Mr. Chairman, it is a pleasure to appear before you today to contribute to the Strategic Planning process of the National Institute of Diabetes, Digestive Disorders and Kidney Disease.

The American Obesity Association is grateful for this opportunity to participate. We are also very grateful for the leadership and commitment that this Institute, the lead Institute for obesity research at the National Institutes of Health, has demonstrated over the years. NIDDK's activities include the work of the National Task Force on Prevention and Treatment of Obesity, the Weight-Control Information Network, support for Clinical Nutrition Research Units, CORE Research Centers, liaison with other components of the National Institutes of Health, and support for basic and clinical research on obesity. In particular, the SHOW Clinical Trial is very important and NIDDK is to be applauded for leadership in this critical study.

This meeting could not be held at a more important time. Evidence mounts daily that the United States, indeed the world, is in the grips of an obesity epidemic. Prevalence rates are increasing. Illnesses caused by obesity are proliferating. Children are more overweight and obese than ever and suffering from diabetes and hypertension at alarming rates. The AOA commissioned a study on the direct health costs of obesity by the Lewin Group. Their study, reported at our conference last month, indicated that persons with a BMI e30 who constitute 22% of the adult population incur in 1999 34% of health care expenditures, largely due to five comorbid conditions heart disease, type II diabetes, hypertension and arthritis.

In addition, they confirmed the dramatic linear progression of weight and risk of selected health conditions. Overall,

obesity in adults, defined as a BMI e30, costs the health care system $238 billion out of a total of $1.3 trillion or one out of five health care dollars. $102 billion of the $238 billion is directly attributable to 15 adverse health conditions caused by obesity.

The environment, which is so critical in the spread of obesity, shows no signs of changing trends in the availability of low price energy dense foods or in the movement to a more and more sedentary style of life. Researchers, clinicians and leading public health officials, such as the Surgeon General, recognize the scope and scale of the obesity epidemic. Yet commitment to reversing this disease is slow. The Federal Government is spending billions of dollars to increase agricultural output and consumption, to increase the enjoyment of television and entertainment and computer literacy and to export these forces abroad. In the meantime, we have witnessed physical education being expelled from the schools in this country. Our compulsion to lead in global competition has made the American worker the world's leader in hours worked, increasing behaviors such as eating out and snacking which almost always involve calorie dense food products.

Under the leadership of the National Institutes of Health, we now know that obesity is a multifactorial disease. For many, obesity appears exceptionally simple: energy in-energy out. But current research indicates that body weight is an extremely complex phenotype. It is an amalgamation of everything by which we are physically influenced -everything that influences the weight of any tissue, organ or fluid. As stated by Anthony G. Comuzzie and David B. Allison, “Indeed, obesity may represent the archetype of the so-called “complex phenotypes.” In contrast to simple Mendelian disorders, in which there is generally a one-to-one relationship between genotype at a single locus and the presence or absence of the disorder, obesity arises as a result of numerous behavioral, environmental and genetic factors.” Comussie,AG and Allison, DB, The Search for Human Obesity Genes, Science, May 29, 1998, 280:1374

Unfortunately and tragically, the federal government has been slow to respond to the obesity epidemic. Reference has already been made to the role of the Federal government in creating policies and programs which underpin the environment which causes obesity. In addition, the federal government provides no budget to the Center for Disease Control and Prevention nor the Department of Education for obesity prevention among children and adolescents. The Federal Government also explicitly denies treatment for obesity to Medicare and Medicaid beneficiaries. The Federal Government excludes expenses for treating obesity from the medical deduction on individual tax returns. Just this month, a new regulation from the Social Security Administration goes into effect, dropping obesity from its Listing of Impairments for determination of disability. At best, this regulation will lengthen the time individuals with severe obesity and co-morbid conditions such as arthritis can receive disability and become eligible for Medicare.

In the context then of a government, which actively promotes the obesity-engendering environment and actively excludes persons with obesity from life-saving treatment, the research program of the National Institutes of Health is the one positive and active component of our country's shameful response to the obesity epidemic. The expected inclusion of obesity as one of the Nation's Leading Health Indicators will serve to heighten public awareness of the serious adverse health consequence of obesity and will serve to focus attention in this area in the years ahead.

1.The Role of NIDDK

NIDDK has played a crucial role in the nation's research program on obesity. The NIDDK supports excellent research in fundamental areas of obesity research. These including the physiological, metabolic, psychological and genetic factors affecting food choices, food intake, eating behavior, appetite and satiety; the effects of taste, smell and gastric and humoral responses (including neurotramsmitters) associated with dietary intake and behavior; physiological and metabolic consequences of weight loss or weight gain; the effects of exercise and individual variability in energy utilization and thermogensis; dietary determinants of the growth and control of adipocyte size and number; responsiveness of the adipocyte to various metabolic and pharmacological stimuli; prevention of obesity and eating disorders; improved methods of assessing body composition; health risk factors associated with specific degrees of obesity or body composition and determination of the effect of exercise on body composition. Harrison, B & Hubbard, VS, NIDDK Role in Obesity Research, Obesity Research, 2:6:585, Nov. 6, 1994

In spite of these efforts, the needs in obesity research have far outstripped the capacity of NIDDK. Researchers now identify over 30 health conditions directly caused or affected by obesity. About half of these would be considered well established including, Type II diabetes, hypertension, stroke, heart disease, impaired immune function, gallbladder disease, colorectal, endometrial, renal cell and breast cancer, sleep apnea, end stage renal disease, urinary incompetence and osteoarthritis and rheumatoid arthritis. The other conditions, such as carpal tunnel syndrome, birth defects, asthma are less well established and in need of urgent research.

The health complications of obesity indicate one of three strategies by NIDDK. The first would be a narrow approach of only looking at obesity as the major cause of Type II diabetes and focusing exclusively or largely on the obesity-diabetes connection. This approach would create an inconsistency in that NIH identifies NIDDK as the Institute with responsibility for obesity yet the program of NIDDK would focus on only one, albeit an important, comorbid condition of obesity.

The second approach, as the lead Institute on obesity, is for NIDDK to create a comprehensive research program within its structure to encompass obesity in all its aspects.

The third approach is to act aggressively as a catalyst within NIH to encourage and lead the other Institutes and Centers into more active programs of obesity research.

There is precedent for the latter role. We are now closing out the Congressionally declared “Decade of the Brain.” At the outset of this decade, research on disorders of the brain was largely limited to the National Institute on Neurological Disorders and Stroke and the National Institute on Mental Disorders. Encouraged by strong support from Congress, neuroscience investigations spread during this Decade of the Brain to a host of various institutes who used the information of neuroscience research to inform areas of research within their particular scope.

We can be encouraged about this possibility by recent development in Congress. Thanks to the leadership of Senator Arlen Specter, the report of the Senate Appropriations Committee (Report 106-370) contains the following language:

The Committee is very concerned about the increasing numbers of Americans who are obese. Over one fifth of all adults are obese; over half are overweight. Obesity is known to cause serious diseases including type 2 diabetes, hypertension, stroke and several cancers. Deaths due to poor diet and inactivity are the second leading cause of preventable death in the United States. According to a recent study by the American Obesity Association, the direct health care costs of obesity in 1999 will be over $100,000,000,000. Obesity among women over 20 is increasing at over 1% a year. Obesity is growing among school children with increasing prevalence of diabetes and hypertension at younger ages. Therefore, the Committee encourages the Secretary (of Health and Human Services) to develop a comprehensive plan for expanding research on obesity at the National Institutes of Health and the Center for Disease Control and Prevention as well as education programs at the Department of Education.

(At p.78)

In addition, at AOA's recent conference, Obesity: The Public Health Crisis, Congressman John Porter, Chair of the House Appropriations Committee for Labor, Health and Human Services and Education, echoed his strong support for a more vigorous research program in obesity.

It should be a priority for the NIDDK Advisory Council to consider such options and for the incoming Director of NIDDK and the incoming Director of NIH to define an effective approach and to take leadership in the Congress's directive to the Secretary of Health and Human Services.

