Obesity - American Council on Science and Health€¦ · 04/03/2009 · on weight-loss treatments (BW 2008), ranging from prescription drugs to diet programs and nutritional supplements.

AND NEW PHARMACEUTICAL APPROACHES

Obesity

American Council on Science and Health

OBESITY AND NEW PHARMACEUTICAL APPROACHES

by Steven Marks

for the American Council on Science and Health

Ruth Kava, Ph.D., R.D.Project Coordinator and Editor

February 2009

AMERICAN COUNCIL ON SCIENCE AND HEALTH1995 Broadway, 2nd Floor, New York, NY 10023-5860

Phone: (212) 362-7044 • Fax: (212) 362-4919acsh.org •HealthFactsAndFears.com

E-mail: [email protected]

Nigel Bark, M.D.Albert Einstein College of Medicine

Thomas G. Baumgartner, Pharm.D., M.Ed., FASHP,BCNSPUniversity of Florida, Gainesville

George A. Bray, M.D.Pennington Biomedical Research Center

Joseph F. Borzelleca, Ph.D.Medical College of Virginia

Jack C. Fisher, M.D.University of California, San Diego

Donald A. Henderson, M.D., M.P.H.University of Pittsburgh Medical Center

Ruth Kava, Ph.D., R.D.American Council on Science and Health

Kathryn Kolasa, Ph.D., R.D., LD/NEast Carolina University

Gilbert L. Ross, M.D.American Council on Science and Health

Thomas P. Stossel, M.D.Harvard Medical School

Elizabeth M. Whelan, Sc.D., M.P.H.American Council on Science and Health

ACSH accepts unrestricted grants on the condition that it is solely respon-sible for the conduct of its research and the dissemination of its work to thepublic. The organization does not perform proprietary research, nor does itaccept support from individual corporations for specific research projects.All contributions to ACSH—a publicly funded organization under Section501(c)(3) of the Internal Revenue Code—are tax deductible.

Copyright © 2009 by American Council on Science and Health, Inc.This book may not be reproduced in whole or in part, by mimeograph or anyother means, without permission.

T H E F O L L O W I N G P E O P L E R E V I E W E D T H I S P U B L I C A T I O N .

CHAPTER 1Executive Summary

CHAPTER 2Introduction

CHAPTER 3What’s Under the Hood: How the Body Regulates theBalance Between Food Intake and Energy Expenditure

CHAPTER 4Current Treatments: How Effective Are They?

CHAPTER 5New Approaches: Putting the Central and PeripheralMechanisms to Work

CHAPTER 6Central Targets: The Role of the Hypothalamus

a. The Serotonin System: A Safer Redux?b. Gut Hormones: Ensuring Fuel for the Short Trip

CHAPTER 7Peripheral Mechanisms: Energy Expenditure

a. Metabolismb. Fat Storage

CHAPTER 8Toward the Future

CHAPTER 9Conclusion

ACKNOWLEDGMENTS

REFERENCES

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CHAPTER PG

C O N T E N T

Dietary and behavioral changes offer only limitedhelp; although some people benefit from anti-obesity drugs, expectations are often unrealistic.

The effectiveness of current treatments is limited;for the morbidly obese, surgery is the most effectiveoption, although it is not risk-free.

Efforts to foster weight loss are countered by thebody’s inherent need to preserve weight.

Considerable progress has been made in identifying new means of treating obesity, particularly those that suppress appetite or restrictfat absorption.

The extremely complexity of the body’s energy system means that altering one part affects others,as well as other biological systems.

The development of new drugs should focus onhelping patients eat less and better utilize what they eat; thus far, drugs that stimulate the use of existing fat stores are in the early stages ofdevelopment.

Pharmaceutical agents will not solve the obesityproblem by themselves; lifestyle adjustments willlikely always be necessary.

For the immediate future, the most effective treatment is likely to be a combination of drug andbehavioral therapy, along with changes in diet, rest,and exercise.

Obesity and New Pharmaceutical Approches / Chapter 1 / 1

C H A P T E R

Executive Summary

Obesity is a growing problem worldwide, with serious health and quality- of-life implications.

