JAMA

doi: 10.1001/jama.282.16.1502pmid: N/A

It is said that the average American is increasing in girth, and that the typical Uncle Sam with his lank body in its swallow-tail and striped trousers is more than ever before a gross caricature of the national type. A New York paper claims that figures collected from clothing dealers show that while the average American of 1889 was easily fitted with a waistband of forty-six inches, which it was then thought would never be exceeded, in 1899 he requires one of forty-seven and a half inches. It goes on to make the calculation that, at this rate of increase, he will reach in 1909, a circumference of forty-nine or fifty inches, and that in A. D. 2899 the American girth will be sixteen feet. The above facts, not the deductions quoted, are credited to one of the scientific government bureaus, and it is stated that the increased consumption of farinaceous and fat-producing foods is alleged as a possible cause. The dairy lunch counters that have sprung up so numerously within the past few years are credited in part with this result. The editor adds his own theories, that the labor-saving inventions, the elevators, telephones, and other contrivances supposed to make people indolent and fat, have their part in producing this result. Whether these are anything more than guesses is doubtful; the real reason of the fact, so far as it is such, is probably yet to be given. There are probably many factors co-operating, not the least of which is the improved physical surroundings of the present generation. The ideal Yankee still exists, but it is a long time since he fairly represented the average American citizen. It will probably be a still longer time, however, before we take trouble to change our comic national personification.

Barach, Paul

doi: 10.1001/jama.282.16.1592pmid: N/A

The nation's teaching hospitals are facing financial shortfalls brought on by the growth of managed care and government efforts to cut costs in its health care programs. As many as 100 teaching hospitals could be in the red by 2002.1 Others face a bleak and uncertain future. Congress can help by restoring some of the cuts made to Medicare in the Balanced Budget Act of 1997. But the long-term financial health of teaching hospitals will depend on finding new ways to finance their special missions and requiring that they operate under reasonable cost controls. All hospitals are facing the same pressures—cuts in government payments and managed care's demand for lower hospital fees and shorter hospital stays. Many have responded by reducing staff and merging with other institutions. Some teaching hospitals have taken these steps, but their problems are compounded by the extra obligations that they have long assumed, which include training new physicians and other health care personnel, conducting medical research, and providing free care for the poor. Teaching hospitals shape the future of medicine by providing most of the clinical research in new procedures, technology, treatments, and medications. They are the major providers of indigent care in the United States. Managed care has changed that by making it much more difficult for hospitals to cover the costs of charity care and medical education by charging higher fees. At the same time, these hospitals have been especially hard hit by government cuts because they derive much of their revenues from Medicaid and Medicare patients. These pressures are especially severe in large cities such as New York, NY and Los Angeles, Calif, which have the nation's largest concentrations of teaching hospitals. Many government funding cuts to hospitals came from the Balanced Budget Act of 1997. While the Act had the welcome result of cutting Medicare expenditures in the first half of this fiscal year, it also had a disproportionate impact on teaching hospitals. Among other cost controls, the law sharply cut the Direct Medical Education payment, the federal subsidy for graduate medical education that is financed as part of Medicare. The law also froze the number of funded residency and fellowship positions at the 1996 level. Some Medicare patients were encouraged to switch to Medicare health maintenance organizations, which have paid hospitals significantly less than normal Medicare providers pay for the same services. In the public's mind, no clear distinction exists between academic medical centers and community hospitals. We need to promote the message that academic medical centers are different and a national resource. Next week's Resident Forum column will explore some of the suggestions for protecting this resource. References 1. Association of American Medical Colleges. AAMC calls for restoration of BBA Medicare cuts to teaching Hospitals. Available at: http://www.aamc.org/newsroom/pressrel/990428.htm. Accessed September 20, 1999.

doi: 10.1001/jama.282.16.1502L-JJY90034-2-1pmid: N/A

The Washington correspondent of an eastern paper, the Brooklyn Eagle, states that the chemists of the Department of Agriculture have of late been giving attention to the numerous breakfast foods that are being so actively pushed before the purchasing public. Samples were obtained of the advertised brands and repeated analyses made, with the result, the correspondent states, "that the official report, which will be issued before long, will show that the makers of these preparations have been so enterprising in advertising their wares as to forget to stick closely to facts." While the analyses proved that there was practically no adulteration, they found that there was no discoverable relation between quality and prices. Some of these preparations are sold at four or five times the cost of the others of the same constitution and equal merit. . . . It is well in these days of food and diet fads to keep in mind the commercial reasons for the existence of the numerous preparations advertised as "health foods," etc. The forthcoming report of Dr. Wiley will be of interest to medical men who are so often consulted in regard to these articles. JAMA. 1899;33:1108