Whichever option is taken, it will be necessary for NIDDK to both expand the depth and breadth of its commitment to obesity research. In either event, NIDDK should create a new division of Obesity Research. Currently, obesity research is organizationally located as one of five programs in one of three branches in one of six divisions of NIDDK. Under any of the three formulations, it will be necessary for NIDDK to have the leadership and administrative support in place to affect the direction of not only NIH's response to the obesity epidemic but other governmental organizations as well.

2. Strategic Planning Process

To a large extent, today's meeting is a culmination of a long process of discussions of planning within NIH.

In 1997 the National Institutes of Health elucidated its priority setting process in Setting Research Priorities at the National Institutes of Health. That document articulated criteria which NIH uses in its overall priority setting. These included:

Public Health Needs

Scientific Quality of Research

Potential for Scientific Progress

Portfolio Diversification, and,

Adequate Support of Infrastructure.

Subsequently, the Institute of Medicine was asked to review NIH's criteria. AOA was pleased to testify before the IOM committee chaired by Leon E. Rosenberg. We pointed to glaring inconsistencies in terms of the funding devoted to the conditions caused by obesity and obesity research itself. (See attached graphs.) The IOM committee made several recommendations including broadening the criteria beyond the medical model to the preservation and maintenance of health and function.

Whether one looks to the NIH criteria or the additional components suggested by the Institute of Medicine, few could argue that obesity is comparable to other major diseases. AOA's Fact Sheets (attached) clearly indicate the public health needs and researchers are uniform in both the quality of current research and the enormous potential for progress, especially as we can see the completion of the Human Genome Project and the infrastructure to maximize new information into programs for the prevention and treatment of obesity.

However, it is equally clear that obesity research has been significantly underfunded. NIH is supposedly committed to basic research on the causes and treatment of disease. Yet, far greater funding has gone into research on conditions clearly caused by obesity than into obesity itself. Historically, significantly more funding and number of grants have gone into conditions caused by obesity than obesity itself.

Clearly these disparities must be recognized and addressed.

It is therefore unfortunate that NIDDK has organized this Strategic Planning Process as it has. The IOM was very clear in its support for the opportunity for the public and advocacy groups to address their specific disease interests to the relevant Institutes at NIH. By organizing this process around cross-cutting research opportunities with diseases only as models and by organizing this day to provide the majority of time to NIDDK speakers, leaving just three minutes to each representative of specific advocacy organizations, NIDDK has short-circuited the process espoused by NIH itself for public input.

2.Needs in Obesity Research

It is beyond our capacity to catalogue the important research opportunities in obesity research. Rather, we have attempted to identify several key areas for which substantial research programs are needed. These include the areas of:

C.Genetics,

D.Gender Differences

E.Racial and Ethnic Disparities,

F.Childhood Obesity

G.Disease Process,

H.Co-morbid and Related Conditions,

I.Treatment Outcomes Research,

J.Prevention,

AA. Intervention,

BB. Discrimination and Stigma,

CC. Disability Research, and,

DD. International Obesity Epidemic

EE. Training

In 1994, the National Task Force on the Prevention and Treatment of Obesity stated:

Thus, in seeking answers to each of the research questions below, it will be important to consider the heterogeneity of obesity in various obese subgroups and individuals, especially for tailoring treatment and prevention strategies. Examination of the differences between obese and normal-weight individuals and populations will also will be critical to understanding and addressing the problems of obesity. At both clinical and basic levels, research should examine variations such as: ethnic and gender differences; characteristics of those with co-morbid conditions, including unhealthy lipid profiles, hypertension, elevated insulin levels, and insulin resistance; the consequences of differing fat distributions; the effects of age; and the contrasts between therapeutic responders and non-responders. Particular attention should be paid to investigation of the different characteristics of specific minority populations with highest obesity prevalence. Towards Prevention of Obesity: Research Directions Obesity Research, 1994: 2:6:571-584.

That statement is as true today as it was five years ago.

A. Genetics

One of the truly historic events of the new century will be the completion of the mapping of the Human Genome. This accomplishment will open the doors to refine our understanding of the interplay of genetics, environment and behavior in obesity.

Long-term studies are needed to prospectively test hypotheses that have been developed on the interaction between a child's genetic predisposition and environmental factors that produce childhood obesity. For example, investigating the possibility that genetic differences contributing to obesity are manifest in individual differences in feeding and exercise predisposition and should include a joint focus on intake and expenditure. Future research should include children and their families identified as differing in familial risk for obesity, in whom definitions of risk that include behavioral factors such as parenting practices, parental adiposity, and dieting history. Birch L and Fisher J, Development of Eating Behaviors Among Children and Adolescents, Pediatrics, 101:539-549; 1998.

Whether parental obesity exerts genetic influence on offspring or an environmental influence in terms of eating habits and role modeling is uncertain and needs further exploration. Hernandez B et al, Prevalence and Correlates of Obesity in Preschool Children, J of Pediatric Nursing, 13(2); 1998.

Research is needed on the identification of genes that regulate weight. Collaborative gene finding efforts – pooling raw data from multiple studies may be a strong viable strategy. This strategy is being applied in genetic studies of type II diabetes and autism. Comuzzie AG and Allison DB, The Search for Human Obesity Genes, Science, 280:1374-1377, May 29, 1998.

Research must be continued on the function of obesity genes that have been discovered. Few obesity genes have been found to date. However, all have been found in less than 10 years, beginning with CPE found by Prochazka et al. Others include: LEP, LEPR, and TNFA found in 1995, TUB in 1996, and POMC and ASIP in 1997. Comuzzie AG and Allison DB, The Search for Human Obesity Genes, Science, 280:1374-1377; May 29, 1998. Most recently the Mahogony gene was discovered to play a role in the regulation of calorie burning.

Understanding the influence of genes on eating behavior and obesity also is important for understanding the complementary role of the environment in obesity as well as for identifying specific etiologic factors that may lead to some individuals being at high risk. For example, identifying the genetic basis for behavioral phenotypes, such as impairments in satiety, may be important in developing more focused treatments that target specific behaviors instead of the usual broad-based group methods for treatment. Epstein L. et al., Treatment of Pediatric Obesity, Pediatrics, 101:554-570;1998.

Research must be continued on defective genes that can cause obesity in humans. Some gene flaws involved in obesity have already been discovered. First – a defect in the leptin gene; second – a defect in PC-1, involved in processing the insulin hormone as well as various brain chemicals implicated in regulating weight; third - a defect in the PPAR-gamma gene interferes with the body's normal function to control PPAR-gamma or “turn it off”, thus contributing to weight gain. PPAR-gamma is a protein that apparently contributes to the body's ability to make fat cells and store fat cells within the cells.

The role of genetics in dietary preferences needs to be research.

Following advances in genetics, animal models need to be developed to identify new loci controlling body weight.

B. Gender Differences

While obesity trends are largely the same in men and women in various age, racial and ethnic groups, differences are present and can be significant in terms of intervention and prevention strategies and risks for specific comorbid conditions. Furthermore, research on gender differences can enlighten our understanding of both obesity and a number of serious comorbid conditions.

Fear of obesity among adolescent women is likely to contribute to the use of inappropriate weight control strategies including eating disorder behavior and the initiation of smoking. Research is needed not only to identify who may be at risk for such inappropriate behavior but also on effective methods of health communication to encourage medically sound approaches to weight maintenance.

Of major concern is a study which appears to indicate that obese pregnant women who take folate may still remain at risk of delivering babies with neural tube defects. Waller MM et al, Prepregnant Weight in Relation to Neural Tube Defects, JAMA 1996, 275:1089-1092. Given the major investment of the NIH and public health programs in increasing folate use and the increase in the numbers of women of childbearing age who are obese, this topic needs immediate attention.