One of the parents is overweight and the other is obese,wrote the Harvard Medical School professor and directorof the Optimal Weight for Life Clinic (Ludwig 2007). Allfive of the children are even more severely obese, andalthough they are still young, they already face theprospect of lives limited by chronic medical problems. One of the youngsters shows the first signs offatty liver, while another has high blood pressure. Threehave marked insulin resistance, the first sign of type-2diabetes; four have abnormal cholesterol profiles, andtwo complain of orthopedic problems. The children allexpress serious emotional distress, stemming from theirobesity. Were the G family unusual, their health problemscould be written off as medical curiosities. Unfortunately,families like that of Mr. and Mrs. G and their children arebecoming all too common in industrialized nations aroundthe world.

Today, about 66% of all Americans are overweight orobese (Ogden 2006). Researchers from the Centers forDisease Control and Prevention (CDC) report that since1970, the number of overweight children and adolescentsbetween the ages of 6 and 19 years has tripled, meaningthat more than 9 million young Americans (or nearly one-in-five) are at risk for a wide range of obesity-relatedproblems, including diabetes, hypertension, high choles-terol, coronary artery disease, respiratory problems,sleep apnea, gallbladder disease, osteoarthritis, and sev-

eral forms of cancer (Cooke 2006). These trends suggestthat the current generation of Americans may be the firstin the past 200 yeas to have a shorter life expectancy than their parents had,according to physicians at the University of IllinoisMedical Center in Chicago (Olshansky 2005). This ishardly the definition of progress.

In addition to the health consequences, obesity alsoentails substantial economic and social costs. An obeseworker costs his employer an estimated $2,500 per year in added medical expenses and lost productivity,according to studies from RTI International and the CDC.Overall, business and industry pay a hefty price for obesity:$13 billion a year, estimates the Washington, DC-based National Business Group on Health, a healthpolicy group comprising the nation’s largest corporations(Harper 2007).

Obese people themselves are often stigmatized.Documented cases of discrimination extend to employment, education, and healthcare. There have alsobeen suggestions of bias in adoption proceedings, juryselection, housing, and other areas of public life, according to Yale University investigators (Puhl 2001).

Obesity is now the nation’s second-biggest public healthproblem, right after smoking. Although lifestyle changes,


C H A P T E R

Introduction

The endocrinologist David Ludwig calls his patients, the seven-member G family, “a microcosm of 21st-century America.”

2

most notably dietary adjustments and increased physical activity, can help people lose weight and staveoff obesity, many find it difficult to comply with suchweight-loss regimens. Shedding surplus pounds is frequently a struggle, but for many people, it's a battlethey are genetically programmed to lose. (Later on, we’lllearn just why this is so.) For this reason, a great deal ofinterest – and hope – rests on the potential effectivenessof pharmaceutical therapies for obesity.

Americans currently spend more than $33 billion a yearon weight-loss treatments (BW 2008), ranging from prescription drugs to diet programs and nutritional supplements. Not all such treatments are credible (see“Buyer Beware” sidebar in Chapter 4), and the results canbe disappointing for even those treatments that havevalue. Nonetheless, the pharmaceutical industry hasinvested enormous capital in the search for effective andsafe weight-loss drugs that target the body’s intricateenergy-regulation mechanisms. The research and development continues today.


It can be determined using a variety of means, including underwater weighing, CT scans, and bioelectric impedance analysis, an exam in which a low-voltageelectric current is used to determine lean body mass – themore fat a body has, the more resistant it is to the current.Many of these tests are not easy to perform, and somerequire sophistcated technology. To overcome these limitations, the U.S. Government in the late 1990sbeganto use a simpler, actuarial-based measure of obesity, the“Body Mass Index” (BMI). BMI is the ratio of weight toheight (kg/m2, or pounds/in2) (Table 1). People are saidto be overweight if they have a BMI between 25 and 29.9 kg/m2; those with a BMI above 30.0 kg/m2 are considered obese. That would be a weight of 175 poundsfor a 5 foot 4 inch person.

Several caveats are in order when interpreting BMI. The index is an initial warning that an individual might becarrying excess body fat. It is most accurate for peoplewho are generally inactive; for these people, a high BMI is a warning to look more closely for signs of obesity-related diseases. For example, a sedentary individual with a BMI of 31 might want to measure the circumference of his waist to determine if he has excessabdominal fat, a condition associated with an increasedrisk of metabolic syndrome, diabetes, and cardiovasculardisease. Tests of blood glucose (for incipient diabetes)and lipids (for coronary artery disease) also might beordered. On the other hand, a BMI of 31 in a body builder,tennis player, or other well-trained athlete would not because for concern. Excessive body fat is not an issue for

people who have increased muscle mass. In other words, BMI is helpful to identify those at risk for seriousobesity-related diseases, although its utility as anindicator of health status and risk is limited. (For more onthe use of BMI, see, “Are Our Athletes Really Fat?” atwww.acsh.org/factsfears/ newsID.517/news_detail.asp.)

