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Spring 1998, Vol.5, No.1
Obesity: From the Mouse House to the Ambulatory Care Clinic Stephen H. Tsang'99 The National Health and Nutrition Examination Survey (1978-1980) reported that about 26% of Americans between the ages of 20 and 75 are obese. At any point in time 40% of women and 24% of men are trying to lose weight. However, a dilemma exists in today's society: those who are not obese are trying to lose weight, while others who do need to lose weight are failing to do so. More than $35 billion is spent on weight loss programs every year in America.1 Unfortunately, these weight-loss efforts fail miserably and almost all weight lost is regained within 5 years.2 Obesity is of major primary care concern and is targeted as a national health objective in Healthy People 2000. The national objective is to reduce the prevalence of obesity to less than 20%. In the last 10 years, the number of overweight Americans has increased from 26 to 34%. This increase has been disproportionately high in women, the poor, and minority groups. Without addressing the fundamental basis of the obesity problems, conventional dietary and behavioral treatment have failed in long-term management. Fortunately, analyses of mouse mutants has led to the creation of potential drugs that modify feeding behavior and metabolism. Future studies of the patients in the primary care clinic will generate additional genetic loci that affect the control of body weight. Adverse Health Effects of Obesity. Obesity has been associated with major medical problems, including hypertension, coronary artery disease, congestive heart failure, cerebrovascular disease, reduce their side effects and enhance their effectiveness. A recent study5 indicated that long term use of medication apparently cannot reset the body weight control mechanism to a lower level. Surgery and Complications For severely obese patients who present with medical complications from their obesity, surgery is an option. The gastrointestinal bypass surgery includes either bypassing the stomach, duodenum, and portions of the small intestine or bypassing most of the small intestine, where absorption of nutrients takes place. The general effect of this gastrointestinal bypass surgery is to generate malabsorption of vital nutrients. Diarrhea, nutritional deficiencies and severe metabolic alkalosis are some complications. This bypass surgery is as sociated with significant morbidity and mortality. Even in skilled hands, the gastric restrictive procedure still has about a 4% mortality rate. Gastric restrictive surgery, on the other hand, can produce mineral and B12 deficiencies. Current Strategies for Weight Reduction Do Not Target the Fundamentals of Obesity In summary, new modalities of treatment need to be explored in order to assist the individual in attaining long term weight loss. Current strategies only address the symptoms of obesity but not its causes. Improved understanding of the determinants of obesity will be essential in preventing and treating this disorder. Since one's amount and distribution of adipose tissue, metabolic rate, cell number and distribution of adipose tissue are all genetically determined, genetic approaches should allow the dissection of the etiologies of obesity. Genetic defects in basal metabolism, dietary thermogenesis, appetite, satiety, endocrine function and fat storage may also play a role. Effective Strategies for Weight Reduction are Dependent on Addressing the Etiology of Obesity Obesity as a Genetic Disease The evidence for a genetic origin of human obesity came from observation of twins, comparisons of adopted and biologic children reared in the same family, and analyses of familial patterns of fatness of twins. The concordance rates of body mass index (BMI) amongst monozygous and dizygous twins or adoptees and their biological parents strongly suggested that inheritance of obesity far exceeds that of many other traits thought to have a substantial genetic component, such as atherosclerosis, alcoholism and schizophrenia. Heritability of BMI for men is 74% and 69% for women. Albert Stunkard and colleagues definitively showed that sharing the same childhood environment has minimal or no influence on BMI6. Stunkard's results confirm previous data obtained by comparing intra-pair differences in mono- and dizygotic twins.7 In an adoption study, Stunkard's group further demonstrated a correlation among the four weight classes (thin, median weight, overweight, or obese) and the BMI of the biologic parents. If the biological mother was overweight, there was a 74% chance that her children would be overweight. If the biological mother was thin, there was also a 74% chance that her children would be thin. However, no relation was detected between the weight class of the adoptees and the BMI of their adoptive parents.8 The BMI of adoptees was also correlated with that of their siblings and showed evidence of recessive inheritance. Another study conducted in Muscatine, Iowa, suggests