Additional observational studies of associations between intentionality and weight loss and mortality are needed to replicate present findings. French SA et al., Prospective Study of Intentionality of Weight Loss and Mortality in Older Women: The Iowa Women's Health Study, Am J Epidemiology, 149:504-514;1999.

C. Racial and Ethnic Disparities

As with gender differences, disparities exist between racial and ethnic groups in the prevalence of obesity and in mortality and morbidity risks. Research is needed to reduce disparities regarding obesity, and increase the understanding of the effects of obesity on specific populations.

Studies suggest that African-American women may engage in less leisure-time physical activity than whites. Future research should include development and validation of culturally specific physical activity questionnaires and objective measurements of physical activity. Kushner RF et al., Measurement of Physical Activity Among Black and White Obese Women, Obesity Research, 3(2):261S-265S;1995.

“Further studies with larger samples of black and white NIDDM patients are needed to better understand the behavioral and physiological factors that may explain the poorer weight loss performance in blacks. This information would be helpful in developing more effective weight loss programs for black NIDDM patients.” Wing RR and Anglin K, Effectiveness of a Behavioral Weight Control Program for Blacks and Whites with NIDDM, Diabetes Care, 19(5):409-413;1996.

“Obesity and hypertension are strongly associated. Though the mechanisms by which obesity causes hypertension are not completely understood. There is almost certainly a causal relationship. Obesity-associated hypertension is characterized by an abnormal pressure natriuresis relationship, increased heart rate and cardiac output, and normal peripheral resistance. Several mechanisms have been proposed for the initiation of these changes, but these mechanisms are as yet poorly understood. Further studies are needed to investigate this important relationship and how it may account for excess prevalence of hypertension and cardiovascular disease in African Americans.” Jones DW, What is the Role of Obesity in Hypertension and Target Organ Injury in African Americans?, Am J Med Sci, 317(3):147-152;1999.

“Regardless of which index of adiposity is most predictive of CHD, concern is growing that the prevalence of obesity in the US is rising markedly. Moderate-to-severe obesity is a risk factor not only for CHD, demonstrated once again in these data, but also for other chronic diseases. Data do not suggest that African Americans are spared more than whites from the CHD risks accompanying obesity. This observation is especially important because in African Americans the prevalence of obesity (and, thus, its attributable risk for CHD) is high. Clearly, continued and more-effective population-wide efforts to prevent and treat obesity are needed.” Folsom et al., Body Mass Index, Waist/Hip Ratio, and Coronary Heart Disease Incidence in African Americans and Whites, Am J Epidemiology, 148(12):1187-1194;1998.

D. Childhood Obesity

The increasing prevalence of obesity among the nation's children and adolescents is especially disturbing. Already, we are seeing increasing rates of diseases such as Type II diabetes and hypertension among children. It is reasonable, therefore, to expect that physicians will be under increasing pressure from parents and children to prescribe anti-obesity pharmacological compounds and to prescribe pharmacological compounds used in treating diabetes and hypertension (as well as products used for other comorbid diseases of obesity). However, almost all such products are not approved for children, so their use would be off-label but permissible under current law. Studies on the safety and efficacy of such products are going to be needed as the society struggles to respond to obesity among children. NIDDK needs to coordinate with other components of NIH as well as the Food and Drug Administration to respond to this aspect of the obesity crisis.

Major questions abound in the field of childhood obesity. Does moderate childhood obesity lead to worsening of risk factors for NIDDM and cardiovascular disease, and does this begin in childhood or adulthood? Does the risk of obesity-associated co-morbidities vary with the age of onset, duration, or severity of childhood obesity? What is the best method of assessing childhood overweight and obesity? How does childhood obesity affect socialization? Does childhood obesity alter relationships of the obese child with adults or other children systematically? How does childhood obesity affect socialization as an adult? How can food intake and energy expenditure be accurately assessed in children? How and why is the distribution of BMI is changing over time in children and adolescents, and what specific intervention efforts should be targeted at the more overweight children and adolescents, who may be at the greatest risk of additional weight gain. How should adult diseases such as NIDDM, hyperlipidemia, and hypertension be treated in overweight children? How should these diseases be treated and how does treatment affect the risk for adult disease? What are the effects of childhood obesity on the risk for adult chronic disease, even if the obesity does not persist into adulthood? What are the risks/benefits of treating children with pharmacotherapy for obesity and obesity related co-morbid conditions? When do the medical risks of childhood obesity begin? A great deal of research is needed to better understand how eating and physical activity patterns develop and how patterns learned in childhood track into adulthood. Most existing studies are cross sectional, and there is a great need for longitudinal studies, following subjects through childhood and adolescence. Hill J and Trowbridge F, Childhood Obesity: Future Directions and Research Priorities, Pediatrics, 101:570-574; 1998.

Measurement issues related to assessment of dyslipidemia and insulin action also are important. Additional studies are needed to identify microassays to screen for lipid profile, assess insulin action, and determine cardiovascular health. These techniques should potentially be applicable in large groups for routine screening and monitoring of general health status related to obesity. Additional research is needed to identify a more unified approach for the assessment and interpretation of body composition and energy expenditure in children. This will provide a more useful approach for comparing and combining data. The highest priority in terms of method development is for techniques related to assessment of physical activity and food intake. The lack of strong techniques in this area is severely limiting research progress into the causes, treatment and prevention of childhood obesity. Goran M, Measurement Issues Related to Studies of Childhood Obesity: Assessment of Body Composition, Body Fat Distribution, Physical Activity, and Food Intake. Pediatrics 101:505-518, 1998.

Longitudinal studies are needed to explore both the psychological and medical risks of longstanding obesity. Hernandez B et al, Prevalence and Correlates of Obesity in Preschool Children, J of Pediatric Nursing, 13(2); April, 1998.

The apparent increase in the fatness of adults and children over the past few decades implies and the lack of success in maintenance of a reduced body weight in reduced-obese individuals suggests that the degree of body fatness an individual defends metabolically may be altered by early environmental influences. Additional identification of systems that oppose maintenance of an altered body weight, the age at which these systems become operant, and the environmental cues that affect the regulatory setpoint of these systems may identify an optimal age at which therapy could be instituted to prevent a child who is genetically at risk of becoming obese from expressing that genetic tendency. Rosenbaum M and Leibel R, The Physiology of Body Weight Regulation: Relevance to the Etiology of Obesity in Children, Pediatrics, 101:525-539, 1998.

There is little evidence about how factors influencing children's food preferences and intake, especially child-feeding practices, may differ systematically across socioeconomic and racial groups. In addition, little research has been conducted with infants and toddlers, in whom dramatic dietary change is occurring, or with adolescents, in whom most research has focused on eating disorders, and to some extent, on dieting behavior. Both infancy & adolescence are critical periods in the development of the controls of food intake during these periods. Birch L and Fisher J, Development of Eating Behaviors Among Children and Adolescents, Pediatrics, 101:539-549; 1998.

A key factor in treating children and adolescents may be their ability to comply with dietary and physical activity recommendations. In one study 70% of children at the 85th percentile for weight at a tertiary care clinic had some coexisting cognitive or exercise-limiting comboridity. These include asthmatic patients controlled by corticosteroids or exercised-induced asthma; nonambulatory children with myeolodysplasia; mental or developmental delay whose families use food to control disruptive behavior; children with suspected hypertension, depression, or upper airway obstruction. Family dysfunction inhibiting compliance was not included in the study. Smith, JC et al. Coexisting Health Problems in Obese Children and Adolescents that Might Require Special Treatment Consideration Clin Pediatr. 1999;38:305-307 Strategies to overcome such obstacles need to be designed, tested and evaluated.

