the toxin in the dye industry that was recognized as the source of weight loss. Clinics developed in the 1920’s utilizing dinitrophenol to cause weight loss. This agent uncouples mitochondria, but there is no selectivity and the patients often became sick. Uncoupling mitochondria can be quite dangerous if done it on a diffuse basis, i.e., cyanide or strychnine poisoning. These nonspecific poisons affect too much of the mitochondrial energy system to allow survival without major risk to the patient. In 1997 uncoupling proteins, however, were described. Some of these uncoupling proteins are unique to fat cells. Brown fat, which represents a high mitochondrial variant of fat, has an uncoupling protein–UCP I. Activation of this uncoupling protein allows for heat genesis which is the mechanism for the important role that brown fat plays with thermal challenges. Other uncoupling proteins are not unique to fat cells but are certainly quite important. Uncoupling protein III may help the body cope with dangerous free radicals–an important component for the aging process. As a side light there was an interesting article in Science Magazine, January 2002 that described a life extension process in a type of worm associated with ingestion of a component of the diet–coenzyme Q. Interestingly, the activation of oxidative phosphorylation by dietary coenzyme Q allows high energy metabolism to occur but also may give risks associated with free radicals in active oxygen species which are important in the aging process. The life span of the test species was extended by depleting this coenzyme which forces the mitochondria into a more anaerobic respiration. The proton gradient that drives ATP synthesis is directly related to these anaerobic versus aerobic application in the mitochondria. Uncoupling proteins will have a major effect in the energy factor though important in mitochondria. The possibility of using endogenous uncoupling proteins to active from fat would actually allow a freedom from the biological consequences of excessive food ingestion. The real problem with brown fat is that it does not represent a significant amount of the fat in the human body–except in the newborn who uses it in particular to stay warm. However, brown fat can be induced in the human body, and in test animals a cold challenge as well as specific activating factors will clearly increase the amount of brown fat available. It is known that beta III receptors will increase the amount of brown fat production, and mesenchymal stem cells are sensitive to specific activators that have been described. A combination of uncoupling protein activator, especially in conjunction with a brown fat differentiation factor, would have a dramatic impact on our ability to eat without consequences… I will review later some drug companies that are pursuing this role, though, I am unaware of any that are pursuing it as a combination.