that more than 75% of the variation was explained by genetic factors that included a single recessive locus. About 6% of the population should have 2 copies of the recessive gene, while 37% were predicted to have 1 copy of this gene.9 Energy Expenditure is Genetically Controlled Monozygotic twins were examined to determine the genetic component of the response to overfeeding. Twelve pairs of identical Canadian male twins were overfed 1000 kcal per day, 6 days a week, for 100 days. Body weight, percentage of fat, fat mass, and estimated subcutaneous fat were then examined. When the effect of overfeeding was compared within the twin pairs and in the total group, it was found that the members of a pair resembled one another much more closely in weight gain and fat distribution than they resembled others in the group, illustrating again the importance of genetic factors in weight gain. These data strongly suggested that an individual's genotype governed the tendency to store energy as fat or lean tissue as well as the various determinants of resting energy expenditure. These genetic factors account for the intrapair similarity in the adaptation to long-term overfeeding and for variations in weight gain and fat distribution among the pairs of identical twins. Individual differences in the tendency toward obesity and in the distribution of body fat are inherited.10 In another study, energy expenditure directly correlated with the rate of body weight change over a 2-year follow up period in southwestern American Indians.11 Other Forms of Inherited Obesity Several genetic syndromes featuring obesity include Prader-Willi syndrome, Bardet-Biedl syndrome, Alstrom syndrome, and Cohen syndrome. Certain inbred populations, such as the Pima Indians and some Micronesian islanders, have a high incidence of obesity. Identification of the molecular defect in these disorders may allow the determination of important genes involved in the pathogenesis of obesity. Of Mice and Men: The Basis of Obesity & Rational Drug Design To understand the basis for a complex trait such as obesity, analyses of mutant mice provide a model system in which genetic tools can be readily applied. The problems of genetic heterogeneity can be minimized because inbred mice can be kept in uniform environments on identical diets. Designing specific crosses as desired will allow the isolation of alleles that will suppress or modify the mutant phenotype. Further, the recent development of transgenics and gene targeting to manipulate the mouse genome make it possible to test the roles of specific genes in complex disease. There are four well-known recessive mutations in mice causing obesity: obese (ob), diabetes (db), fat (fat), and tubby (tub). Due to one of these single genetic defects, these mice become obese and weigh three times heavier than normal mice. When ob/ob and db/db mice are bred into the same genetic background, their phenotypes are almost identical. Their increase in weight is apparently due to increase in food intake and decrease in metabolism (as for obese humans). Similar phenotypes were also found in animals with surgical lesions of the ventromedial hypothalamus which suggested that these mouse mutants may lack the ability to integrate or respond to nutritional information within the central nervous system. These mutant mice also have features that resemble NIDDM in humans with the severity dependent on the strain background. In the C57BL/Ks background, both the ob/ob and db/db mice develop severe diabetes with ß cell necrosis, islet atrophy and insulinopenia. The decompensation of pancreatic ß cells in C57BL/Ks mice can be prevented by estrogen but induced by androgens. On the contrary, in the C57BL/6J background, both ob/ob and db/db mice develop a transient insulin-resistant diabetes which is later compensated by ß cell hypertrophy as in human NIDDM. Ob/Ob Mouse Story Recent advances in mouse molecular genetics permitted the isolation of the genetic defect in the ob/ob mouse by Friedman's laboratory at the Rockefeller University. The DNA sequence of the ob transcript suggested that it encoded a secreted protein, i.e., a hormone. Subsequently, Amgen, Inc. spent $70 million to obtain commercial rights to OB. The 16kD OB gene product, found in mouse and human plasma, was undetectable in ob/ob mouse plasma.12 Daily injection of the ob/ob mice with OB gene product resulted in lowering body weight, percent body fat, food intake, and serum concentrations of glucose and insulin.13 The metabolic rate, body temperature, and activity levels were also increased by these injections. These parameters were not altered beyond the levels observed in normal controls, thus the OB protein normalized the metabolic status of ob/ob mice. Peripheral and central administration of OB protein decreased food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice.14 These behavioral manifestations observed after the administration suggested that OB can directly regulate the neuronal pathways controlling feeding and energy