E. Disease Process

Much is unknown regarding the mechanism of action of various factors related to obesity. Obesity is multi-factorial and complex. While small pieces of the puzzle are beginning to unravel answers to some questions, much remains unclear about why obesity occurs in some persons and not others. Why do some obese persons have obesity-related co-morbid conditions while others do not? Why did some people who took fenfluramine or dexfenfluramine develop heart valve disorder while others did not? What is the mechanism of action leading to heart valve disease in a product like fenfluramine? Research is needed to determine why and how the process of obesity occurs in various different populations, and what treatment options most appropriate under specific circumstances (i.e., obese persons with specific co-morbid conditions) and for specific populations (i.e., racial-ethnic groups, various age groups and both genders). What are the mechanisms for modulation oxidation and storage of macronutrients. The roles of adipocyte and body composition in energy balance and health need further understanding. Questions continue about the control of regional fat deposition and hypertrophy and hperplasia of adipocytes.

Further research is needed on human tissues, including fat and muscle, that uncouple metabolism and energy production. Study on the human uncoupling protein (UCP) could help increase the understanding of obesity and improve treatments. Variation in UCP production or activity may help explain why some people have a lower or higher metabolic rate and thus have a greater or lesser tendency to become obese. UCPs may also be good targets for obesity therapy since they mainly act in fat and muscle versus the brain – as do many other weight-regulatory molecules. DNA sequences and the association with the UCP2 gene are found primarily in people with low metabolic rates. Research needs to be done to verify the relationship of body mass and body fat percentage in obese persons with the UCP2 gene and DNA sequences and the relationship of a variation of diets and exercise intensity with the activity of the UCP2 and UCP3 genes. Development of drug therapy that would slightly increase the level of uncoupling enough to create safe weight loss would be highly desirable. Gura T, Uncoupling Proteins Provide New Clue to Obesity's Causes, Science, 280:1369-1370, May 29, 1998.

In many ways, obesity can be seen as a disease of accelerated aging. Exploring the mechanisms by which obesity accelerates this process can inform work on understanding of the aging process in the absence of obesity.

Central Nervous System

More research is needed in understanding the central nervous system role in energy homeostasis and regulation by adiposity signals.

Efforts need to be made to further dissect the circuitry and mechanisms underlying individual components of the integrated response to fluctations in an authentic circulating index of peripheral energy stores. Functional mapping approaches based on patterns of stimulus-induced immediately-early gene expression, either alone or in combination with phenotyping and/or trait-tracing protocols offer means for advancing this area. Experiments can test hypotheses concerning the situation specific dependence of the activation of a given output neuron population on the integrity of particular afferents. Sawchenko, PE, Toward a New Neurobiology of Energy Balance, Appetite, and Obesity: The Anatomists Weight In J Com Neuro 402:435-441 (1998).

Physical Fitness

“Much of our lack understanding of determinants of physical activity in children and adolescents is related to a lack of understanding of accurate ways to measure physical activity. Without an accurate assessment of the outcome of interest, studies of predictors of that outcome are at risk of showing null results, even if a real association exists. More work must be done in development and validation of methods of physical activity assessment for children and adolescents.” Kohl H and Hobbs K, Development of Physical Activity Behaviors Among Children and Adolescents, Pediatrics, 101:549-554;1998.

Increasing amounts of physical activity or maintaining high levels of physical activity for purposes of weight control might be most important in preventing the increases in weight known to occur with aging, from the early 20s through the late 60s. Although much less research has been conducted in this area of prevention in humans, the limited research to date is promising, and the animal research is very clear that animals that exercise weigh less and have lower absolute and relative body fat levels than do their sedentary counterparts. This preventive aspect must be an area of priority for future research attempting to better understand the role of physical activity in weight regulation. Wilmore JH, Increasing Physical Activity: Alterations in Body Mass Index and Composition, Am J Clin Nutr, 63(suppl):456S-460S,1996.

More studies need to be conducted examining methods of increasing individual, family, group, and community patterns of physical activity. Work focusing on frequency, intensity, and units of time is particularly needed as individuals often want to know about the minimal dose of physical activity they can perform to yield certain benefits. Many of the barriers to the initiation and early adoption of physical activity may no longer be as potent now that individuals have a variety of ways to get their "dose" of exercise. Several studies have highlighted the usefulness of applying process-oriented approaches to understanding the stages and processes people go through in their decisions to consider, prepare for, initiate, and maintain increases in physical activity. However, much more work is needed in this area in order to formulate the most effective interventions for individuals at these different stages of participation. In particular, investigations of the early stages of readiness for physical activity participation are scarce. The developmental stages that individuals progress through during their lives have a great deal to do with their ability to succeed at a lifelong practice of regular physical activity. Potentially important transitional periods that deserve further exploration include adolescence, entry into college or the workforce, pregnancy, parenthood, menopause, and retirement. Examining how these and other transitional periods can enhance or inhibit physical activity participation is important as is examining the barriers most prevalent during each of these transitions. Many adults report that greater availability of exercise facilities would help them to be more involved in regular exercise. Policy level work needs to occur so that more people can have access to safe, low-cost, climate controlled places to walk and perform other physical activities. Environmental changes are essential for changing the societal norm such that physical activity becomes a part of daily life. Marcus B, Exercise Behavior and Strategies for Intervention, Research Quarterly for Exercise and Sport, 66(4):319-323;1995.

Environmental Factors

Researchers have long recognized that environmental factors play a significant role in the development of obesity. These factors include the availability of low-cost energy dense foods and the increase in sedentary behavior. Such factors are at least partially the product of governmental policies at the federal, state or local level. For example, school boards and departments of education have decided to eliminate physical education in elementary and secondary schools. Zoning boards and city councils decide on the availablility of sidewalks, bike trails and safe parks. The Federal Government has decided to require producers of meat and diary products, among others, to fund advertising promoting their products to consumers. The Internal Revenue Service has decided to disallow individuals from deducting the cost of obesity treatment as a medical deduction but allows approximately $7 billion in advertising of high fat, low nutrition products to be deducted from corporate income taxes. The Federal Communications Communication actively promotes enhancement of television, which is clearly implicated in the development of childhood obesity. Research is urgently needed to

evaluate the extent to which environmental factors may be modified by governmental decision-making and which policies may have the most significant contribution to the reduction of obesity.

F. Co-Morbid and Related Conditions

Obesity has been called the disease of diseases because it is an independent risk factor for so many conditions. Current literature review indicates some 30 conditions associated with obesity. Several of these are well established compared to others. Well established conditions include: arthritis, breast cancer, heart disease, colorectal cancer, Type II diabetes, endometrial cancer, end stage renal disease, gallbladder disease, hypertension, liver disease, low back pain, obstructive sleep apnea, stroke and urinary incontinence. Less well established conditions include: birth defects, carpal tunnel syndrome, esophageal cancer, impaired immune response, wound infection, obstetric and gynecological complications, pain, surgical complications, and teeth injuries. Other conditions or activities, such as bulimia, binge eating, smoking, and alcohol use are important areas where relationship to obesity needs further research.

Research is needed to identify all conditions related to obesity in order to better inform society not only for the prevention and treatment of obesity but also to contribute to our understanding of the other disease processes.

Following are some research topics related to specific comorbid or related conditions and obesity.

Alcohol

“We have previously suggested that an endocrine abnormality, consisting of a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, might be the cause of centralisation of body fat, due to an increased cortisol secretion, as clearly seen in Cushing's syndrome. One might speculate that psychosocial and socio-economic handicaps, as seen in both genders, might lead to a depressive stress reaction, similar to that described in experimental animals. The traits of depression and anxiety found repeatedly in cohorts of both men and women, might be part of such a reaction, which then would be expected to be followed by an activation of the HPA axis. This interpretation is strongly supported by studies of other primates which when stressed by psychosocial manipulations develop submissive, depressive reaction and signs of hyperactive HPA axis with visceral fat accumulation. It seems likely that tobacco smoking exaggerates the centralisation of fat through similar mechanisms, because smoking is followed by increased cortisol secretion. Alcohol consumption has the same effects, but the consistency of an association between alcohol and the Waist to Hip Ratio is not as robust as that with depression and smoking, and needs further studies with more refined methodology.” Rosmond E and Bjorntorp P, Psychosocial and Socioeconomic Factors in Women and Their Relationship to Obesity and Regional Body Fat Distribution, Int J Obesity, 23:138-145;1999.