doi: 10.1001/jama.282.16.1502L-JJY90034-3-1pmid: N/A

November 25, 1899 Not long since the JOURNAL noticed the increasing girth of the average American as reported from tailors' measurements. These apparently gave evidence that at the present rate of progress the future Yankee would be of Falstaffian proportions, which, as one would naturally prefer to be an Apollo rather than an exaggerated Bacchus, is not in all respects satisfactory. We can take some satisfaction, therefore, from the recently-expressed opinion of a distinguished Italian authority, Professor Angelo Mosso, who finds Americans far better developed and stronger than his countrymen, and who speaks of physical education being carried here to perfection. As an Alpinist of some reputation, as well as noted physiologist, Professor Mosso's opinions on this subject, however flattering, are entitled to respect, and we may comfort ourselves accordingly. Still another authority, not as high in medicine but undoubtedly a competent observer, Mr. Julian Ralph, has also noted the contrast between English and American women and children, the latter being, according to him, much better developed and more healthy than the former, the English boys being apt to be "runts" in comparison with the American boys at the same age. The stature of American women and their superior health is also, he says, a matter of astonishment to foreigners. When we read the jeremiads of certain medical writers in this country the above may come to us as a sort of comfort; we may not be as bad off as we had thought. The question arises, however, whether in our improving development we are to see a product like Hawthorne's celebrated description of the British matron, a result not to be earnestly desired. Let us hope that climatic and other influences, while perfecting the race, will also save us from any altogether unesthetic results. JAMA 1899;33:1366

doi: 10.1001/jama.282.16.1497pmid: N/A

Obesity research A JAMA THEME ISSUE Edited by Phil B. Fontanarosa, MD Obesity has become a major public health problem in all regions of the United States, with an estimated national prevalence of 17.9% in 1998. Obesity in the US and Related Disease Risks, Mortality Based on data from Behavioral Risk Factor Surveillance System telephone surveys, 1991 to 1998, Mokdad and colleaguesArticle found that the prevalence of obesity (body mass index [BMI] ≥30 kg/m2) among US adults aged 18 years or older rose from 12.0% in 1991 to 17.9% in 1998. Increases in the prevalence of obesity occurred in all states, in both sexes, and across all age groups, races, and educational levels. In an analysis of dataArticle from 16,884 adults aged 25 years or older who participated in the Third National Health and Nutrition Examination Survey (NHANES III), Must and colleaguesArticle found that as the severity of excess weight increased from overweight (BMI, 25.0 to 29.9 kg/m2) through obesity class 3 (BMI ≥40.0 kg/m2), the prevalence of type 2 diabetes mellitus, gallbladder disease, hypertension, and osteoarthritis in both sexes and coronary heart disease in women increased. Using mortality hazard ratios associated with BMI from 6 US prospective cohort studies and 1991 population data from NHANES III, Allison and colleagues estimated the annual number of deaths attributable to obesity among US adults to be 280,184. More than 80% of deaths attributable to overweight or obesity occurred among persons with BMIs of 30 kg/m2 or greater. In an editorialArticle, Koplan and Dietz call for a comprehensive national program to prevent and treat obesity. Dietary Fiber and Cardiovascular Disease Risk Factors To determine the effect of dietary composition on levels of insulin secretion, weight gain, and other cardiovascular disease (CVD) risk factors, Ludwig and colleagues analyzed data from 2909 adults, aged 18 to 30 years at enrollment and followed up for 10 years, in the Coronary Artery Risk Development in Young Adults Study. Fasting insulin levels, weight gain over 10 years, and other CVD risk factors were inversely related to levels of dietary fiber intake. In contrast, intake of fat, carbohydrate, and protein had inconsistent or weak associations with fasting insulin levels and other CVD risk factors. See Article Cardiorespiratory Fitness, Weight, and Mortality Cardiorespiratory fitness may be as important as other disease conditions and risk factors predictive of mortality. Wei and colleagues report that among 25,714 adult men enrolled between 1970 and 1993 and followed up through 1994, obese men (body mass index [BMI] ≥30 kg/m2) had a 2.6 times higher risk of cardiovascular disease (CVD) mortality and a 1.9 times higher risk of all-cause mortality compared with normal-weight men. The strongest predictor of mortality in all BMI groups was baseline CVD, but the risk of mortality associated with low cardiorespiratory fitness was comparable to the risks associated with diabetes mellitus, high cholesterol levels, hypertension, and smoking in all BMI groups, and was highest among obese men compared with overweight and normal-weight men. See Article Strategies to Treat and Prevent Obesity The effectiveness of strategies to prevent and treat obesity in adults and children is often limited and of short duration. Among 115 sedentary, overweight women aged 25 to 45 years randomly assigned to traditional continuous exercise (long-bout exercise, LB group), multiple short-bout exercise (SB group), or multiple short-bout exercise with home exercise equipment (SBEQ group), Jakicic and colleaguesArticle found that at 18 months, weight loss in the SBEQ group was significantly greater compared with that in the SB group and was similar to that in the LB group. Weekly duration of exercise for months 13 through 18 was significantly greater in the SBEQ group compared with the other 2 groups. In a study of 192 third- and fourth-grade children, Robinson foundArticle that the group that received a 6-month classroom curriculum to reduce television, videotape, and video game use had significant relative decreases in body mass index and other anthropometric measures of adiposity compared with the control group. The amount of television viewing and the frequency of eating meals in front of the television decreased significantly in the intervention group compared with the control group, but changes in high-fat food intake, moderate-to-vigorous physical activity, and cardiorespiratory fitness were similar. Contempo 1999 Genetic factors that regulate energy balance and body weight. See Article Medical News & Perspectives Gene technology applied to mice and rice helps attack, respectively, problems of obesity and malnutrition. See Article Recombinant Leptin Aids Weight Loss Results of a preliminary controlled trial of exogenous recombinant leptin administration demonstrate a dose-response relationship with weight and fat loss in lean and obese subjects. See Article Weight and Exercise Counseling Fewer than half of obese patients reportArticle being counseled by a health care professional about weight loss and only about one third of a national sample of patients report being counseled about exercise. See Article and editorial Article JAMA Patient Page For your patients: A primer on obesity. See Article