balance. Independent research teams at Rockefeller, Roche, and Amgen also found that OB can cause normal mice to lose weight. Normal mice receiving the OB injection eat less. The Rockefeller group showed that high dose injection of the OB protein led to 12% loss of their body weight and all of their fat (from 12.2 to 0.7%) in 4 days. These mice can maintain their new weight for 2 weeks if they continue to receive injections.15 It is known that the OB protein acts to regulate the size of body fat deposits and regulates signaling between the adipose tissue and a satiety center in the central nervous system. In an environment of limited food resources, the ability to adapt to starvation is essential to survival of the species. Falling OB concentration is a critical signal that initiates the neuroendocrine response to starvation: limited procreation, decreased thyroid thermogenesis and increased secretion of corticosterone, which together are likely to have survival value during prolonged starvation.16 The OB Receptor, Diabetes Mouse, and Fatty Rat
Weight gain stimulates the OB gene product to decrease food intake and raise metabolism to return body weight to the original set point. The ventromedial nucleus of the hypothalamus in the brain detects OB levels, much as a thermostat detects temperature, and directs the body to make the appropriate adjustments. If the satiety factor, i.e., OB protein, is low, this "lipostat" will inform the body that there is not enough fat and that it needs to gain weight. High levels of this satiety factor will be translated into turning down the animals' appetite and causing them to burn more fat by increasing their energy expenditures (Fig. 1). Decrease in Neuropeptide Y and Increase in Appetite The increase in metabolism triggered by the ligand binding to OB receptors/DB seemed to lower neuropeptide Y release from the arcuate nucleus of the hypothalamus. The receptor for the neuropeptide Y, Y5, was found mainly in the paraventricular nucleus of the hypothalamus and the amygdala, which is involved in feeding and emotions.19 Such a neuronal connection could be responsible for why some people tend to crave their favorite foods under emotional stress. Activation of Y5 receptor led to inhibition of adenylate cyclase and a decrease in cAMP. Within four hours of administration of synthetic peptide agonists to the Y5 receptor, stimulation of food intake occurred.19 These results imply that selective Y5 antagonists could be utilized for treatment of obesity. Furthermore, neuropeptide Y can stimulate metabolic rate through the activation of ß3-adrenergic receptors. A drop in neuropeptide Y levels causes appetite suppression and release of norepinephrine from sympathetic nerve terminals. Norepinephrine activates ß3-adrenergic receptors on adipose tissue, causing the expression of uncoupling protein (UCP). UCP, located in the inner membranes of mitochondria, burns fat by releasing the energy generated from fatty acid hydrolysis as heat (Fig. 1). The Diabetes Mouse as a Model for Human Obesity To examine the role of OB in the regulation of human metabolism and weight, OB concentrations in lean and obese subjects and in obese subjects placed on a liquid protein diet of only 800 calories/day (Optifast) were measured. The effects of food consumption on OB concentrations in both normal-weight and obese individuals were measured. Surprisingly, the OB levels were 4 times higher in obese individuals than in controls. Adipocytes of obese individuals overexpress the OB gene. No mutation has been detected in the OB gene in obese subjects. Weight reduction in obese people led to a drop of 53% in OB levels.20 Friedman's group also reported that in humans, there is a high correlation between the amount of fat stored in the body and OB levels. Decreased sensitivity to OB would explain the higher levels of OB found in obese people. The body must produce OB at a greater rate to compensate for a defective OB signaling process or action. OB levels decreased with dieting and thus, the reduced OB level means that less is available to stimulate the satiety center. Increased hunger and slower metabolism prevail and weight gain recurs. OB levels were elevated 20 fold in the diabetic db/db mice, in mice with induced hypothalamic lesions and in transgenic mice with ablated brown fat. In other words, humans behaved similarly to the db/db mice whose fat tissue made excess OB protein but their brains failed to respond to it properly. If nonfunctional OB receptor/DB account for most of human obesity, agonists that could activate the mutant OB receptor will have significant use in the primary care clinic. Other Mouse Models In contrast to ob/ob and db/db mice, the tubby/tubby and fat/fat mice exhibit maturity-onset obesity which resembles the pattern of weight gain frequently observed in humans. In other words, obesity usually develops in adults rather than in children. The Recessive tubby/tubby Mouse The tubby/tubby mice start out slim but gain weight as they age. They also develop insulin