Arthritis

Further work is needed to confirm observations of an association between obesity and rheumatoid arthritis (RA), and to explore the possible mechanisms for the potential triggers of RA. Symmons DPM et al., Blood Transfusion, Smoking, and Obesity as Risk Factors for the Development of Rheumatoid Arthritis, Arthritis and Rheumatism, 11: 1955-1961; Nov 1997.

Osteoarthritis (OA) of the knee might especially benefit from weight reduction. Intervention studies might reveal whether the induction or the progression of the disease is prevented with weight reduction. Van Saase JL, et al., Osteoarthritis and Obesity in the General Population. A Relationship Calling for an Explanation, J Rheumatology, 15:1152-1158, 1988.

Furthermore, the amount of weight loss needed to alleviate symptoms and prevent disease progression of osteoarthritis is unknown and needs to be researched. For those with knee osteoarthritis, being overweight is likely to be a risk factor for rapid disease progression; those who have osteoarthritis in one knee are at higher risk of developing it in the other knee if they are overweight. What is the role of weight loss in persons with early cartilaginous lesions of osteoarthritis. The mechanism by which obesity causes osteoarthritis is unknown. Although the increased force per unit area in the knee of obese patients is probably the cause of disease, there are other possibilities. The pathogenic pathway by which obesity causes osteoarthritis of the knee needs further study. Felson DT, Weight and Osteoarthritis, Am J Clin Nutr, 63(suppl):430S-432S,1996.

Further study is needed of the disability consequences of overweight in arthritis populations – does severe overweight causes or elevates disability for arthritis people? If so, at what BMI does it begin? Does losing weight alleviates it, or do disability and ensuing reduced activity cause weight gain? Verbrugge LM et al., Risk Factors for Disability Among US Adults with Arthritis, J Clin Epidemiol, 44(2):167-182, 1991.

Asthma

Further study is needed to determine whether exercise-induced bronchospasm leads to exercise avoidance and obesity or whether obesity causes or enhances bronchial hyperactivity to exercise, leading to an increased diagnosis of asthma in persons with obesity. Basic research is needed to understand the mechanisms responsible for the increased prevalence of obesity in children with asthma, with a particular emphasis on testing the hypothesis that the obesity is due to reduced physical activity and lowered total energy expenditure. This research may provide a basis for improved treatment for asthma in youth. Gennuso J et al., The Relationship between Asthma and Obesity in Urban Minority Children and Adolescents, Arch Pediatr Adolesc Med, 152:1197-1200;1998.

Further studies in overweight asthmatic children are needed, including the effect of weight loss on lung function and other markers of asthma severity. Luder E et al., Association of Being Overweight with Great Asthma Symptoms in Inner City Black and Hispanic Children, J Pedr, 132:699-703;1998.

The nature of the association between fatness and asthma has yet to be clarified and one cannot say whether obesity per se has contributed to the rise in asthma. Whilst further observational studies, particularly longitudinal, would be of interest, the definitive test of whether fatness causes asthma must come from controlled intervention studies. A first step, in view of recent findings in children, might be a trial in asthmatic individuals to examine the impact of weight reduction on severity of disease. It remains to be seen whether asthma will be added to the list of chronic diseases linked to obesity, but for the moment we need to keep an open mind. Is it possible that there is a direct mechanism linking fatness to asthma in adults? The stronger findings in women may be relevant. Estrogens have been implicated as a risk factor for adult asthma and might contribute in part to the higher prevalence of asthma and wheeze in women. Estrogenic effects on asthma might be enhanced in fatter women because obesity is associated with higher levels of bioavailable estrogen in premenopausal women. We need to identify other mechanisms to explain why fatness is also associated with asthma in young children and why fatness might be related independently to atopy. The lack of an association in boys in a study by Huang et al. may simply be because BMI is not an equivalent measure of fatness in boys and girls. It would be of interest to clarify whether a gender difference in the association is also present in younger children. How might the nature of the association between BMI and asthma in adults be clarified? It would be of interest to see whether BMI is associated with an objective measure of asthma such as bronchial hyperreactivity, and to determine whether dietary factors might account for such a link. Continued follow up of this or other cohorts may establish whether raised BMI, or an increase in BMI, predates the onset of asthma. However, such an association would be difficult to detect if the onset of asthma is close in time to an increase in BMI. An alternative approach, particularly in view of recent findings in children," would be to conduct a controlled trial of weight reduction in adults with asthma to examine the impact on the presence and severity of disease. Shaheen SO, Obesity and Asthma: Cause for Concern?, Clinical and Experimental Allergy, 29:291-293,1999.

Breast Cancer

Future research investigating the association between obesity and breast cancer in young women should attempt to account for differences seen in women aged less than 35 years as opposed to women aged 35 or greater. Peacock SL et al., Relation between Obesity and Breast Cancer in Young Women, Am J Epidemiology, 149:339-346;1999.

Bulimia/Binge Eating

There is an increasing body of evidence that obese binge eaters demonstrate more psychological and psychiatric vulnerability although, the causal direction remains unclear. Future studies should focus on understanding the development of the relationship between binge eating and weight cycling. In studies of the psychological effects of weight fluctuations among obese individuals, researchers should control for a history and current status of binge eating behavior and evaluate the independent effects of weight cycling and binge eating on psychological well-being. Use of clinical interviews, as well as self-ratings to clarify and confirm dieting history, psychological-psychiatric status, and presence or absence of Binge Eating Disorder (BED) would represent a significant methodological improvement. Venditti EM et al., Weight Cycling, Psychological Health, and Binge Eating in Obese Women, Journal of Consulting and Clinical Psychology, 64(2):400-405, 1996.

Focusing on particular subgroups of dieters, rather than on dieting in general, might be a successful strategy in preventing bulimia nervosa. If this strategy were adopted, knowledge of which dieters are at particular risk for the development of bulimia nervosa would be important because this would assist in the targeting of preventive interventions. Our findings suggest that bulimia nervosa is most likely to develop in dieters who are at risk of obesity and psychiatric disorder in general. There is a need for prospective studies of the onset of bulimia nervosa to illuminate the causal processes that are likely to be involved, because a shift in research emphasis is required away from risk factors and toward risk mechanisms. Prospective studies would also have the advantage of recruiting incident cases, whereas in our study the cases were well established. Fairburn CG et al., Risk Factors for Bulimia Nervosa, Arch Gen Psychiatry, 54:509-517, 1997.

Carpal Tunnel Syndrome (CTS)

There is growing literature relating obesity to CTS. Risk factors for CTS, such as age, gender, BMI, and exercise level are similar to the risks for cardiovascular and pulmonary disease. Diagnosis and prevention may, therefore, be fashioned along similar lines, such as increasing fitness through aerobic activity and decreasing weight. This would improve the health of the entire human body and should, logically, improve the health of the median nerve. Retrospective study designs that have been previously used cannot prove that this would necessarily be true. A long-term prospective study specifically measuring nerve conduction before and after weight changes would be helpful in this regard. In CTS, the initial electrical abnormality is a delay in the conduction of the median response across the carpal tunnel. Because the axons are spared the initial compression, there is no effect on the amplitude. As the neuropathy progresses, axonal involvement occurs and a reduced amplitude of the action potential is also recorded. It is also true in patients with obesity that difficulty in testing the nerves due to the patient's weight may lead to reduced amplitude. It would be interesting to determine what percentage of patients with CTS had reduced amplitudes who are not obese as compared to those who are obese. Stallings S et al., A Case-Control Study of Obesity as a Risk Factor for Carpal Tunnel Syndrome in a Population of 600 Patients Presenting for Independent Medical Examination, J Hand Surg, 22A:211-215, 1997.