Yanovski, Jack A.;Yanovski, Susan Z.

doi: 10.1001/jama.282.16.1504pmid: 10546681

More than 50% of US adults are overweight, with a body mass index of more than 25 kg/m2 (calculated as weight in kilograms divided by the square of height in meters).1 Even more concerning, the percentage of Americans who are obese (body mass index ≥30 kg/m2) has increased by more than 50% in the past 20 years, and the number of overweight children has doubled.2 Most overweight individuals can successfully lose some of the weight, but the majority regain that weight within 5 years.3 Heritability studies suggest that as much as 70% of the variability in human body weight may be accounted for by genetic factors.4,5 Yet it is virtually impossible that changes in the genetic background of Americans over the past 2 decades are solely responsible for the trend of increasing body weight. Easy access to good-tasting, high-fat foods6 and decreased physical activity7 are both likely contributors to the current worldwide epidemic of obesity.8 However, even in this obesity-promoting environment, there are those who remain resistant to weight gain. For body weight, there is a significant interaction between genes and environment. Recent advances in the study of body weight regulation are helping to shed light on how nature and nurture interact to cause or prevent obesity. Body weight is dependent on the balance between energy intake, in the form of food and drink, and energy expenditure. Daily energy expenditure consists of resting energy expenditure, the energy required to metabolize food (thermic effect of food), and energy expended as a result of activity (Figure 1). When energy intake and expenditure are in balance, weight remains stable. A net excess in energy, whether through greater intake or lesser expenditure, leads to weight gain. In children, some of this extra energy may be used for linear skeletal growth; but in both children and adults net excess energy intake leads to increases in both lean body mass and adipose tissue. The genetic and environmental factors that lead to imbalances in energy flux are thus key factors in determining body weight. Over the past 5 years, we have learned a great deal about several genes that participate in body weight regulation. The first major advance was the discovery of the adipocyte-derived hormone leptin,9 and shortly thereafter, the leptin receptor.10,11 A hormonal signal from the fat cell to the brain was long suspected because of the experiments by Coleman12 demonstrating that a circulating factor present in the DB mouse strain, which is obese and diabetic, could reverse the obesity of the phenotypically similar OB strain. The OB mouse was found to have mutations disrupting the leptin gene. Mice of the OB strain have low circulating leptin, and can be cured of their obesity and diabetes through leptin injections.13-15 Leptin-treated OB mice spontaneously eat less food. They also burn more energy than do pair-fed, placebo-treated OB littermates.14 The DB mouse was discovered to have inactivating mutations in the leptin receptor. Mice of the DB strain have high circulating leptin, and are resistant to leptin treatment.14 Proving their relevance for human obesity, mutations disrupting the leptin16 and leptin receptor17 genes were then identified in humans, and the chromosomal locus containing the leptin gene was genetically linked to human body weight.18 However, the vast majority of obese individuals appear to have normal genetic sequences for leptin and its receptor, and have high levels of leptin in proportion to their body fat stores.19 Indeed, there is evidence to suggest that leptin's primary function is not to protect against obesity, but to serve as a signal for inadequate energy intake.20 Circulating leptin may also be a signal indicating whether there are sufficient energy stores for the initiation of pubertal development.21 Studies to determine the safety and efficacy of recombinant human leptin for weight reduction are ongoing.22 Attention has since been directed to elucidating the functions of the hypothalamic neurons that contain leptin receptors and the functions of the cells that receive neural input from leptin receptor-containing neurons. Several neurotransmitter systems, which may in part be effectors for leptin, have been shown to be important for body weight regulation in animals and perhaps humans, although leptin may also have direct effects on body tissues.23 Among the many peptides implicated in the control of appetite are neuropeptide y, proopiomelanocortin (the precursor peptide for adrenocorticotropic hormone), melanocyte stimulating hormone, and the endorphins and/or enkephalins (Figure 2). Recently, mutations in the proopiomelanocortin gene sequence, which prevent proopiomelanocortin from being enzymatically cleaved into α-melanocyte stimulating hormone and adrenocorticotropic hormone, were found in humans with obesity, red hair, and adrenal insufficiency.24 Obesity is hypothesized to be the result of insufficient hypothalamic-melanocyte stimulating hormone, which may regulate appetite when it binds to the melanocortin-4 receptor. Activity of the melanocortin-4 receptor is believed to be an important regulator of appetite. Melanocortin-4 receptor gene mutations cause obesity that is inherited in an autosomal-recessive fashion in mice25 and are found in a few severely obese humans.26,27 The melanocortin-4 receptor's importance for body weight has been demonstrated in an