Perhaps a more useful way to consider the problem ofexcessive fat is to examine the physiology of weight gain.In this regard, obesity is the end result of a long-termimbalance between the amount of energy, or calories, weconsume and the amount we use. Eat or drink too muchor get too little exercise and the result is the same – an expanding waistline. However, the two sides of theequation are not quite equal; in fact, many obesity expertsnow focus their attention on the “energy out” component.Whereas the consumption of high-calorie foods and beverages was once believed to be the primary cause ofobesity, the lack of exercise is now understood to be atleast as important. As the Harvard cell biologist BruceSpiegelman says, “The precise contribution of overeatingto obesity is unclear. Studying diet in obese patients


C H A P T E R

What’s Under the Hood?How the Body Regulates the Balance Between Food Intake and Energy Expenditure

What is obesity, biologically speaking? Simply put, obesity is an excessiveaccumulation of body fat.

3

Obesity is the end result of a long-term

imbalance between the amount of energy,

or calories, we consume and the amount

we use. Eat or drink too much or get too

little exercise and the result is the same –

an expanding waistline.


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is confounded by the fact that these patients tend tounder-report their food intake by as much as 30%.Overeating can be gauged only in relation to that individual’s energy expenditure (Spiegelman 2007).” Thisobservation means that people who follow a regular exercise regime and do not overeat routinely tend tomaintain their weight. However, even small changes indiet or in the amount of physical activity can affect body weight when the changes extend over a long periodof time.

Under normal conditions, the body’s energy balance is strictly regulated and controlled. Consider that mostpeople consume about 700,000 calories each year; evenso, body weight usually does not vary by more than 1kilogram up or down – about 7,000 calories (3,500 calories = 1 pound). This means the body is able to maintain its fat stores to an accuracy of 99% (Hofbauer2007). The bad news for those trying to lose weight is thatfewer than 20 excess calories a day over the course of ayear will put on 1 pound of fat.

“That the body can regulate such a small amount ofovereating – one cannot measure 20 calories accurately– is a sign of how finely balanced is our energy maintenance system,” said Randy G. Seeley, Ph.D.,associate director of the Obesity Research Center at theUniversity of Cincinnati, in a telephone interview.Evolutionary pressures, which required prehistoric man tomaintain his energy reserves in the face of a harsh environment and limited food supplies, predispose ourbodies to prevent weight loss more strongly than weightgain. Our energy regulatory system contains many redundant mechanisms to keep us from starving.“Ourbodies were not designed to restrict our intake of food butto help us survive,” Dr. Seeley added. Although cavemenstruggled to find food and constantly teetered on the edge


Figure 1. Nerve signals from adipose tissue and gastrointestinal organs such as the stomach and intestines influence appetite and

satiation (feelings of fullness) via central and peripheral mechanisms. All of these signals are integrated in the hypothalamus. Fat-cell

signals are primarily responsible for the long-term regulation of hunger, while messages from the organs such as the stomach and

intestines control immediate energy needs and satiety. Adapted from Hofbauer KG, Nicholson JR, and Boss O.

Although cavemen struggled to find

food and constantly teetered on the edge

of starvation, contemporary Americans

eat – and overeat – for many reasons

other than hunger. Humans eat for

social purposes and to relieve stress and

sometimes for no other reason than that

they can. People find it hard to pass by the

local convenience store if they feel like

enjoying a burrito and fries, and the energy

regulatory system is happy to oblige.

of starvation, contemporary Americans eat – and overeat– for many reasons other than hunger. Humans eat forsocial purposes and to relieve stress and sometimes forno other reason than that they can. People find it hard to pass by the local convenience store if they feel like enjoying a burrito and fries, and the energy regulatory system is happy to oblige. In other words, getting fat is easy for most people, but losing weight canbe a major struggle.