If a causal relationship between obesity and a slowing of median conduction across the wrist exists, it may relate to increased fatty tissue within the carpal canal or to increased hydrostatic pressure throughout the carpal canal in obese individuals compared to normal or slender individuals. Magnetic resonance imaging has demonstrated increased fatty tissue in the carpal canal being associated with CTS in 1 patient, but there has not been a systematic study of the intracarpal canal anatomy in obese compared to slender individuals. Likewise, intracarpal canal pressures have been demonstrated to be higher in individuals with CTS, but the relationship between body size and intracarpal canal pressure has not been explored. Werner RA et al., The Relationship between Body Mass Index and the Diagnosis of Carpal Tunnel Syndrome, Muscle and Nerve, 17:632-636,1994.

Diabetes

“Most patients with Type 2 diabetes are significantly overweight, and diet-induced weight loss can provide marked improvement in their glycemic control. As conventional therapy combining diet and exercise usually has a poor long-term success rate, more aggressive weight reduction programs have been proposed for the treatment of severely obese diabetic patients, including very-low-calorie diets, antiobesity drugs and bariatric surgery. Very-low-calorie diets usually have a remarkable short-term effect, and energy restriction and weight reduction are positive factors for the glycemic control of obese diabetic subjects. However, the long-term efficacy of these methods remains doubtful since weight regain is a common phenomenon. Although anti-obesity {anorectic} drugs may help patients to follow a restricted diet and lose weight, their overall efficacy on body weight and glycemia is generally modest, and their long-term safety still questionable. Interestingly, serotoninergic anorectic agents have been shown to improve both the insulin sensitivity and glycemic control of obese diabetic patients independently of weight loss. Bariatric surgery may be helpful in well-selected patients. The correction of weight excess after successful gastroplasty fully reverses the abnormalities of insulin secretion, clearance and action on glucose metabolism present in markedly obese non-diabetic patients, and allows interruption or reduction of insulin therapy and antidiabetic oral agents in most obese diabetic patients. In conclusion, weight loss is a major goal in treating obese patients with Type 2 diabetes, and aggressive weight reduction programs may be used in selected patients refractory to conventional diet and drug treatment. However, long-term prospective studies are needed for more precise determination of the role of such a strategy in the overall management of obese diabetic patients.” Scheen AJ, Aggressive Weight Reduction Treatment in the Management of Type 2 Diabetes. Diabetes & Metabolism, 24:116-123, 1998.

Nonautoimmune forms of youth-onset diabetes are becoming increasingly prevalent as rates of obesity in children and adolescents accelerate. This trend is particularly pronounced in minority populations. Research directed to an understanding of the basic biology of insulin production in youth deserves high priority. The development of therapy for non-type 1 diabetes that is safe and acceptable to youth is also important. Most importantly, behavioral and dietary programs that are able to effect long-term change and prevent obesity need to be developed within the communities affected.” Rosenbloom AL et al., Emerging Epidemic of Type 2 Diabetes in Youth. Diabetes Care, 22:345-354;1999.

NIDDM subjects were found in one study to report less understanding of their disease than IDDM subjects. Further investigation of factors accounting for poor comprehension is essential to developing strategies leading to optimal management of NIDDM in youth, both short and long term. This is particularly critical because many of these youths already had hypertension, increasing their risk for diabetic nephropathy. Thus the need for successful treatment of NIDDM in youth is particularly critical given the possible onset of secondary complications from this disease at such early ages. Pihoker C et al., Non-Insulin Dependent Diabetes Mellitus in African-American Youth of Arkansas. Clin Pediatr, 37:97-102;1998.

Esophageal Cancer

There is mounting evidence that high body mass index is associated with increased adenocarcinoma risk, particularly of the esophagus. The growing prevalence of obesity that has been documented in a number of Westernized countries suggests that obesity and/or associated dietary patterns may account for part of the rising incidence of this disease. Additional studies should focus on the role of obesity to determine whether adenocarcinoma risk varies by the pattern of fat deposition and by patterns of weight over a lifetime. Intervention trials aimed at reducing weight among persons at high risk of esophageal adenocarcinoma, such as persons with Barrett's metaplasia are also indicated to establish its causal role and determine thc usefulness of dietary intervention in reducing rates of neoplastic progression to cancer. Vaughan TL et al, Obesity, Alcohol, and Tobacco as Risk Factors for Cancers of the Esophagus and Gastric Cardia: Adenocarcinoma versus Squamous Cell Carcinoma. Cancer, Epidemiology, Biomarkers and Prevention, 4:85-92,1995.

BMI has been found to be a strong risk factor for esophageal adenocarcinoma and a moderate risk factor for gastric cardia adenocarcinoma. “The elevated risks appear related mainly to excess weight per se and not to weight changes over time. In contrast, BMI was largely unrelated to esophageal squamous cell carcinoma and noncardia gastric adenocarcinoma. These findings suggest that the increasing prevalence of obesity in the population has contributed to the rising incidence trends for adenocarcinomas of the esophagus and gastric cardia. Further epidemiologic, clinical, and laboratory studies are needed to identify the mechanisms by which obesity increases the risk of these tumors.” Chow W et al., Body Mass Index and Risk of Adenocarcinomas of the Esophagus and Gastric Cardia. J Natl Cancer Inst, 90:150-155;1998.

Gallstones

The increased risk for gallstone formation associated with weight loss raises the possibility of learning more about the causes of gallstone disease as well as several clinical issues. Of great importance is the need to define the factors during weight loss that lead to gallstone formation. Indeed, the high risk for developing gallstones during a short period of weight loss provides the most assessable human model to date for the study of gallstone pathogenesis and prevention. The development of an animal model of weight loss associated with gallstone formation could also be instructive for human cholesterol gallstone disease and should be actively sought. Obese patients contemplating a weight-reducing diet, particularly a very low calorie diet, should be aware that they are at increased risk for developing symptomatic gallstones. The risk for developing gallstones needs to be defined for various diets composed of differing nutrient and caloric contents to evaluate whether diets with higher fat contents or more calories lessen the risk. Similarly, it could be determined if smaller, more frequent meals to decrease the fasting period would also lower the incidence of gallstones. Other risk factors for the occurrence of gallstones during voluntary weight loss should be defined. Preventive interventions might then be targeted toward persons who are at particularly high risk, such as hypertriglyceridemic patients with a BMI of more than 30 kg/m2 who lose substantial weight during the first few weeks of dieting. Unfortunately, not enough data are available to make such a recommendation. A study of the effects of low calorie diets on persons with preexisting gallstones is also needed. Such a study would address the issue of safety of such a diet as well as potentially help define the natural history of asymptomatic gallstones. Everhart JE, Contributions of Obesity and Weight Loss to Gallstone Disease, Ann Intern Med, 119:1029-1035,1993.

Immune Function

Research is needed to determine the clinical implications of alterations in various measures of immune function associated with obesity, and whether various interventions such as weight loss, exercise or nutrient supplementation can help ameliorate them. Nieman DC et al., Influence of Obesity on Immune Function, J Am Diet Assoc, 99:294-299,1999.

Obese patients may be at increased risk for perioperative infectious complications, particularly wound complications. Since these complications did not impact adversely on death rates, obese patients should be offered surgical treatment for their disease when surgery constitutes the most appropriate therapy. Further studies to more accurately determine the perioperative risk for complications associated with varying degrees of obesity are needed in order to improve outcome and contain costs. Choban PS et al., Increased Incidence of Nosocomial Infections in Obese Surgical Patients, The American Surgeon, 61:1001-1005, 1995.

Hypertension

“The mechanisms leading to hypertension in obese persons are not completely known. It is hypothesized that increased sympathetic nervous system activity, insulin resistance and hyperinsulinemia, sodium retention, and enhanced vascular reactivity are involved in the development of hypertension. Some investigators have reported a decrease in plasma renin activity and plasma aldosterone levels after weight loss; this suggests that the renin-angiotensin-aldosterone axis may play a role in causing hypertension in obese persons.” Further exploration is needed. Huang Z et al., Body Weight, Weight Change, and Risk for Hypertension in Women, Ann Int Med, 128(2):1081-1088;1998.

