Maturity-onset Obesity Research Articles

A prevalent polymorphism in the promoter of the UCP3 gene and its relationship to body mass index and long term body weight change in the Danish population.

Variability of the uncoupling protein 3 (UCP3) promoter has been associated with increased body mass index (BMI) and altered lipid profiles. Here we tested the hypothesis that variation of the UCP3 promoter is associated with either juvenile or maturity-onset obesity or body weight change over a 26-yr follow-up among Danish subjects. Mutation screening of approximately 1 kb 5' upstream of the UCP3 gene revealed one previously described -55 C-->T variant. The frequency of the polymorphism was evaluated by restriction fragment length polymorphism analysis in four groups of subjects: 1) a group of 744 obese Danish men who at the draft board examinations had a body mass index (BMI) of at least 31 kg/m(2), 2) a randomly selected control group consisting of 857 draftees, 3) 258 middle-aged subjects, and 4) 409 60-yr-old subjects. The frequency of the T allele was 26.0% (95% confidence interval, 23.8-28.2%) among the obese draftees and 26.9% (24.8-29.0%) in the control group (P = 0.6). The variant was not associated with BMI at a young age or with weight gain after a 26-yr follow-up. The frequency of the T allele was 29.5% (25.6-33.4%) in the middle-aged group and 25.8% (22.8-28.8%) among the 60-yr-old subjects. The polymorphism was not associated with increased BMI or percent body fat in these 2 groups. It is concluded that this variant does not play a major role in the development of common obesity among Danish subjects.

GFP-tagged expression and immunohistochemical studies to determine the subcellular localization of the tubby gene family members

The tubby gene family consists of four members, TUB, TULP1, TULP2 and TULP3, with unknown function. However, a splice junction mutation within the mouse tub gene leads to retinal and cochlear degeneration, as well as maturity onset obesity and insulin resistance. Mutations within human TULP1 have also been shown to co-segregate in several cases of autosomal recessive retinitis pigmentosa (RP) and TULP1 deficiency in mice leads to retinal degeneration. The primary amino acid sequences of the tubby family members do not predict a likely biochemical function. As a first step in defining their function, we present a detailed characterization of the cellular and subcellular localization of the human ( TUB) and mouse ( tub) homologous gene products. We report the isolation of TUB splice variants which have different subcellular localizations (nuclear versus cytoplasmic) and which define a nuclear localization signal. In addition, using green fluorescent protein (GFP) tags, we observe a nuclear localization for TULP1, similar to TUB splicing forms TUB 561 and TUB 506. Finally, we report tubby expression in mouse brain by in situ hybridization and by immunohistochemistry with polyclonal antibodies. Protein was found in both the hypothalamic satiety centers and in a variety of other CNS structures including the cortex, cerebellum, olfactory bulb and hippocampus. Both nuclear and cytoplasmic signals were detected with a series of independently generated polyclonal antibodies, consistent with the presence of multiple alternatively spliced isoforms within the CNS.

Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation.

The mouse tubby phenotype is characterized by maturity-onset obesity accompanied by retinal and cochlear degeneration. A positional cloning effort to find the gene responsible for this phenotype led to the identification of tub, a member of a novel gene family of unknown function. A splice defect mutation in the 3' end of the tub gene, predicted to disrupt the C terminus of the Tub protein, has been implicated in the genesis of the tubby phenotype. It is not clear, however, whether the Tub mutant protein retains any biological activity, or perhaps has some dominant function, nor is it established that the tubby mutation is itself responsible for all of the observed tubby phenotypes. To address these questions, we generated tub-deficient mice and compared their phenotype to that of tubby mice. Our results demonstrate that tubby is a loss-of-function mutation of the tub gene and that loss of the tub gene is sufficient to give rise to the full spectrum of tubby phenotypes. We also demonstrate that loss of photoreceptors in the retina of tubby and tub-deficient mice occurs by apoptosis. In addition, we show that Tub protein expression is not significantly altered in the ob, db, or melanocortin 4 receptor-deficient mouse model of obesity.