C. Environmental causes of the obesity epidemic. Obesity as a disorder has only recently been accepted as an actual disease state that would qualify for IRS benefits. Obesity as a disorder would include 100 million Americans who are either obese or overweight. It does account for approximately 300,000 excess deaths per year and health care related costs in the neighborhood of 7%-10% of the total health care budget. In westernized society the “thrifty genotype hypothesis” does not have a major benefit. Precursor humans had a benefit for being able to store fat during times of plenty. If one looks at the populations most affected by obesity it is in fact aboriginal type tribes in Australia as well as Indian tribes such as the Pima or Hopi type tribes. These tribes are now having to deal with a genotype that has become accustomed during the past 100 years to refined foods and rare episodes of starvation or limited capacity to obtain food. The recent Rand Report by Sturm appearing in March 2002 confirms that obesity tops smoking and alcohol for medical-related costs in the United States. Being obese actually increases costs dramatically more than any other environmental risk factor except possibly aging 20 years during the middle age of life. While legislation to control access to smoking and drinking has actually controlled or even slightly decreased the incidents since 1980 of these problems–the incidence of obesity in this country has dramatically increased since 1980. One can anticipate in the coming ten years that the realization that obesity is a controlled environmental issue that should be dealt with as a disease rather than simple poor judgement will evolve in the approaches to this public health issue. Over the years, some relatively crude methods have evolved to determine the total body fat and infer the associated risks that develop as a function of the fat storage have evolved. Body mass index has been utilized over the years in population studies since it is easily obtained data and can be shown to be an effective predictor of the obesity phenotype. From 1991 to 2000 the number of people in America with obesity have increased 60%. This transition began in 1980 and does not have any clear change in sight regarding the higher transition rate toward overweight/obesity status. Certainly, having more than 50% of the American public fall into this category of being overweight or obese reflect factors that may be beyond simple genetics. Otherwise approaches to body fat estimation have evolved over the years and are mentioned in the slides accompanying this lecture. Actually, I think these approaches are also very crude, and it is only the advent of the genotype system that will give us in the next ten years access to the date necessary for prediction of a patients risk as well as predictions as to the best approach to control the obesity. The use of oligonucleotide segments placed on silicon chips will offer a dramatic change in screening for underlying genes that interact to cause a patient to become obese. Genechips can have more than 50,000 fragments characterized on a single chip and lead to massive amounts of information about an individual’s genetic makeup. This type of approach with biochips in the future can likely be anticipated in not just obesity management but also in a host of other polygenic disorders such as heart disease and atherosclerosis.The energy intake of an individual has much to determine the final outcome–obesity. A normal adult consumes 700,000 to one million kilocalories per year. Food storage as fat can have a dramatic impact even if it is just 200-300 calories per day. As I reviewed potential reasons for the marked increased frequency and obesity during the last twenty years, initially I thought that much would be attributed to changing exercise patterns, increased television, or even more likely increased internet/video games. However, I think that one easily controllable factor that has had much ado with this issue is that of soft drinks. Soft drinks are unique in that they have very little, if any, nutritional background and may well bypass the normal satiety factors so important in controlling our calories. Soft drinks currently account for 25% of all drinks sold in the United States. There were 15 billion gallons of soda sold in the year 2000. Americans currently spend 54 billion dollars a year on soft drinks. Studies now show that in various age groups sodas account for somewhere between 20%-40% of children’s calories. 13-18-year-old boys average three cans per day, and 10% of that age group will have seven cans per day. 60% of all middle and high schools in this country serve soda with their lunch program. The marketing and potential subversive marketing associated with the soda companies have far reaching consequences. Coca-Cola pays the Boys and Girls Club of America 60 million dollars a year for exclusive rights in their 2000 clubs. Cola-Cola and other soda companies pay direct money straight to the school systems for the privilege of having sodas placed in machines or on the lunch lines. Logo recognition of Coca-Cola is probably the greatest penetration world wide of any logo. Interestingly, a company called Munchkin Bottling, Inc. produces baby bottles that have Coke, 7-Up, and Dr. Pepper logos. Having infants and babies imprint these logos at an early age may well be playing a role with the advent of ballooning soda sales. There is a remarkable report in Lancet February 2002 that was a longitudinal study of 548 children over 19 months in Massachusetts. Drinking soda proved to be an “independent risk factor for obesity.” For each additional daily soda the risk of childhood obesity increased 1.6 fold. This is a remarkably important feature since the number of fat cells in the body are determined for the individual early in life. One can gain weight from hypertrophy (increased size) or hyperplasticity (increased numbers of cells). If a child has onset of increased numbers of fat cells as a youth these fat cells will become a burden later in life. It is actually far easier to lose weight if the total number of fat cells is diminished. A normal lean person will have approximately 25 billion fat cells and an obese person will have 100-150 billion fat cells. Fat cell size and number, therefore, play a major role in the weight loss efforts of the future, and childhood obesity is a ballooning problem that may well be related to these soft drinks. I also think that there is a role for review of caffeine placement in soft drinks. There is absolutely no reason to put caffeine in non-cola drinks, and yet the caffeine is present. This is a truly subversive act by the bottling companies, and I would suspect that there may come a time in which plaintiff lawyers will be sueing bottling companies for getting children “hooked” at an early age and causing medical complications later in life. Certainly, there are other features as to why obesity is a markedly increasing issue in this country, but it won’t be surprising if some of the pending California and other state legislation for obesity-related taxes on soft drinks were to be proven successful. Other issues of obesity can be seen in a recent Reader’s Digest article on the subject showing pictures of the problem of super-sizing. It seems that the American way is always bigger and having more food than one needs is a conceptual issue that deals with the central nervous system pathways but certainly increases the sales of the refined fast food industry. Some of the subtleties of the fast food industry are well described in the recent book Fast Food Nation by Eric Schlosser. Having fast food access is now seen in such diverse areas as the middle school Creative Learning Center here in Pensacola which offers a different fast food for every day of the month. Even Sacred Heart Hospital has included a fast food restaurant in its medical mall, and this trend continues across the country. On a somewhat lighter note, there is a description of an infectious form of obesity that may play a role that is poorly described to date but will be avidly studied in the near term. There are examples of viral-induced animal obesity. An interesting outbreak of adenovirus in chickens led researches to examine adenovirus involvement as a possible role in human obesity. Adenovirus 36 when injected into chickens, mice, and monkeys leads to actual weight gain. There is a recent study in Germany that tested adeno-36 virus titers in obese subjects. 100 of the 373 obese subjects had a positive titer while only 4 of 92 lean subjects had a positive titer. Interestingly, simultaneous twins studies revealed an increased BMI involved in the twins that were uniquely positive in titer for AD-36. It has been shown that stem cells infected with AD-36 show a 3-fold increase in lipocyte production. Infectious obesity, therefore, may have some significant impact, though, interestingly leptin metabolism does affect a person’s immune system. We will discuss leptin further in a later section, but it is possible that obese patients are more susceptible to adenovirus rather than adenovirus causing the obesity. In any event, this has ramifications since those who are obese and proximally related a virus may have an easier response to certain drugs to control the obesity. Additionally, the virus has been shown to be stable in the conditions of a blood transfusion, and it has been suggested that blood be screened so that one does not get a transfusion and get fat at the same time.