autosomal-dominant animal model of obesity, the yellow mouse. Yellow animals have both obesity and a yellowish coat color because they overexpress the agouti protein that is translated from the agouti gene.28 The agouti protein is normally made only in hair follicles, where agouti antagonizes the α-melanocyte stimulating hormone's ability to bind to the melanocortin-1 receptor and stimulate eumelanin synthesis. Yellow mice overexpress the agouti protein in many tissues. Most important for obesity, agouti protein becomes expressed in the hypothalamus, where it affects melanocortin-4 receptor signal transduction.29 By inhibiting normal melanocortin-4 receptor function, unregulated expression of the agouti protein is believed to cause excessive appetite and body fat gain. Subsequent studies discovered an agouti-related peptide, which is quite similar to agouti and is made by hypothalamic neurons. Agouti-related peptide appears to antagonize the actions of α-melanocyte stimulating hormone at the melanocortin-4 receptor. The search for molecular defects causing obesity has not been limited to genes exerting their effects within the hypothalamus. Genes that might affect how adipocytes store fat, and how energy is expended by lean tissues such as muscle cells, have also received considerable attention. One gene mutation, which may affect the number of adipocytes available to store fat, is the γ-2 type peroxisome proliferator-activating receptor. Preadipocytes, the nonlipid-storing precursor cells from which mature adipocytes develop, normally contain γ-2 type peroxisome proliferator activating receptor. When this receptor is activated, γ-2 type peroxisome proliferator-activating receptor can cause preadipocytes to change into mature fat cells. Activating mutations of γ-2 type peroxisome proliferator-activating receptor that cause unregulated receptor signal transduction, and thus presumably stimulate preadipocytes to differentiate into lipid-storing adipocytes, have recently been described in some severely obese humans.30 Regulation of energy expenditure within body tissues may be an important determinant of body weight. A family of uncoupling proteins (UCPs) has been recently described that can reroute the flow of protons generated by oxidative phosphorylation away from mitochondrial adenosine triphosphate synthesis and thereby waste energy as heat, rather than allow it to be used or stored. The UCPs have genetic linkage to human obesity, and 1 study31 has reported that a polymorphism in the UCP-3 gene is associated with altered human resting energy expenditure. The importance of UCPs for human obesity requires further delineation. One area in which differences in energy expenditure are believed to play a role is in the resistance to weight gain. There is a strong genetic component to the amount of weight gained during experimental overfeeding, and the variability of weight gain cannot be attributed to differences in resting energy expenditure. A recent study32 examined the hypothesis that the amount of weight gained during overfeeding is related to the amount of nonresting energy expended. Sixteen individuals were overfed by 4200 kJ/d, and their resting energy expenditure, thermic effect of food, energy expenditure from physical activity, and total energy expenditure were studied. Two thirds of the increase in energy expenditure observed with overfeeding was attributable to increases in fidgeting, maintenance of posture, and other activities of daily living, which the authors termed nonexercise activity thermogenesis. Changes in nonexercise activity thermogenesis accounted for much of the variability in resistance to fat gain among the subjects of this study. The role of nonexercise activity thermogenesis in body weight regulation leads to the intriguing possibility that we might decrease the prevalence of obesity by instructing people to fidget more. While it is likely to be difficult to sustain what are essentially involuntary behaviors over the long-term, this study does show the potential impact of relatively low-intensity physical activity on weight regulation. Among those already obese, physical activity has consistently been found to be of great importance in weight maintenance after weight loss. Most individuals who have successfully maintained large weight losses over extended periods of time report engaging in regular physical activity.33 Despite advances in understanding energy balance, our ability to treat obesity successfully lags far behind. The National Institutes of Health has issued guidelines for the identification, evaluation, and treatment of obese adults that provide clinicians with an evidence-based approach,3 and an expert committee has issued recommendations for pediatric obesity evaluation and treatment.34 Both documents emphasize that diet and exercise remain the mainstays of treatment, but acknowledge the difficulties in sustaining long-term weight loss. The few medications that were approved by the Food and Drug Administration and are available for long-term treatment of obesity do not work for all individuals, and on average induce only modest weight loss. Surgical treatment, although effective,35,36 is appropriate only for the severely obese patient and can have substantial procedure-related morbidity.37 Future therapies based on a greater understanding of the behavioral and metabolic processes underlying body weight regulation are cause for excitement. It is likely that the future will bring more targeted and effective treatments for obesity. Insights into the importance of energy expenditure for resistance to weight gain and for maintenance of weight loss provide strong evidence that increased physical activity, in conjunction with a healthful diet, are the best hope for Americans to achieve and maintain a healthy weight. References 1. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States. Int J Obes Relat Metab Disord.1998;22:39-47.Google Scholar 2. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults. JAMA.1994;272:205-211.Google Scholar 3. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Obes Res.1998;6(suppl):51S-209S.Google Scholar 4. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med.1990;322:1483-1487.Google Scholar 5. Allison DB, Kaprio J, Korkeila M, Koskenvuo M, Neale MC, Hayakawa K. The heritability of body mass index among an international sample of monozygotic twins reared apart. Int J Obes Relat Metab Disord.1996;20:501-506.Google Scholar 6. Rolls BJ, Hammer VA. Fat, carbohydrate, and the regulation of energy intake. Am J Clin Nutr.1995;62(suppl):1086S-1095S.Google Scholar 7. Hill JO. Physical activity, body weight and body fat distribution. In: Leon A, ed. Physical Activity and Cardiovascular Health: A National Consensus. Champaign, Ill: Human Kinetics; 1997:272. 8. World Health Organization, Division of Noncommunicable Disease, Programme of Nutrition Family and Reproductive Health. Not Available June 3-5, 1997; Geneva, Switzerland. Abstract 276. 9. Zhang Y, Proenca R, Maffei M. et al. Positional cloning of the mouse obese gene and its human homologue. Nature.1994;372:425-432. [published correction appears in Nature. 1995;374:479].Google Scholar 10. Tartaglia LA, Dembski M, Weng X. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell.1995;83:1263-1271.Google Scholar 11. Chua Jr SC, Chung WK, Wu-Peng XS. et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science.1996;271:994-996.Google Scholar 12. Coleman DL. Obesity and diabetes. Diabetologia.1978;14:141-148.Google Scholar 13. Campfield LA, Smith FJ, Guisez Y. et al. Recombinant mouse OB protein. Science.1995;269:546-549.Google Scholar 14. Halaas JL, Gajiwala KS, Maffei M. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science.1995;269:543-546.Google Scholar 15. Pelleymounter MA, Cullen MJ, Baker MB. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science.1995;269:540-543.Google Scholar 16. Montague CT, Farooqi IS, Whitehead JP. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature.1997;387:900.Google Scholar 17. Clement K, Vaisse C, Lahlou N. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature.1998;392:398-401.Google Scholar 18. Perusse L, Chagnon YC, Weisnagel J, Bouchard C. The human obesity gene map: the 1998 update. Obes Res.1999;7:111-129.Google Scholar 19. Considine RV, Sinha MK, Heiman ML. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med.1996;334:292-295.Google Scholar 20. Ahima RS, Prabakaran D, Mantzoros C. et al. Role of leptin in the neuroendocrine response to fasting. Nature.1996;382:250-252.Google Scholar 21. Chehab FF, Mounzih K, Lu R, Lim ME. Early onset of reproductive function in normal female mice treated with leptin. Science.1997;275:88-90.Google Scholar 22. Greenberg AS, Heymsfield SB, Fujioka K. et al. Preliminary safety and efficacy of recombinant methionyl leptin (rL) administered by SC injection in lean and obese subjects. Diabetes.1998;47(suppl):LB-16.Google Scholar 23. Considine RV, Caro JF. Pleiotropic cellular effects of leptin. Curr Opin Endocrinol Diabetes.1999;6:163-169.Google Scholar 24. Krude H, Biebermann H, Luck W. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet.1998;19:155-157.Google Scholar 25. Huszar D, Lynch CA, Fairchild-Huntress V. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell.1997;88:131-141.Google Scholar 26. Vaisse C, Clement K, Guy-Grand B. et al. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet.1998;20:113-114.Google Scholar 27. Yeo GS, Farooqi IS, Aminian S. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet.1998;20:111-112.Google Scholar 28. Bultman SJ, Michaud EJ, Woychik RP. Molecular characterization of the mouse agouti locus. Cell.1992;71:1195-1204.Google Scholar 29. Lu D, Willard D, Patel IR. et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature.1994;371:799-802.Google Scholar 30. Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn CR. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med.1998;339:953-959.Google Scholar 31. Argyropoulos G, Brown AM, Willi SM. et al. Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. J Clin Invest.1998;102:1345-1351.Google Scholar 32. Levine JA, Eberhardt NL, Jensen MD. Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science.1999;283:212-214.Google Scholar 33. Klem ML, Wing RR, McGuire MT, Seagle HM, Hill JO. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr.1997;66:239-246.Google Scholar 34. Barlow SE, Dietz WH. et al. for the Maternal and Child Health Bureau. Obesity evaluation and treatment. Pediatrics.1998;102:E29.Google Scholar 35. Sjostrom CD, Lissner L, Sjostrom L. Relationships between changes in body composition and changes in cardiovascular risk factors. Obes Res.1997;5:519-530.Google Scholar 36. Karlsson J, Sjostrom L, Sullivan M. Swedish obese subjects (SOS)—an intervention study of obesity. Int J Obes Relat Metab Disord.1998;22:113-126.Google Scholar 37. Gastrointestinal surgery for severe obesity. Nutrition.1996;12:397-404.Google Scholar