Tyrosine Phosphorylation of Tub and Its Association with Src Homology 2 Domain-containing Proteins Implicate Tub in Intracellular Signaling by Insulin

A mutation in the tub gene leads to maturity-onset obesity, insulin resistance, and progressive retinal and cochlear degeneration in mice. tub is a member of a growing family of genes that encode proteins of unknown function that are remarkably conserved across species. The absence of obvious transmembrane domain(s) or signal sequence peptide motif(s) suggests that Tub is an intracellular protein. Additional sequence analysis revealed the presence of putative tyrosine phosphorylation motifs and Src homology 2 (SH2)-binding sites. Here we demonstrate that in CHO-IR cells, transfected Tub is phosphorylated on tyrosine in response to insulin and insulin-like growth factor-1 and that in PC12 cells, insulin but not EGF induced tyrosine phosphorylation of endogenous Tub. In vitro, Tub is phosphorylated by purified insulin receptor kinase as well as by Abl and JAK 2 but not by epidermal growth factor receptor and Src kinases. Furthermore, upon tyrosine phosphorylation, Tub associated selectively with the SH2 domains of Abl, Lck, and the C-terminal SH2 domain of phospholipase Cgamma and insulin enhanced the association of Tub with endogenous phospholipase Cgamma in CHO-IR cells. These data suggest that Tub may function as an adaptor protein linking the insulin receptor, and possibly other protein-tyrosine kinases, to SH2-containing proteins.

An agouti mutation lacking the basic domain induces yellow pigmentation but not obesity in transgenic mice.

Chronic antagonism of melanocortin receptors by the paracrine-acting agouti gene product induces both yellow fur and a maturity-onset obesity syndrome in mice that ubiquitously express wild-type agouti. Functional analysis of agouti mutations in transgenic mice indicate that the cysteine-rich C terminus, signal peptide, and glycosylation site are required for agouti activity in vivo. In contrast, no biological activity has been ascribed to the conserved basic domain. To examine the functional significance of the agouti basic domain, the entire 29-aa region was deleted from the agouti cDNA, and the resulting mutation (agoutiDeltabasic) was expressed in transgenic mice under the control of the beta-actin promoter (BAPaDeltabasic). Three independent lines of BAPaDeltabasic transgenic mice all developed some degree of yellow pigment in the fur, indicating that the agoutiDeltabasic protein was functional in vivo. However, none of the BAPaDeltabasic transgenic mice developed completely yellow fur, obesity, hyperinsulinemia, or hyperglycemia. High levels of agoutiDeltabasic expression in relevant tissues exceeded the level of agouti expression in obese viable yellow mice, suggesting that suboptimal activity or synthesis of the agoutiDeltabasic protein, rather than insufficient RNA synthesis, accounts for the phenotype of the BAPaDeltabasic transgenic mice. These findings implicate a functional role for the agouti basic domain in vivo, possibly influencing the biogenesis of secreted agouti protein or modulating protein-protein interactions that contribute to effective antagonism of melanocortin receptors.

Identification and functional analysis of novel human melanocortin-4 receptor variants.

Inactivation of the melanocortin-4 receptor (MC4-R) by gene-targeting results in mice that develop maturity-onset obesity, hyperinsulinemia, and hyperglycemia. These phenotypes resemble common forms of human obesity, which are late-onset and frequently accompanied by NIDDM. It is not clear whether sequence variation of the MC4-R gene contributes to obesity in humans. Therefore, we examined the human MC4-R gene polymorphism in 190 individuals ascertained on obesity status. Three allelic variants were identified, including two novel ones, Thr112Met and Ile137Thr. To analyze possible functional alterations, the variants were cloned and expressed in vitro and compared with the wild-type receptor. One of the novel variants, Ile137Thr, identified in an extremely obese proband (BMI 57), was found to be severely impaired in ligand binding and signaling, raising the possibility that it may contribute to development of obesity. Furthermore, our results also suggest that sequence polymorphism in the MC4-R coding region is unlikely to be a common cause of obesity in the population studied, given the low frequency of functionally significant mutations.

Melanocortin-4 receptor: a novel signalling pathway involved in body weight regulation.