D. Genetic obesity syndrome. There are a host of genetic obesity syndromes with over 100 genes already identified that have some role in obesity. Many of these studies come out of the model. For years there was a tremendous interest in OB mouse. This mouse showed genetic obesity to the point that major health effects occurred in the mouse. In the late 1960’s and early 1970’s parabiotic blood studies were done between normal and obese mice. These suggested that a circulating factor may be present affecting the mouse’s obesity. The search for that circulating factor is with conclusion in 1994 when it was identified using an exceptionally elegant scientific approach called “positional cloning.” This technique was therefore able to identify the gene associated with the obese mice protein product and cloned this gene. This gene turned out to be making a protein called leptin which is a 167 amino acid protein. This protein turns out to be remarkably important in fat metabolism and transfers information from the fat cell to multiple cells in the body including the central nervous system. This transfer of information is basically hormonal in character and thus the fat cell became part of the endocrine system of the body. Much excitement was engendered in the press as well as amongst pharmaceutical companies that a fat factor had been identified and might possibly be a future modality of treatment. Amgen actually paid 20 million dollars the year after this gene was discovered for the rights to use the gene its medical research. Leptin is nicely described in many hundreds of articles. Briefly, it is released by the fat cells as an indicator of actual fat content. The leptin circulates and is able to interact with receptors in the brain and transport its signals to the hypothalamus. The hypothalamus, of course, is the main control center that has been known for some years to have much to do with problems of appetite, satiety, and eating behavior. Many factors interface with the hypothalamus including input from the limbic system giving pleasure to eating as well as input from sight and smell cranial nerves–all playing a role to modulate the eating. The net affect of leptin is to decrease food intake as well as increase energy expenditure peripherally. The latter is via the thermogenesis mechanism previously discussed. There is increase in glucose metabolism, increase in fat metabolism, and variable functions in regards to neuro endocrine activity. Leptin, therefore, is affecting neuropeptides in the brain, the latter of which represent an exceptionally complicated combination. There are a number of neuropeptides, and they can basically be classified as orexigenic or anorexigenic. These neuropeptides affect the system in the central nervous system that has to do with food intake, sympathetic tone, and signals to the periphery regarding eating and fat oxidation. Some of these are summarized in the accompanying slides and will not be restated here. I think the complexity associated with processes to block neuropeptides or the subsequent conduction pathways involving noradrenaline or serotonin pathways reflect a very difficult state of affairs in trying to have adequate dietary control using central nervous system modulators. These multiple pathways have feed back loops that will predictably have back-up pathways, and again, I don’t know that this is going to be as effective as other potential methods that have already been discussed, i.e., uncoupling proteins or activation of latent genes. I do think that a peripheral pathway is well worth discussing amd was just described in the December 2001 Science Magazine by Dr. Flier and associates in Boston. This remarkable article is entitled “A transgenic model of visceral obesity and the metabolic syndrome.” Careful review of the data in this article does suggest that the unique characteristics of the enzymes they describe in fat cells alone will have a unique impact on obesity and in fact may have a future major impact on obesity management through various blocking agents. The uniqueness of this enzyme has similarities to the uniqueness of the hydrogen potassium ATPase enzyme when the original blocking agent Prilosec was described in about 1980. Certainly, the latter revolutionized the treatment for acid peptic disease, and I am suspicious that this discovery could a similar impact on management of visceral obesity. Basically, the enzyme is remarkably important on the intracellular level in regards to steroids which are known to affect patients giving them obesity. Normal visceral fat deposition apparently is also controlled by a mechanism involving activation of intracellular cortisol–a steroid. It is particularly important that visceral obesity is the obesity that is associated with risks of heart disease and diabetes, etc. An adequate blocking agent for this enzyme activity would have a remarkable affect on losing the waistline… They were able to amplify the activity of this enzyme in elegant studies involving transgenic mice. These mice and dysmetabolic parameters are very similar to that which is associated with human obesity.

E. Drugs and Outlook. The drug treatment for obesity to date has been crude indeed as I have already alluded. It has not been particularly successful. There was quite a bit of excitement about the use of serotonin releasing compound, the so-called fen-phen story. This drug combination did have quite a bit of utilization until it was discovered that the serotonin effects also involved mesenchymal precursor cells. These precursor cells led to increased problems of fibrosis in the lung as well as heart valves. Actually, it is not too surprising that a drug that would affect serotonin release might have such a problem since there has been a problem in the past with a migraine medication named Methysergide. This particular drop had to stop utilization because of retroperitoneal fibrosis. The release of serotonin, therefore, affects the stem cells and has led to quite a bit of issues regarding medical liability cases. There are only two currently available drugs that are prescription for control of obesity. Sibutramine does affect serotonin but by decreasing uptake rather than causing release. It also affects norepinephrine and this modulates the central nervous factors previously discussed to induce a sense of satiety. There is an additional drug Orilistat which blocks pancreatic lipase and therefore decreases the body’s ability to absorb fat. The combination of decreased uptake and foul-smelling diarrhea teaches patients not to eat as well as helping them not gain the weight from what they eat. I have included a slide in my slide section that lists a numbers of companies that are currently looking and various blocking agents. Some of these blocking agents involve more selective access to the leptin system and other leptin control points. I think, however, that we have some unprecedented options coming that will not involve such complicated interactions systems as the CNS. I have already alluded to thermogenesis control and uncoupling proteins. This in combination with increasing the amount of brown fat in a person could give a dramatic affect on weight control.

Although I included hibercare in the talk initially to catch the eye of my listener, I do think there is a chance that reversing some of the sleeping genes and making them active with transcription factors could lead to quite remarkable means of controlling weight. The remarkable metabolism of a polar bear may still teach us much about the metabolism of humans.

Roger Orth, M.D.

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