The relationship between energy intake (i.e., food consumption), energy expenditure (i.e., body functions,such as heart beat and breathing, and physical activity),and weight is often expressed as “calories in” versus“calories out.” Too many calories consumed and too fewcalories burned off can lead to overweight, and in time,obesity. This simple equation explains why understandingthe connection between energy intake and expenditure isso important. The balance between the two is regulatedby a host of complex biological processes that involve two basic types of mechanisms – the “central” and“peripheral.” Central mechanisms include neuronal systems in the brain that monitor caloric intake and useand respond to signals from the body that contain information about energy stores and availability, much asa warehouse manager keeps track of inventory.Peripheral mechanisms include hormonal signals fromthe gastrointestinal tract, as well as from fat cells to suchorgans as the liver and pancreas, skeletal muscle, andeven disease-fighting immune cells that carry out variousmetabolic (biochemical) functions important to energy

regulation (Hofbauer 2007) (see Figure 1). These are theorders the warehouse must fill, sometimes immediatelyand other times later in the day.

Here is how the two mechanisms work. First, feelings ofhunger cause one to fix a sandwich or grab an apple.Eating triggers the process of digestion, and then signalsemanating from the stomach tell the brain you are satisfied and have had enough to eat. The brain gathersthis information, along with other neuronal and hormonaldata relating to the body’s overall energy status, to produce a coordinated response to the change in the nutritional state. In this respect, the role of the hypothalamus, the part of the brain that regulates homeostasis (stability), is critical, says Richard Palmiter,Ph.D., professor of biochemistry at the University ofWashington and an obesity investigator at the HowardHughes Medical Institute (personal communication).Ongoing obesity drug research has targeted both centraland peripheral mechanisms in the search for safe andeffective treatments (Table 2). This research investigatesstrategies to reduce food intake by altering appetite, feelings of satiety (i.e., fullness or satisfaction), and fat absorption, and to elevate energy expenditure byboosting metabolism.


AREAS OF INVESTIGATIONAREAS OF

CURRENT RESEARCHDRUGS NOW IN USE

Central (appetite, satiation, metabolism)

LeptinMelanocortin systemSerotonin system

LoracaserinMelanin-concentrating hormoneCannabinoid receptors

Zimulti*Gut hormones

Peptide YYCholecystokininGhrelinSynthetic GLP-1

MeridiaSympatomimetics

PhenterminePhendimetrazieBenzphetamine

Glucophage and Sandostatin†

Peripheral (metabolism, energyuse, fatnstorage)

Uncoupling proteinsAdipokines

Adiponectin

XenicalAlli (OTC)

* Currently in final clinical studies prior to FDA review

† Used for treatment of adolescent obesity, although not approved for that indication

Centrally acting Meridia blocks the action of several important chemicals involved mainly in promoting hunger and, to a lesserdegree, food intake. In the clinical trials of Meridia, patients lost about3% to 4% of their body weight, most of which occurred during the firstsix months of treatment. Continued use of the drug helped maintainthe weight loss. Patients also experienced reductions in triglyceridelevels and increases in good (HDL) cholesterol, which could help prevent the development of metabolic syndrome, diabetes, and heartdisease. However, this benefit was counterbalanced by a slightincrease in blood pressure and heart rate. As a result, for patients withhypertension or who have had an excessively rapid heart beat in thepast, the use of Meridia may require regular monitoring. The drug didnot affect bad (LDL) cholesterol.

In contrast, Xenical and Alli work on the gastrointestinal system,where they prevent the absorption of fat. People using these drugslose about the same amount of weight as those taking Meridia.Ongoing treatment also appears to keep the weight off. Unfortunately,Xenical and Alli may have some socially disturbing side effects thatstem from their special mechanism of action: the fat that is notabsorbed remains in the gut, where it can contribute to flatulence andthe need for frequent bowel movements, which can be difficult to control. These gastrointestinal difficulties usually occur at the beginning of treatment and tend to diminish over time, especiallywhen fat intake is reduced.

A fourth drug, Zimulti/Accomplia (rimonabant), is in late clinical development and should also be noted. Researchers were promptedto study the effects of Zimulti and sister drugs on appetite suppressionbecause cannabis (the active ingredient in marijuana) has long beenknown to promote feelings of hunger, the so-called “munchies.” This


C H A P T E R

Current Treatments: How Effective Are They?

The Food and Drug Administration (FDA) has approved three drugs for thelong-term treatment of obesity, Meridia (sibutramine), Xenical (orlistat), andAlli, an over-the-counter (OTC) version of Xenica. Each primarily addressesone of the two mechanisms described above.