For many years, genetically obese mouse strains have provided models for human obesity. The Avy/-agouti mouse, one of the oldest obese mouse models, is characterized by maturity-onset obesity and diabetes as a result of ectopic expression of the secreted protein hormone, agouti protein. Agouti protein is normally expressed in hair follicles to regulate pigmentation through antagonism of the melanocortin-1 receptor, but in-vitro studies have demonstrated that the hormone also has potent antagonist activity for the melanocortin-4 receptor (MC4-R). Subsequent development of the MC4-R knockout mouse model demonstrated that MC4-R plays a role in weight homeostasis as these mice recapitulated the metabolic defects of the agouti mouse. Further evidence for this hypothesis was obtained from pharmacological studies utilizing peptides with MC4-R agonist activity, that inhibited food intake (when administered intracerebrally). Additional studies with peptide antagonists have now implicated the MC4-R in the leptin signalling pathway. Finally, evidence that the MC4-R may play a role in human obesity has been obtained from the identification of a dis-functional variant of the receptor in genetically obese subjects.

Prominent neuronal-specific tub gene expression in cellular targets of tubby mice mutation.

The tubby strain of mice exhibits maturity-onset obesity and sensory deficits in vision and hearing. The mutated gene, tub , responsible for this phenotype was identified recently, but the function of the TUB protein has not been deduced from its amino acid sequence. This prompted us to undertake expression mapping studies with the hope that they might help to elucidate the biological role of the TUB protein. We report the tub gene expression pattern in embryonic, fetal and adult mice tissues as determined by northern blots and in situ hybridization, using antisense oligonucleotidic probes. In mouse embryos, tub is expressed selectively in differentiating neurons of the ensemble of central and peripheral nervous systems, starting at 9.5 days after conception. In adult mice, tub is transcribed in several major brain areas, including cerebral cortex, hippocampus, several nuclei of the hypothalamus controlling feeding behavior, in the spiral ganglion of the inner ear and in the photoreceptor cells of the retina. These structures contain potential cellular targets of the tubby mutation-induced pathogenesis. The neuronal-specific tub gene distribution allows the establishment of a genotype-phenotype correlation in the tubby mice. This correlation is reminiscent of that observed in fat/fat mice, whose phenotype, also characterized by obesity, is caused by a null mutation in the carboxypeptidase E (CPE) gene. Our observations highlight similarities between CPE, prohormone convertases, several neuropeptides and tub gene expression patterns during embryogenesis, and may narrow down the avenues to explore in order to determine ultimately the function of the TUB protein.

Evidence of altered hypothalamic pro-opiomelanocortin/ neuropeptide Y mRNA expression in tubby mice

The tubby mouse is characterized by an autosomal recessive mutation which results in the development of maturity-onset obesity and sensorineural hearing loss and retinal degeneration. Although the tubby mutation which leads to a splicing defect of the tub gene has been identified recently, the mechanism by which it causes the obesity syndrome has not been established. In this study, the potential dysfunction of several hypothalamic neuroendocrine pathways involved in the central regulation of energy metabolism was investigated in tubby mice. In comparison with the wild-type controls, a significant reduction (20%) of pro-opiomelanocortin (POMC) mRNA expression was observed in the arcuate nucleus (ARC) of the mature, obese but not in the juvenile, non-obese tubby mice. Similarly, an age and body mass-dependent induction (about 30-fold) of neuropeptide Y (NPY) mRNA was observed in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei of the tubby mice. However, NPY mRNA in the ARC was decreased by approximately 30 to 40% in both juvenile and mature tubby mice. The hypothalamic expression patterns of corticotropin releasing hormone (CRH) and the long form leptin receptor (OB-Rb) were not significantly altered in the mutant mice. These results suggest that the altered hypothalamic POMC and/or NPY functions may be important contributing factors for the development of obesity in this animal model.

The Role of the agouti Gene in the Yellow Obese Syndrome ,

The yellow obese syndrome in mice encompasses many pleiotropic effects including yellow fur, maturity-onset obesity, hyperinsulinemia, insulin resistance, hyperglycemia, increased skeletal length and lean body mass, and increased susceptibility to neoplasia. The molecular basis of this syndrome is beginning to be unraveled and may have implications for human obesity and diabetes. Normally, the agouti gene is expressed during the hair-growth cycle in the neonatal skin where it functions as a paracrine regulator of pigmentation. The secreted agouti protein antagonizes the binding of the α-melanocyte–stimulating hormone to its receptor (melanocortin 1 receptor) on the surface of hair bulb melanocytes, causing alterations in intracellular cAMP levels. Widespread, ectopic expression of the mouse agouti gene is central to the yellow obese phenotype, as demonstrated by the molecular cloning of several dominant agouti mutations and the ubiquitous expression of the wild-type agouti gene in transgenic mice. Recent experiments have revealed that the hypothalamus and adipose tissue are biologically active target sites for agouti in the yellow obese mutant lines.