resistance, and increasing blindness and deafness, reminiscent of some medical conditions associated with obesity. The candidate tubby transcript was found in the paraventricular, ventromedial, and arcuate nuclei of the hypothalamus. Based on sequence analysis, the transcript encoded a phosphodiesterase; it is known that mutation in a subunit of a cGMP phosphodiesterase can cause neuronal degeneration.21 Age related degeneration of hypothalamic neurons could be responsible for late onset human obesity. The Recessive fat/fat Mouse The fat/fat mouse has a defect in the carboxypeptidase E that processes prohormone intermediates such as proinsulin. Fat/fat mice developed obesity within 8-12 weeks and a chronic hyperinsulinemia after weaning.22 Obesity and hyperinsulinemia /diabetes are frequently found in humans. Genetics and Primary Care of Obesity Obesity is a chronic medical condition for which the understanding of its molecular basis is needed to develop effective therapy. New tools in genetics in conjunction with the availability of a complete clinical profile of the primary care population will allow opportunities to determine the roles of human OB, DB, FAT, TUBBY and ß3-adrenergic receptor genes in obesity.23 Pharmacological manipulation of OB receptor/DB, neuropeptide Y, ß3-adrenergic receptor and other components of the OB signaling pathway should yield new approaches to treat obesity. There should be no difficulty in
recruiting volunteers for clinical trials of these drugs. Agonists to the OB receptor or ß3-adrenergic receptor and antagonists to neuropeptide Y5 receptor are expected to be used in the primary care clinic within the next three years. Administration of these biological response modifiers should suppress appetite and increase burning of calories. Future collaborative studies of patients in the outpatient clinic will allow primary care physicians and geneticists to identify additional loci that affect the control of body weight and other primary care health concerns that are frequently associated with obesity. The synergy between general internal medicine and genetics will undoubtedly transform our understanding of feeding behavior and obesity. Primary care providers and geneticists are as well matched as an older couple, immortalized in the nursery rhyme: Jack Sprat could eat no fat References 1. Bray GA. Barriers to the treatment of obesity. Ann Int Med 1991; 115:152-153. 2. National Technology Assessment Conference Panel. Methods for Voluntary Weight Loss and Control: Technology Assessment Conference statement. Ann Int Med 1993;119:764-770. 3. Bray GA. Complications of obesity. Ann Int Med 1985; 103:1052-1062. 4. Harris MI. Epidemiological correlates of NIDDM in Hispanics, whites,and blacks in the U.S. population. Diabetes Care 1991;14 (suppl. 3):639-648. 5. Weintraub M. Long-term weight control study: conclusions. Clinic Pharmacol Ther 1992;581-585. 6. Stunkard A J, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. NEJM 1990;322:1483-1487 7. Borjeson M. The etiology of obesity in children. Acta Scand 1975; 65:279-286. 8. Stunkard AJ, et al. An adoption study of human obesity. NEJM 1986;314:193-198. 9. Moll PP, Burns TL, Lauer RM. The genetic and environmental sources of body mass index variability: the Muscatine family study. Am J Hum Genet 1991;49:1243-1255. 10. Bouchard C, et al. The response to long-term overfeeding in identical twins. NEJM 1990; 322:1477-1482. 11. Ravussin EL, Knowler S, Christin WC, et al. Reduced rate of energy expenditure as a risk factor for body-weight gain. NEJM 1988; 318:467-472. 12. Zhang Y, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372: 425-432. 13. Pelleymounter MA, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540-542. 14. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-549. 15. Halaas JL, et al. Weight-reducing effects on the plasma protein encoded by the obese gene. Science 1995;269:543-546. 16. Ahima RS, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382: 250-252. 17. Chua SC, Jr., et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 1996;271:994-996. 18. Tartaglia LAD, Weng M, Deng X, Culpepper N, Devos J, Richards R, Campfield GJ, et al. Identification and expression cloning of a leptin receptor,OB-R. Cell 1995;83:1263-1271. 19. Gerald C, et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 1996;382:168-171. 20. Considine RV, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. NEJM 1996; 334:292-295. 21. Tsang, SH, et al. Retinal degeneration in mice lacking the g subunit of rod cGMP phosphodiesterase. Science 1996;272:1026-1029. 22. Naggert JK, et al. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet 1995;135-142. 23. Leibel RL, Chung WK, Chua SC Jr. The molecular genetics of rodent single gene obesities. J Biol Chem 1997;272 :31937-31940. Acknowledgements: I would like to thank Jonathan Lin, M.A. and Douglas Weiner (Duke University) for their critical discussions.
Address correspondence to: Stephen H. Tsang c/o Dr. Stephen P. Goff
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