4

The shelves of grocery stores and pharmacies are

stocked floor to ceiling with various and sundry

dietary aids, including vitamins, minerals, herbs

and botanicals, and other substances such

as enzymes, amino acids, glandulars, and

metabolites. Some carry the labels “natural” and

“clinically proven.” Others guarantee dramatic

weight-loss results. Don’t believe a word of it.

Snake oil is still snake oil, even when wrapped in

fancy packaging.

Alli is the only FDA-approved, over-the-counter

treatment for obesity. This means its prescription

version, Xenical, has met rigorous standards for

safety and effectiveness. The difference between

Alli and Xenical relates to dose – Alli is half as

potent (60 mg) as Xenical (120 mg) and therefore

deemed safe for consumer use without a doctor’s

order. In contrast, other weight-reducing aids have

not undergone human clinical testing. Under

current law, these products are categorized as

“dietary supplements” (i.e., foods); as such, they

can be sold without proof of efficacy. Dietary

supplements can be also harmful. The active

ingredients may interact with common prescription

medications or analgesics such as Tylenol or

aspirin, raising the risk of a serious side effect.

Even sorbitol, the sweetener used in sugarless

gum, can cause severe diarrhea and bowel

problems if over-consumed (Bauditz 2008).

(Before taking any dietary supplement, review the

ingredients with a doctor or pharmacist.) The

bottom-line on miracle weight-loss pills: if the

claim sounds too good to be true, it probably is.

BUYER BEWARE

drug blocks a class of receptors in the brain that respondto cannabis (cannabinoid receptors), which, in theory,should reduce the desire to overeat. In clinical trials,weight loss achieved with Zimulti had positive effects ona number of risk factors for heart disease, including cholesterol and triglyceride levels and insulin resistance.Blood pressure was not affected, which was surprising inlight of the fact that patients taking Zimulti also lost about3% to 5% of their weight and therefore should have expe-rienced a reduction in blood pressure. Nearly 20

countries around the world have approved this medication for use. However, in 2007, the FDA rejectedZimulti because of the risk of psychiatric side effects,including depression, anxiety, and loss of sleep. Themanufacturer plans to conduct additional studies andthen resubmit Zimulti for approval.

In addition to Meridia, Xenical, and Alli, which aredesigned and approved for chronic therapy, the FDA alsohas approved several other drugs for short-term use.Phentermine, phendimetrazine, and benzphetamine allbelong to a drug class known as sympathomimetics.These medications act as appetite suppressants by mimicking the hormones adrenaline or noradrenaline.The sympathomimetics commonly prescribed for thetreatment of obesity can serve as helpful adjuncts to aregimen of diet and exercise. Because these drugs canbe habit-forming and may cause serious side effects,including high blood pressure, agitation, depression, andeven psychoses, physicians limit their use to two to threeweeks. (See “The Serotonin System: A Safer Redux” section in Chapter 6.) The sympathomimetics are not recommended for children and adolescents because ofthe potential for abuse and adverse events.

Current obesity drugs offer only modest benefits.Moreover, combining Xenical and Meridia does not havean additive effect – the weight loss remains the same.The lack of robust results puts patients and physicians ina quandary. Patients are often disappointed to discoverthat the drugs will help them lose only about 3% to 4% of their body weight. A 1997 study examined patientexpectations for obesity drugs and produced startlingresults. Obese patients indicated that they hoped to losefrom 31% to 38% of their weight. Twenty-five percent wasdeemed acceptable, and 17% was rated as disappointing(Foster 1997). These findings suggest that obesity doctors may have a difficult time managing their patients’expectations for drug therapy.

“It’s true that it has been difficult to develop scientificallyrational treatments that produce the kind of weight lossthat people want,” says Dr. Seeley. “As things now stand,our treatments aren’t even effective enough to be disappointing!” More important, maintaining even themodest reduction in weight requires life-long treatment.“There is a common misconception that any effectiveobesity drug can be used for a limited time – until thedesired weight loss is achieved – and then stopped,” saysRudolph Leibel, MD, professor of molecular genetics atColumbia University and co-director of the Naomi BerrieDiabetes Center, in an interview. “In this respect, treatingobesity is no different from treating hypertension or highcholesterol. Any successful drug or combination of drugswill probably have to be taken indefinitely.” The hope isthat, in the future, doctors will have a wider range of drugtherapies that they will be able to use selectively on thepatients best able to benefit from them. That remains the objective of current pharmaceutical research anddevelopment.