Low Back Pain (LBP)

The positive association between obesity and LBP is consistently present and, in particular, in those with LBP lasting >30 days. The association between obesity and LBP lasting >30 days is also monotonically increasing. The interpretation of these findings could be that excessive weight aggravates minor LBP of short duration, resulting in chronic or recurrent problems. It is also possible that obese people have a sedentary lifestyle that more easily leads to chronicity in simple LBP. This theory is supported by the finding that the previously mentioned positive gradient was found to emanate from men in jobs involving sitting and women in jobs involving mixed sitting, standing, and walking. In other words, if people are relatively sedentary at work, an additional obesity-related sedentary leisure-time lifestyle may become an extra obstacle to recovery from simple LBP. Further information is needed to reach a final conclusion. It would be interesting to know whether monozygotic twin pairs, dissimilar in BMI, have different rates of LBP >30 days or whether the difference disappears. Interactions between BMI, type of work, gender, and LBP of long duration should be further elucidated in monozygotic twins. It would be useful to know whether obesity precedes LBP. Leboeuf-Yde C et al., Low Back Pain and Lifestyle. Part II – Obesity, Spine, 24 (8):779-784, 1999.

The positive gradient found between relative weight and recurrent or chronic low back pain suggests that excessive weight contributes to something important hidden in the heterogeneous mass of low back pain. Epidemiologic research remains at a descriptive and hypothesis-generating level until low back pain can be differentiated into etiologically distinct groups. Thus, causal inference about the possible role of obesity in back disorders will hardly be within reach very soon. Ideally, a risk factor is defined in terms of incidence rather than prevalence. Longitudinal population studies are therefore needed. The anatomic distribution of excessive fat in relation to low back pain also remains to be studied, as does the possible role of muscularity or lean body mass. The unique opportunities of extensive twin registers are needed for further research, as the twin control method is a powerful tool to overcome confounding factors. Heliovaara M,Point of View, Spine, 24(8):783-784,1999

Mental Disorders

Eating disorders constitute an important component for research on obesity. In addition, other aspects of mental health, such as depression, anxiety, obsessive-compulsive disorder, familial relationships, parental use of food and the use of food for the allievation of stress are important aspects to inform efforts for prevention and intervention.

Pancreatitis

Obesity is an independent prognostic parameter, simple to measure, of the development of early complications (especially systemic) in acute pancreatitis, although a negative influence on mortality was not found. Obesity-associated diseases do not modify the effect of obesity on the occurrence of complications. It seems that adiposity in the trunk is the kind of obesity related to the worse clinical course of acute pancreatitis. Further studies, however, are needed to confirm this finding. Martinez J et al., Obesity: A Prognostic Factor of Severity in Acute Pancreatitis, Pancreas, 19(1):15-20, 1999.

Definition of a group of obese acute pancreatitis patients with increased risk for severity allows one to address further studies to evaluate different BMI strata or other anthropometric indices (such as waist/hip ratio) to determine the precise prognostic weight of obesity in AP, the possible mechanisms involved in its deterrent effect, and the possible therapeutic options. Barahona J et al., Obesity: A risk factor for Severe Acute Biliary and Alcoholic Pancreatitis, The American Journal of Gastroenterology, 93:1324-1328, 1998.

Obese men have a tendency for progression of stage B1-D1 prostate cancer although further studies are necessary to confirm this. Further research is needed to clarify whether obesity is related to the risk of prostate cancer, particularly with regard to hormonal analyses. Furuya Y et al., Smoking and Obesity in Relation to the Etiology and Disease Progression of Prostate Cancer In Japan. Int J Urol, 5:134-137;1998.

Various aspects of body size are related to the risk of prostate cancer. “Since anthropometric measurements reflect nutritional, hormonal, neuroendocrine, and other factors during various periods of life, much more research is needed to clarify precisely the mechanisms by which these factors may influence carcinogenic processes in the prostate. Anthropometric measures were found consistently more strongly associated with mortality than with incidence RRs of prostate cancer. If these quantitatively small differences hold up in future studies, one might speculate that measures of body size—or their determinants—play a role in the progression from latent to aggressive prostate cancer.” Anderson S et al., Body Size and Prostate Cancer: a 20-Year Follow-Up Study Among 135,006 Swedish Construction Workers. J Natl Cancer Inst, 89:385-389;1997.

Renal Cell Cancer

“Given the increasing prevalence of obesity and the rising incidence of renal cell cancer in the US, additional studies are needed to disentangle the effects of BMI from various correlates and to identify the mechanisms by which obesity affects risk.” Chow W, et al., Obesity and Risk of Renal Cell Cancer. Cancer, Epidemiology, Biomarkers and Prevention, 5:19-21,1996.

Smoking

According to Katherine Flegal and colleagues, perhaps 20% of the increase in overweight adults may be due to smoking cessation. According to Thomas Wadden, men typically gain 8 to 9 pounds and women 11 to 13 pounds when they quit smoking. Taubes G, As Obesity Rates Rise, Experts Struggle to Explain Why, Science, 280:1367-1368; May 29, 1998. Further research is needed to examine the relationship between weight gain and smoking cessation.

Spinal Cord Injury

The incidence of secondary complications in persons with SCI is extremely high. Only 4.4% of patients with chronic SCI were free of medical complications at the time of their routine physical examination. Three or more complications were present in 58% of the patients in this sample. Obesity, pain, spasticity, urinary infections, and pressure sores continue to be problematic for many people with SCI in spite of educational and medical interventions now available to them. Obesity and other secondary conditions provide an example of this kind of interrelationship. Further research is needed to clarify the relationships (eg., whether increased weight causes medical problems or medical problems cause increased weight or both). Anson CA and Shepherd C, Incidence of Secondary Complications in Spinal Cord Injury, International Journal of Rehabilitation Research, 19:55-66, 1996.

Trauma

Animal studies have shown adipose tissue blood flow is severely and irreversibly reduced in hemorrhagic shock. Whether adipose tissue effects are magnified in a patient whose fat depots are proportionally larger is unknown. The effects of nonperfused fat depots on long- term survival or the pulmonary effects of high levels of circulating free fatty acids in the hormonal milieu of obese trauma patients are unknown. These concerns certainly demand further investigation, since the factors leading to a poor outcome in these severely overweight patients are complex. Choban PS et al., Obesity and Increased Mortality in Blunt Trauma, The Journal of Trauma, 31(9):1253-1257;1991.

Urinary Stress Incontinence

Obesity is a potent risk factor for several urinary symptoms after pregnancy and delivery, and a substantial number of women still have problems 6 to 18 months postpartum. Obesity significantly increases the risk of transient and persistent stress incontinence as well as having a social or hygienic problem with the leakage. A possible prevention of persistent stress incontinence may be extended use of pelvic floor exercise during and after pregnancy. It seems reasonable to offer a course of pelvic floor exercise during pregnancy to obese women, but further investigation on this subject is necessary. Rasmussen KL, Obesity as a Predictor of Postpartum Urinary Symptoms, Acta Obstet Gynecol Scand, 76:359-362,1997.

Obese patients are often at risk for significant morbidity from operative procedures, and many operations involving the abdomen and pelvis are undoubtedly more difficult to perform. Morbidly obese women with stress urinary incontinence can undergo operations for this disorder with a good chance of success. Sling operations may be the procedure of choice for stress incontinence in morbidly obese women, however more research is needed on this procedure on morbidly obese women to confirm this. Cummings JM et al., Surgical Correction of Stress Incontinence in Morbidly Obese Women, J Urology, 160:754-755,1998.

G. Treatment Outcomes Research

Obesity is a life-long chronic disease. Currently there are a variety of treatment options available to adults. These include bariatric surgery, pharmacological compounds, medical programs, commercial programs, dietary supplements, self help programs and dietary changes and physical activity. Some of these are well researched and others are not. Over a quarter of Americans report engaging in efforts to lose or maintain weight at any given time. Little research is available comparing treatment approaches. NIH should support ongoing treatment outcome studies utilizing multiple treatments in diverse populations to better inform providers and the public as to useful treatment approaches.