Stephenson, Joan

doi: 10.1001/jama.282.16.1507pmid: 10546682

Chubby mice with blond bellies and an artfully disabled gene are giving scientists new insights into factors that can contribute to obesity, according to a new study reported last month (Nat Med. 1999;5:1066-1070). View LargeDownload A fat "knockout" mouse that lacks the gene that encodes pro-opiomelanocortin (POMC)—shown with its normal littermate—is providing new insights into the factors that contribute to obesity. (Photo credit: Nature Medicine) Besides shedding light on obesity, the rotund rodents are also shedding weight when treated with a drug that helps compensate for the genetic defect, a finding with potential implications for treating obesity in humans. View LargeDownload In addition to being obese, a POMC-deficient mouse (shown with its normal littermate) has yellowish pigmentation, most noticeable on the animal's belly. (Photo credit: Nature Medicine) In the new study, a team of researchers from the National Institutes of Health, Bethesda, Md, Eleanor Roosevelt Institute, Denver, and the Oklahoma Medical Research Foundation, Oklahoma City, created the mice using genetic techniques that enable the investigators to incapacitate, or "knock out," a specific gene. In this instance, the KO'd gene of interest encodes pro-opiomelanocortin (POMC), a complex molecule largely produced in the brain and skin. A serendipitous finding Because POMC is the precursor of a number of neurotransmitters and hormones, including beta-endorphin and melanocortin peptides, its absence would be expected to have multiple effects. Melanocortin peptides, such as alpha-melanocyte–stimulating hormone (alpha-MSH) and adrenocorticotrophic hormone, have a remarkable range of functions in the body, including roles in pigmentation, adrenocortical function, food intake and fat storage, and immune and nervous system function. The investigators originally set out to make their POMC-deficient mice for studies of neuropeptide signaling during the development of the central nervous system, anticipating that such mice might not even survive to birth, explained Miles B. Brennan, PhD, of the Eleanor Roosevelt Institute. "We were expecting a developmental defect of an extreme sort, but that wasn't what we got," said Brennan. Instead, the researchers found themselves with obese mice with altered pigmentation—yellowish fur (rather than brownish-black), particularly on the belly—and virtually no adrenal tissue. Soon after Brennan and his colleagues set out to create their mutant mouse, a human counterpart to the POMC-deficient mice surfaced when a group of German investigators identified, for the first time, a rare genetic condition caused by mutations in the Pomc gene (Nat Genet. 1998;19:155-157). The researchers described two children whose Pomc gene mutations and complete lack of melanocortins was manifested by severe obesity within the first few months of life, adrenal insufficiency, and red hair. Exactly how the Pomc mutation leads to obesity remains to be determined, but feeding studies with standard and high-fat diets indicate that the mutant mice not only increase their food intake compared with normal littermates, but they also store fat more readily. "The mutation clearly has an effect on appetite," said Brennan. "But they also have an altered fat metabolism." Therapeutic potential? The chubby blond mice are expected to be a useful animal model for exploring mechanisms that underlie obesity as well as possible interventions, said Greg Barsh, MD, PhD, a Stanford University researcher who wrote a commentary that accompanied the report on the POMC-deficient mice (Nat Med. 1999;5:984-985). Of particular interest are compounds that target the predominant melanocortin receptor in the brain, he noted. Researchers have found that mutations that inactivate this receptor cause an obesity syndrome in mice and humans. Brennan and his colleagues found that when they injected the obese POMC-deficient mice with an alpha-MSH agonist, the mice rapidly lost weight—so rapidly, in fact, that a drop within 1 day of the first injection prompted a double-take from the surprised scientists, said Brennan. Mice treated with daily injections of the compound shed 38% of their excess weight within 1 week and 46% by 2 weeks, and their coats lost their yellowish hue. In contrast, the injections caused no substantial weight loss in normal littermates. And about 10 days after injections were discontinued, the POMC-deficient mice began to gain weight, nearly reaching their pretreatment weight after another 2 weeks. At the same time, their yellow coat color gradually reappeared. Although the mice slimmed down in part because they ate substantially less, their dramatic weight loss is also likely due to changes in fat metabolism, because the mice lost more weight than could be accounted for from the expected difference between calories consumed and calories required for normal activity and physiological processes. "We suspect there was increased lipolysis; otherwise, it would be really difficult to explain that rapid weight loss," said Brennan. Melanocortin receptors are found on fat cells, and the lipolytic effects of melanocortins have been known for some time. Only very small amounts of the drug were needed to reverse obesity—an amount that approximates the normal blood level of MSH, he noted. Melanocortin-based drugs also may be useful in treating obesity due to factors other than POMC deficiency. In preliminary studies with another strain of obese mice, a strain that is deficient in leptin rather than POMC, the investigators found that injections of an MSH analog also prompted those mice to slim down. It seems likely that the approach may be generalizable to obesity stemming from causes other than the very rare POMC gene mutations, agrees Barsh. "I suspect that melanocortins are likely to be useful for people who have obesity due to genetic defects that lie upstream of the melanocortin system as well as those who have environmental obesity." Brennan noted that some of the substances he and his colleagues are testing in obese mouse strains are MSH analogs originally developed (due to their effects on pigmentation) as potential agents to promote cosmetic tanning or treat vitiligo. He and his colleagues are now looking for a pharmaceutical partner to conduct clinical trials of such compounds to treat obesity.

Friedrich, M. J.