Obesity as a Pleiotropic Effect of Gene Action

Obesity, an easily detected and quantifiable phenotypic endpoint, is often considered, colloquially, as a disease. However, the study of obesity in rodents suggests that it is merely a convenient indicator of diverse underlying metabolic and physiologic dysregulations, rather than a disease entity in itself. To illustrate this concept, the differences between the murine Lepob/Lepob and Avy/- “obesity” syndromes are delineated. In both syndromes, pleiotropic effects of single mutations play a major role in altering the homeostatic regulation of energy metabolism and a myriad of extra- and intracellular processes in a diversity of tissues and cell types. The Lepob/Lepob syndrome mimics juvenile-onset obesity, whereas the Avy/- syndrome resembles maturity-onset obesity. The Avy/- syndrome has its basis in overabundance of agouti protein, whereas the Lepob/Lepob syndrome results from a lack of active leptin hormone. Lepob/Lepob mice have a smaller lean body mass, whereas Avy/- mice have a larger lean body mass than their respective lean siblings. Lepob/Lepob mice have fewer lung and mammary tumors than their lean Lep/- littermates, and Avy/- develop more mammary and lung tumors than their lean A/- or a/a siblings. Lepob/Lepob mice are infertile or sterile, whereas Avy/- mice are fertile. Thus, although adult Lepob/Lepob and Avy/- mice are both obese, many of the other morphologic and physiologic attributes of one mutant are diametrically opposite to those of the other.

Molecular insights into the regulation of energy intake and expenditure.

The maintenance of a precise caloric equilibrium is one of the most closely regulated parameters, as illustrated by the calculation that a positive energy balance of only ˛0.3% over 30 years would lead to an increase in body weight of over 20 kg. Hence, the caloric input (i.e. appetite) and energy expenditure must be tightly regulated processes. The recent elucidation of the role of the melanocortin-4 receptor (MC4-R) and the cloning of the uncoupling protein 2 (UCP-2) gene have broadened our molecular understanding of the regulation of energy intake and dissipation respectively. I. The role of the melanocortin-4 receptor in regulating food intake The list of peptides involved in the hypothalamic regulation of food intake comprises leptin, neuropeptide Y (NPY), corticotropin-releasing hormone, urocortin, and melanin-concentrating hormone. Melanocortinergic peptides (such as a-melanocyte-stimulating hormone, a-MSH), and their hypothalamic MC4-R in particular, have now to be added to this list. The concept of a potential link between the melanocortinergic system and body weight is derived from the agouti mouse model of genetic obesity. The agouti allele results in the ectopic expression of agouti, a 131 amino acid peptide, which is normally only expressed in the hair follicle where it acts in a paracrine manner. These mutant agouti animals are not only of yellow fur color, but they also develop hyperphagia and maturity-onset obesity due to adipocyte hyperplasia. While the absence of black hair color could be attributed to the antagonistic effect of agouti on a-MSH at the level of the melanocortin-1 receptor (MC1-R) controlling melanin synthesis in hair follicles, the obesity phenotype remained unexplained. Notably, lack of functional MC1-R does not result in obesity, suggesting that the ectopically expressed agouti protein must have other sites of action. In vitro studies have demonstrated that agouti can act as an a-MSH antagonist not only on the MC1-R, but also on the MC4-R, a G-protein coupled receptor primarily expressed in the brain, and particularly in the hypothalamic nuclei implicated in the regulation of food intake (1). In order to test whether the MC4-R is involved in the pathophysiology of the agouti phenotype, and hence in the regulation of appetite, Huszar et al. created a mouse knock-out model for the MC4-R gene (2). Interestingly, these mice lacking MC4-R exhibit maturity-onset obesity with hyperphagia, hyperinsulinemia and hyperglycemia, closely resembling the agouti phenotype. While it is formally possible that the observed phenotype results from abnormal brain development rather than from a role of the MC4-R in regulating feeding, the results of Fan et al. strongly argue against this possibility (3). These investigators identified pharmacological agonistic (MTII) and antagonistic (SHU9119) analogs of a-MSH. In keeping with the hypothesis that melanocortinergic neurons are involved in the inhibition of feeding behavior, the MTII analog not only decreased normal nocturnal food intake in mice, but it also acutely reduced food consumption in several models of hyperphagic obesity, such as the leptin-deficient ob/ob mouse, the obese yellow agouti mouse, and NPY-induced hyperphagia. Conversely, the a-MSH antagonist (and agouti-mimetic) SHU9119 not only blocked the effects of MTII, but it also enhanced nocturnal feeding when given alone. In summary, these observations suggest that the MC4-R and its agonist(s) are involved in the regulation of body weight and that the obesity phenotype in the agouti mice results from the inhibition of this pathway. At a clinical level, a phase II clinical study with MC4-R agonists is currently being conducted in obese type II diabetics, but no data regarding their efficiency are yet available.

Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice

The melanocortin-4 receptor (MC4-R) is a G protein–coupled, seven-transmembrane receptor expressed in the brain. Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome, which results from ectopic expression of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R.

A candidate gene for the mouse mutation tubby.

A mutation in the tub gene causes maturity-onset obesity, insulin resistance, and sensory deficits. In contrast to the rapid juvenile-onset weight gain seen in diabetes (db) and obese (ob) mice, obesity in tubby mice develops gradually, and strongly resembles the late-onset obesity seen in the human population. Excessive deposition of adipose tissue eventually leads to a twofold increase of body weight. Tubby mice also suffer retinal degeneration and neurosensory hearing loss. The tripartite character of the tubby phenotype shows striking similarity to human obesity syndromes, such as Alström and Bardet-Biedl. Here we report the identification of a G --> T transversion in a candidate gene that abolishes a donor splice site in the 3' coding region and results in a larger transcript containing the unspliced intron. This alteration is predicted to replace the 44-carboxyterminal amino acids with a 20-amino-acid sequence not found in the wide-type protein. Additionally, a second, prematurely truncated transcript with the unspliced intron is observed in testis messenger RNA and a 2-3-fold increase in brain mRNA is observed in tubby mice compared to B6. The phenotype features of tubby mice may be the result of cellular apoptosis triggered by expression of the mutuated tub gene.

Insulin as a potential factor influencing blood pressure in amputees.

War-injured, bilateral above-knee amputees are known to be at increased risk for cardiovascular mortality. To evaluate possible risk factors, we compared blood pressures and plasma glucose and insulin responses to orally administered glucose in 19 above-knee amputees from the Vietnam War (mean age, 36 +/- 1 years) with those of 12 age-matched unilateral below-elbow amputees. Body composition by densitometry and maximal oxygen consumption during arm or leg exercise were also determined. Nine of 19 leg amputees were hypertensive compared with one of 12 arm amputees. Their 3-hour average insulin responses were markedly increased (260 +/- 60 microU/ml) compared with those of normotensive leg (125 +/- 24 microU/ml) and arm amputees (101 +/- 20 microU/ml), and their mean body fat content (37.2%) also was elevated compared with that in both of these groups (23.2 and 22.6%, respectively). A unique finding was that both insulin response and body fat content were strongly and independently correlated with diastolic blood pressure (r = 0.55, p less than 0.01, and r = 0.62, p less than 0.01, respectively). We conclude that insulin may be a major factor in blood pressure regulation in the maturity-onset obesity that develops following traumatic leg amputation in young, healthy men.

Prenatal determination of obesity, tumor susceptibility, and coat color pattern in viable yellow (Avy/a) mice. The yellow mouse syndrome.