Current obesity drugs offer only modest

benefits. Moreover, combining Xenical

and Meridia does not have an additive

effect – the weight loss remains the same.

The lack of robust results puts patients

and physicians in a quandary. Patients are

often disappointed to discover that the

drugs will help them lose only about 3%

to 4% of their body weight.

The available therapies only address those mechanisms that fine-tune the energy balance. As one investigator commented, “Thereare lots of new targets under evaluation, and we hope that some ofthem may turn out to be much more effective than the current drugs.We may not have found the right targets yet, but we’re still looking.”


C H A P T E R

New Approaches: Putting the Central and Peripheral Mechanisms to Use

One possible reason for the marginal utility of current drugs, some pharmaceutical researchers believe, is that the body’s most important regulators of weight remain to be characterized.

5

At present, the most dramatic obesity treatment

is surgery. Many severely obese patients who

undergo bariatic surgery (gastric bypass), for

instance, maintain a significant weight loss of 45 to

60 pounds or more for periods of at least a

decade. However, surgery is highly invasive and

not without risks; as Dr. Randy Seeley of the

University of Cincinnati pointed out, high rates

of rehospitalizations and post-operative

complications can be associated with these

procedures. For this reason, techniques such as

gastric bypass or banding usually are reserved for

the most serious cases – people with a BMI >40 or

with a lower score and other coexisting health

problems such as heart disease or diabetes.

Interestingly, scientists from University College in

London recently identified two proteins – P2Y1

and P2Y11 – that control relaxation of the gut

(BBC News 2008). By blocking the P2Y11

receptor, which directs slow relaxation, a drug

could theoretically help control stomach volume in

a manner not unlike gastric banding. Much

research will need to be carried out before this

provocative concept can be proven, but if

successful, it could prove to be a way to achieve

to the benefits of these surgical interventions

without incurring the risks.

BARIATRIC SURGERYA WAY TO BYPASS GASTRIC BYPASS?

Hormones are signaling agents produced by various tissues in the body. Scientists discovered that leptin isreleased from fat cells to inform the brain about the stateof the body’s energy supply. We now know that leptin circulates in the blood to the hypothalamus, providinginformation about the number and size of adipose (fat)cells in the body – the greater the amount of body fat, themore leptin a person produces, the greater the amount ofbody fat. In theory, administration of leptin to obese people would signal the brain that fat stores were abundant, thereby reducing food intake. However, earlystudies using a genetically engineered form of the hormone proved to be disappointing: daily injections ofleptin helped only a small percentage of obese subjectslose weight. This finding led researchers to hypothesizethat many patients are resistant to leptin. At present, obe-sity researchers are investigating techniques to overcome this resistance.

Other hormones that signal the hypothalamus and mayprove useful in the regulation of food intake and energyexpenditure include those in the melanocortin system.The central melanocortin system is arguably the mostimportant neuronal pathway involved in the regulation ofenergy homeostasis; it also is active in a wide array ofother processes, including erectile function, blood pressure, and steroid production. Although obesityresearch on melanocortin pharmaceuticals continues,progress has been stymied by the fact that the thesedrugs also produce undesirable effects on the other biological activities, altering blood pressure and causing

unwanted erections, for example. In addition, there areseveral different kinds of melanocortin receptors, two ofwhich are abundant in the brain, and it is not entirely clearwhat the role of each one is. Thus, it is not yet knownwhether it will be possible to target melanocortin receptors in a way that reduces food intake without causing cardiovascular or sexual side effects. Various approaches to solve this problem are now being explored.

The Serotonin System: A Safer Redux?

Another central mechanism currently under investigationinvolves the serotonin system. This neurotransmitterhelps control appetite – when serotonin levels are low,people feel hungry. Preventing the re-uptake of serotoninin the brain – keeping levels high, in other words – is themeans by which such antidepressants as Paxil andProzac work, and this approach also may help controlweight. The first such serotonin re-uptake blocker, fenfluramine, was used along with the appetite suppressant phentermine in the mid-1990s as a popularanti-obesity regimen. Early in 1996, the FDA approved anupdated version of fenfluramine known as Redux, and it, too, was combined with phentermine. Eighteen months later, both serotonin drugs were suddenly withdrawn from the market following reports of heartvalve problems. Despite this setback, the concept of altering serotonin levels to dampen appetite remains valid. A new product, lorcaserin, which targets a different receptor in the serotonin system than Redux,


C H A P T E R

Central Targets: The Role of the Hypothalamus

As noted above, the hypothalamus serves as the central caretaker of energyhomeostasis. Our understanding of the myriad pathways involved in thisprocess took a giant leap forward in 1994 when a hormone called leptin wasidentified.