doi: 10.1001/jama.282.16.1508-JMN1027-2-1pmid: N/A

St Louis—Although rising rates of obesity—and the concomitant increases in health problems associated with this condition—are issues of global concern, malnutrition, which gives rise to its own set of negative health consequences, remains a worldwide scourge, particularly among the poor in developing countries. Lack of specific nutrients in the diet—not just lack of food—is a major cause of malnutrition. For example, among populations in whom rice is the main food staple, iron and vitamin A deficiencies are common because rice contains low levels of iron and lacks β-carotene, a precursor to vitamin A. View LargeDownload Genetically modified "golden rice" owes its color to its ability to manufacture β-carotene. (Photo credit: I. Potrykus and P. Beyer) Motivated by the potential of gene technology to improve the nutritional quality of this important crop, researchers at the Swiss Federal Institute of Technology in Zurich constructed a strain of "golden rice" that improves the supply of vitamin A and iron in the diet. Results were announced by Ingo Potrykus, PhD, a plant molecular biologist at the institute, at the 16th International Botanical Congress held here in August. Although not ready for distribution, the transgenic rice holds promise for correcting these nutritional deficiencies. Nutrient deficits At the 1990 World Summit for Children, experts targeted deficiencies in iron and vitamin A as two of the most serious micronutrient disorders to be addressed in the coming decade. Adequate intake of these micronutrients is especially crucial for children and women of childbearing age. But as the decade draws to an end, there has been a lack of progress in solving the problem of iron deficiency and anemia, according to the World Health Organization. About 3.7 billion people have deficient stores of iron, and more than half this number have iron deficiency anemia, making it the most common nutritional disorder in the world, said Potrykus, citing UNICEF data. The adverse health effects of iron deficiency anemia include impaired intellectual development and suppressed immune function. Pregnant women with anemia are more likely to give birth to infants with low birth weight and decreased iron stores, and they are at increased risk of hemorrhage, sepsis, and death during childbirth. According to the WHO, although progress has been made in combating vitamin A deficiency, it is still the leading cause of severe visual impairment and blindness among children in developing countries. Potrykus said that up to 250 million young children have subclinically deficient blood levels of vitamin A, making them more vulnerable to infection and death, particularly from diarrhea and measles, and pregnant women with vitamin A deficits are at greater risk of mortality. They also run more risk of transmitting HIV to their newborn infants. Engineering a solution The enormousness of these problems led researchers in Potrykus' laboratory to produce a transgenic rice strain to supply these necessary nutrients. Addressing the lack of vitamin A, they introduced into the rice genome four genes encoding proteins necessary for the biochemical production of β-carotene. Two genes came from the daffodil plant; the other two were from the bacterium Erwinia eurdovora. Successful integration and functioning of the genes resulted in plants that produce yellow-tinted rice kernels, with the intensity of color indicating the amount of β-carotene. Some of the strains produce rice high enough in β-carotene to supply the daily requirement of vitamin A in 300 g of cooked rice, said Potrykus. To improve the bioavailability of iron in rice, Potrykus' group had to engineer a rice that not only had increased iron content but that also allowed for better iron absorption. Potrykus explained that rice, in addition to containing little iron, produces large amounts of an iron-absorption inhibitor called phytate. Potrykus' team was able to increase the iron content by introducing a gene from the French bean that instructs the cell to manufacture ferritin, an iron storage protein. To increase iron absorption, they introduced two other genes. One, taken from the fungus Aspergillus fumigatus, encodes a heat-stabile enzyme called phytase, which can break down phytate in cooked rice, thereby removing this potent inhibitor of iron absorption. The second gene, introduced from basmati rice, encodes a cysteine-rich protein. This gene was chosen, said Potrykus, "because studies have shown that cysteine-rich proteins can dramatically improve iron resorption in the human digestive tract." In the next step, researchers combined the independent rice lines by crossing the β-carotene–producing rice with the iron-enriched strain, fashioning a transgenic rice plant with seven foreign genes conferring the beneficial characteristics. Future efforts Before this new rice can be made publicly available, the genes must be transferred into a common commercial variety of rice called indica, work that will be carried out with the International Rice Research Institute (IRRI) in the Philippines. In parallel with this work, Potrykus said, careful assessments of the possible risks to human health and to the environment from this genetically modified food crop must be carried out. "Only then will it be disseminated to farmers to be used according to their needs," he said. Gurdif Khush, PhD, principal plant breeder at the IRRI, estimated that the rice will be ready for distribution in 2 to 3 years. Because the research was funded by not-for-profit organizations rather than industry, Potrykus said the rice will be available free of any restrictions and free of charge to farmers. This will be a boon, especially to poor farmers in developing countries who are most in need of nutrient supplementation. "It is for these people that we have carried out this work," said Potrykus, adding that had it not been for funding from the Rockefeller Foundation in New York, the work would not have been possible. Gary Toenniessen, PhD, director of Rockefeller's rice biotechnology program, said that at an international meeting on rice biotechnology held in Thailand in late September, Asian rice scientists and rice breeders expressed enthusiasm for this breakthrough and were eager to use these materials in breeding programs that can distribute the "golden rice" where it is needed throughout Asia. He pointed out that this work is "one of the first significant demonstrations that plant biotechnology can contribute to resolving a major world health problem."