Maturity-onset obesity and elevated circulating insulin levels are characteristic of some, but not all, mice bearing the viable yellow mutation (Avy) at the agouti locus. The expression of the Avy/a genotype in individual mice, which become obese and which remain lean is determined during prenatal development by as yet unidentified conditions in the dam's reproductive tract. One Avy/a phenotype is identified by a mottled yellow coat and characterized by adult obesity, elevated circulating insulin levels, and impaired glucose tolerance. These mice are notably more susceptible to hyperplasia and neoplasia. The alternative Avy/ a phenotype has a pseudoagouti coat, remains lean, is normoinsulinemic and normoglycemic, and in numerous other characteristics resembles congeneic lean black (a/a) littermates. Obese mottled yellow and lean pseudoagouti Avy/a mice differ in capacity to support the growth of ascites cells, in the growth response to castration, and in hepatic glutathione S-transferase activity, erythrocyte fragility, immune function, and susceptibility to Plasmodium yoelii pathogenesis. Our working hypothesis is that the constellation of characteristics, except coat color pattern, which differentiate the obese yellow mice from their lean littermates, is largely a consequence of the elevated circulating insulin levels that induce increased lipogenesis and decreased lipolysis, increased DNA and protein synthesis, increased mitosis in sensitive tissues, and increased proliferation of transformed cells.

Methodological issues related to age of onset of obesity

Research related to age of onset of obesity may be hampered by two methodological problems: (a) inconsistencies across studies in the criteria used to define early-onset and maturity-onset obesity and (b) the failure to control for other differences between early-onset and maturity-onset obese patients. Analyzing data from 178 applicants to a behavioral weight control program, this study found that almost twice many patients were classified as early-onset obese when the division was based on their answer to the question, “Were you overweight as a child or teenager?” than when the division was based on self-reported weight at age 21. Moreover, early-onset obese patients were younger and heavier than those with maturity-onset obesity. Further studies are needed to determine the most reliable and valid means of classifying patients as early- or maturity-onset obese.

Personal reaction to weight loss

Psychological maladjustments often account for both the start and preservation of obesity. Although this concept is generally accepted, its obverse has received little attention. What happens to a person attempting successful and permanent weight loss? As he sheds excess weight by dieting, does he also change his selfimage? Will he experience psychological changes in self-image, which afford him the opportunity to work through his feelings, and thereby support the weight-reduction program? Is successful coping with weight loss similar to the coping with other losses, such as loss of a leg? Silverstone categorizes obese persons into three psychological groups: maturity onset obesity, reactive obesity, and early onset neurotic obesity (). Silverstone defines maturity onset as obesity that begins in adult years -about age 30-from decreasing, activity associated with aging without a compensatory decrease in caloric intake. Silverstone estimates that two thirds of the obese are in this category and two thirds of his study sample of 187 obese people apparently belonged in this group. These people keep their former eating patterns despite the reduced physiological need for food and seem to have little psychological dis-

An effective weight control program in a public school system.

IT iS generally well recognized that obesity constitutes a serious health problem in the U. S. population.'2 In adults, experience with weight reduction is for the most part less than satisfactory owing to the difficulties in modifying firmly established and deeply fixed habits of diet and exercise. Our experience with adolescent obese appears to indicate that a similar situation exists at this age level as well. In many instances, however, important basic differences in root causes distinguish maturity-onset obesity from obesity developed in early life. Whereas in adults the problem of excessive fatness is in the main the result of both excessive caloric intake and inadequate caloric expenditure, in the majority of obese children and adolescents the difficulty is not overeating but extreme physical inactivity.2 The dietary problem, in the latter groups, is not so much an excessive caloric intake as faulty food habits, and a lack of balanced diets with a tendency to overindulge in such special foods as candy, potato chips, and the like. In our judgment, the opportunity for greatest success in the control of obesity lies in tackling the problem in the preadult stage, in obese children and adolescents, when the habits of diet and physical activity are more tractable to modifications and are not yet as firmly established as in adult life. In addition, we believe that the scope of the obesity problem in youngsters is so extensive (12%o to 20%o of the pre-adult population), that reliance cannot be placed on the individual initiative of parents and children to obtain weight control therapy where needed. Furthermore, the cost of such therapy through private medicine is generally too high for all but a limited number of individuals. And, significantly, the eventual serious health consequences of the persistence of obesity into middle adult years make early obesity a national public health problem of communities across the country. The public school system, therefore, affords the most suitable and logical focus for an attack on the problem of weight control in our excessively fat youngsters. The advantages of handling this matter in the public school system are obvious. In this setting, the largest