H. Prevention

As the National Task Force on Prevention and Treatment of Obesity stated in 1994, “Major efforts need to be placed on development of pilot projects to demonstrate the feasibility of obesity prevention in susceptible individuals and groups. As more predictors become available, strategies can be targeted more precisely and refined appropriately. Prevention strategies that need to be investigated include: increased physical activity and exercise; effectiveness of low-fat diet combined with increased physical activity; effects of obesity drugs in reducing risk factors of obesity and preventing long-term complication, especially n combination with other interventions; effectiveness of behavior interventions in primary prevention; combinations of the above and new approaches. Towards Prevention of Obesity: Research Directions, Obesity Research Nov. 1994; 2:6:571-584.

Long-term studies with different populations, different ages are needed in various levels of prevention including primary prevention - to prevent obesity before it can occur by screening patients to identify those at risk, secondary prevention - which includes intervention after obesity develops, but before complications occur and tertiary prevention - after complications develop, to prevent the development of end-stage complications from obesity.

Research is needed to determine the primary care provider's role in all aspects of prevention of obesity.

A.Intervention

Without question, new interventions must be developed else we face hundred of thousand more deaths and morbidity from obesity. NIDDK needs to develop an aggressive program to enhance interventions in the treatment of obesity in terms of diet, physical activity, behavioral therapy, pharmacology and surgery.

Media reports would indicate that the pharmaceutical industry is so heavily invested in this area that the commitment of additional resources from NIH in the form of a program for improved interventions is not needed. Such an assumption may be premature. First, increasingly third-party reimbursement for pharmaceuticals is an important part of the financial equation made by pharmaceutical companies when deciding whether or not to invest the resources to develop a compound. Anti-obesity agents are uniformly excluded from coverage by Medicare, Medicaid and the great majority of private insurance programs. Second, the disappointing history of drugs in this area and the enormous attention by the media and public can actually deter some companies from entering such an area and risking litigation costs and damages from the approved or un-approved uses of a new drug. Third, the market for anti-obesity agents may be less strong than many believe. The two drugs approved by the Food and Drug Administration since the withdrawal of fenfluramine and dexfenfluramine have had only modest success. Fourth, any forseable compound to be effective must still be used in a comprehensive program with food intake control and physical activity. Those components, along with behavorial therapy and surgical intervention are greatly in need of additional research to improve their effectiveness. Fifth, since body weight regulation is a complex physiological process using multiple systems, an effective agent must affect several systems or, more likely, be used in combination with other products. A drug working on multiple systems would be extraordinarily complex. A drug working best in combination therapies will require extensive, complex and costly clinical trials to obtain approval of the Food and Drug Administration. Finally, to be most effective, an anti-obesity agent should be introduced as early as possible in order to avoid or postpone significant weight gain. This means developing products for use with children and adolescents. This is a very difficult population to study, much less to utilize in clinical trials. Such usage would be controversial and governmental support through the NIH would be critical.

“Complementary investigations at the pharmacological, physiologic, and behavioral levels will be critical to the evaluation of all new anti-obesity drugs. The most effective pharmacological treatments are likely to be those that involve the use of a combination of drugs, each with a distinct mechanism of action, or a single drug with multiple activities. Obesity is a chronic disease, and the possibility of long-term treatment - either continuous or intermittent treatment throughout adult life—is a concept that is receiving more attention. In this context, the risk-benefit and quality-of-life analyses of pharmacological treatment become increasingly important. Vigorous dialog between health care professionals, patients, the research community, and regulatory authorities is needed to define, in objective and quantifiable terms, the minimum efficacy required to justify long-term treatment. Safety considerations are critical. For example, because women make up the largest group seeking treatment for obesity, potential drugs must be tested in long-term studies for possible undesired effects on reproductive function and hormonal status. Innovative drugs will be most effective when they are used as adjuncts to, rather than substitutes for, lifestyle changes to improve the metabolic fitness, health, and quality of life for obese individuals. Such drugs will likely be part of sequential or combined treatment programs tailored to individual patients.” Campfield LA, Strategies and Potential Molecular Targets for Obesity Treatment, Science, 280:1383-1387; May 29, 1998.

NIDDK needs to implement an aggressive program for the development of improved behavioral, pharmacological and surgical treatment of obesity.

J. Discrimination, Stigma and Legal Research

The best research in the world is not of much value if its fruits are not available for the population for whom it is intended. For many, obesity is still a matter of moral judgment and blame rather than compassion and caring. The health care establishment is not immune to negative views of persons with obesity. The health care field denies insurance coverage for obesity treatment and, according to personal reports, too often fails to provide equipment suitable for persons with obesity or some services, especially preventive health care services. Many persons with obesity report poor communication with their health care provider and in too many instances condescending or hostile comments on the patient's weight. In society, obesity persons are discriminated against in education and employment. Both education levels and income are definitive factors in the health of individuals. NIDDK needs to create a program which will stimulate research on stigma and discrimination against persons with obesity. Further such a program should investigate whether current legal processes, such as the Americans with Disabilities Act, the Equal Employment Opportunities Act and others fairly protect persons with obesity. Precendent for such research exists with the National Insitute of Mental Health, the National Institute on Alcoholism and Alcohol Abuse and the National Institute of Drug Abuse which have recocnized stigma and discrimination as important impediments in the amelioration of health issues under their jurisdiction.

K. Disability Research

Persons with severe obesity frequently have musculekotal or respiratory problems which preclude their usual employment. This may necessitate retraining or qualify the individual for disability income support. Currently, the Social Security Administration pays out approximately $77 million a month for individuals who have qualified for disability due to severe obesity ( approximately a BMI>45 and comorbid conditions.) Research is needed to identify what level of obesity and what co-morbid conditions put the individual at risk of losing the ability to engage in significant gainful employment. Strategies need to be developed to maximize the abilities of persons with severe obesity to engage in productive employment.

“Further research should investigate the role of occupational differences more thoroughly, in particular, the extent to which occupational differences associated with obesity result from discrimination in hiring, promotion or job assignment.” Averett S and Korenman S, Black-White Differences in Social and Economic Consequences of Obesity, Int J Obesity, 23:166-173;1999.

Researchers rarely study people who are stigmatized. In much of the research on confirmation of expectations arising from stereotypes, the targets of the stereotyped expectations were not actually stigmatized people. Rather, they were college students who were randomly assigned to be labeled as members of a stigmatized group. This procedure is ideal for experimental control, but it might miss some important skills and strategies that people who are actually stigmatized have learned or developed to cope with negative expectations. Miller CT, Compensating for Stigma: Obese and Nonobese Women's Reactions to Being Visible, Personality and Social Psychology Bulletin, 21(10): 1093-1106, 1995.

L. International Obesity Epidemic

As the World Health Organization has recognized, obesity is an international epidemic, perhaps second only to smoking, in its impact on public health. The extent of the spread of obesity is of grave concern, especially when it is seen as following the introduction of a Western lifestyle into populations with previously small levels of obesity. The strain which growing rates of obesity and its co-morbid conditions will make on many already fragile health care systems is difficult to grasp.

The process by which Westen lifestyles are introduced into a country may involve efforts by the United States Government to open markets to US agricultural producers, food manufacturers, entertainment and computer industries. NIDDK should embark on a program of epidemiological research to track the development around the world, cooperating with the World Health Organization, the International Obesity Task Force and others to develop methods to prevent the introduction or increase of obesity globally and to learn what specific genetic, dietetic, physical activity or environmental factors affect the progression of obesity in diverse populations.

A.Training

Enhanced training efforts are essential to progress in obesity research.

Interdisciplinary research needs to be fostered among basic researchers and behavioral scientists. In particular the introduction of new technologies, whether in genetics or neurobiology or behavior needs to be accelerated.

Respectfully submitted,
Morgan Downey
Executive Director