Marwick, Charles

doi: 10.1001/jama.282.16.1509-JMN1027-3-1pmid: N/A

Washington—New methods of controlling the behavior of blood in the human body were reported at the 17th Congress of the International Society on Thrombosis and Hemostasis (ISTH) held here last month. Better treatments for clotting and bleeding disorders were central topics of discussion. Reducing clot risk The risk of venous thromboembolism in surgical patients has long been recognized. Now a new study shows that thromboembolism is also a risk in acutely ill medical patients. But an international, multicenter, randomized, double-blind, placebo-controlled trial has shown that a daily dose of 40 mg of enoxaparin (Lovenox, Rhone-Poulenc Rorer), a low molecular weight heparin, reduced the risk of venous thromboembolism in medically treated patients by about one third. Meyer-Michel Samama, MD, emeritus professor of hematology at Hôtel Dieu University Hospital in Paris, reported these findings in a presentation at the ISTH Presidential Plenary session. Samama chaired the 11-member group that conducted the MEDENOX study at 16 centers in nine countries. The study evaluated 866 medical patients with an average age of 73 years who had been diagnosed with heart failure, acute respiratory failure or chronic respiratory insufficiency, acute infections, acute rheumatic disorder, or active inflammatory bowel disease. The patients were randomized to receive enoxaparin in doses of 20 mg, 40 mg, or placebo subcutaneously once daily for 6 to 14 days. There were 288 patients in the placebo group, 287 received a 20-mg dose, and 291 received a 40-mg dose. The primary end point was a clinically detected or venographically confirmed venous thrombotic episode—deep venous thrombosis, pulmonary embolism, or both—within 2 weeks of admission to the study. A secondary end point was a confirmed thrombotic episode within 3 months of admission to the study. By day 14, 15% of the patients receiving the placebo and 15% of those taking the smaller dose of enoxaparin had experienced a venous thrombotic episode. During the same period, however, only 5.5% of the patients taking the 40-mg dose of enoxaparin experienced a venous thrombotic episode. The benefit observed in those receiving the higher dose of the drug was maintained out to 3 months of follow-up, Samama said. Of the 100 patients experiencing deep vein thrombosis during the first 14 days of the study, 92 were diagnosed by bilateral, ascending venography; 94 of the patients were asymptomatic and 6 were symptomatic. There was no statistically significant difference between either of the groups receiving enoxaparin and those taking placebo in the incidence of major hemorrhage or thrombocytopenia. However, six patients taking the 40-mg dose of enoxaparin and four in the placebo group had major hemorrhages. Minor hemorrhages occurred in 36 of those taking the 20-mg dose of enoxaparin and in 34 of those taking the 40-mg dose. "In the last few years there have been major advances in preventing venous thromboembolism in surgical patients and lots of evidence that we can prevent disease in this group. But until now there's been little evidence for the use of prophylactic measures in medical patients," said Alexander Turpie, MD, professor of medicine at McMaster University, Hamilton, Ontario. "This study shows that low molecular weight heparin can be recommended for medical patients," added Alexander Cohen, MD, a vascular physician at Guy's, King's, and St Thomas' School of Medicine and Dentistry, London. Cohen and Turpie are members of the study group. Similar studies are ongoing elsewhere, and the findings are eagerly awaited, because evidence of efficacy will be needed if the US Food and Drug Administration is to approve low molecular weight heparin as prophylaxis against venous thromboembolism in medical patients. Genes for hemophilia Control of clotting abnormalities might be looked at as the reverse of control of bleeding disorders. "We're interested in both. In a sense they are two sides of the same coin. Where the patient with a stroke or myocardial infarction has a thrombotic problem, the hemophiliac has a bleeding problem, yet the biochemistry, biology, and the genetics are really the same," said Victor J. Marder, MD, director of the vascular medicine program at Orthopedic Hospital in Los Angeles and president of ISTH. One of the newest approaches to improving the treatment of hemophilia is gene therapy. Hemophilia is a particularly attractive candidate for gene replacement. Indeed, investigators at the meeting said it is likely to be one of the best test cases for the effectiveness of gene therapy in general. In the past 9 months, three gene therapy trials for treating the disorder have reached clinical status. Hemophilia is a single-gene disease, the gene has been cloned, and monitoring for the presence of factors VIII or IX is simple. The gene can be inserted using a number of different vectors, such as retrovirus, adenovirus, or adeno-associated virus. Katherine A. High, MD, professor of pediatrics and medicine at the University of Pennsylvania School of Medicine, briefly described some aspects of this work using adeno-associated virus. This vector is inserted into the thigh muscle of patients with hemophilia B, and the gene expresses the clotting factor directly in the muscle. A similar study with the same vector, this time delivering the gene directly to the liver, is being done at Stanford University School of Medicine. And at the University of Pittsburgh Medical Center, retrovirus, the original workhorse of gene vectors, is being used to insert the gene for factor VIII. The first clinical study in this area was started last December in Boston by Transkaryotic Therapies Inc, and Beth Israel Deaconess Medical Center. In that study, the gene for factor VIII is inserted into isolated fibroblasts then reimplanted in the patient. "One of the advantages of gene therapy is that there are many different tissues you can go into and make the clotting factor," High said. These trials are essentially dose-escalation trials, she noted, and it is much too early for any results to be known. Impact of technology Gilbert White, MD, professor of medicine and pharmacology at the University of North Carolina at Chapel Hill School of Medicine and executive director of ISTH, said in an interview that "the technology that we learn from these gene hemophilia studies is going to be important for other thrombotic and hemostatic diseases as well. What's so exciting to me is that this field is moving very rapidly; advances are being translated directly into clinical improvements. The results are going to have a very strong impact on the way we treat vascular diseases 5 to 10 years from now."

Voelker, Rebecca

doi: 10.1001/jama.282.16.1511-JQU90008-3-1pmid: N/A

A substantial proportion of elderly Americans with asthma are not being properly diagnosed and treated, according to a new study. In last month's Chest, researchers from Boston University and the Universities of Arizona, Washington, and Pittsburgh analyzed data on asthma that were taken from a large population-based study of cardiovascular disease in people older than 65 years. In the original study of 4581 participants, 4% had confirmed asthma, 4% experienced wheezing and dyspnea, and 11% reported wheezing episodes. The researchers found that 18% of those with confirmed asthma were taking oral corticosteroids, which can have a number of adverse effects. Clinical practice guidelines call for the use of inhaled corticosteroids, which rarely cause adverse effects, and long-acting bronchodilators. The researchers also reported that only 30% of participants diagnosed with asthma by a physician were taking an inhaled corticosteroid. "Not only is asthma underdiagnosed in elderly persons in the United States, but most of those who have had an asthma diagnosis and manifest current symptoms are not being treated optimally," the research team wrote.