6

is now undergoing clinical trials, as is tesofensine, a compound that inhibits serotonin, noradrenaline, and dopamine.

In addition to the serotonin system, another central mechanism that could help lower appetite involvesmelanin-concentrating hormone (MCH). This hormone isproduced by neurons in the hypothalamus and acts onspecific receptors in the brain that control our desire forfood. Several different MCH drugs are also now in theearly stages of development.

Gut Hormones: Ensuring Fuel for the Short Trip

Signals from fat cells (such as leptin) seem to be responsible for maintaining the body’s long-term energysupply. In contrast, neural and hormonal messages fromthe gastrointestinal system contain information about thestatus of immediately available energy stores. Importantgut hormones include appetite suppressants such aspeptide YY and cholecystokinin (CCK), as well asappetite stimulants such as ghrelin. Another gut hormone that helps reduce the desire for food in diabeticpatients is synthetic glucagon-like peptide 1 (GLP-1). The first GLP-1 activator, Byetta, is now available, andothers are in the final stages of clinical development.These medications, which produce weight loss in many diabetics, are under consideration as anti-obesity therapies.

One difficulty facing scientists working on the design of apracticable peptide YY obesity therapy is the chemicalcomposition of the hormone itself: its complex structuremakes a pill formulation difficult, if not impossible, to create. Consequently, a nasal spray is being studied,although this route may reduce the drug’s potential effectiveness. In addition, some patients in clinical studies developed nausea and vomiting, raising concernsabout the potential safety of this approach. Those working on a ghrelin blocker face a different obstacle.Although such a drug could help obese people cut theirappetite, the treatment would have to be given any time a person wanted to eat, a potentially costly and inconvenient approach. Thus, notwithstanding the intriguing hypotheses underlying the research on gut hormones, the viability of these concepts still must beproven in the lab and clinic.



C H A P T E R

Peripheral Mechanisms: Energy Expenditure

Uncoupling proteins (UCPs) are specialized substances contained within theinner layer of mitochondria, the cell powerhouse that helps the body produceenergy. Investigations in animals show that increasing levels of UCPs raisesbody temperature.

7

Figure 2. Adipose tissue is an important hormonal, or endocrine, organ that influences other parts of the body. It releases a variety

of factors, such as leptin; adiponectin; RPB4 and TNF-alpha, which affect insulin resistance; and angiopoietins, which help regulate

blood supply. A mix of hormonal and neural signals to fat cells controls the expression of these factors. More complete discussion of

these processes is contained in the text. Adapted from Hofbauer KG, Nicholson JR, and Boss O.

Unfortunately, early human studies have not been successful, as mitochondria-rich brown fat cells, whichexpress UCP1 and play an important role in temperatureregulation in animals, disappear in humans after birth.Ongoing studies are attempting to find triggers of brownfat/UCP1 in adults, as well as other genes involved inenergy use. The promise of this science is so great thatDr. Spiegelman at Harvard has written that he is “betting”this line of research will lead to treatments that have anoticeable effect on obesity (Spiegelman 2007).

Metabolism

Contrary to popular perception, fat is more than lumpy tissue that makes the wearing of horizontal stripes a diceymatter. We now know that adipose tissue is metabolicallyactive, and its cells are key sources of certain cell messengers, called adipokines, which are essential tomany of the body’s most important functions, includingthose in the brain, liver, skeletal muscles, pancreas, andthe immune system (see Figure 2). Research has shownthat obese people have low levels of one of those messengers, a protein called adiponectin, which is important to the development of insulin resistance, a pre-diabetic condition in which body cells fail to respondto insulin and thus are unable to process or store glucose.In addition to blocking cannabinoid receptors, Zimulti alsostimulates the production of adiponectin; so do such diabetes drugs as Avandia and Actos. Scientists are nowworking on a range of potential chemical approaches toreduce insulin resistance, including drugs that mayincrease adiponectin or target other adipokines that affect metabolism.

Fat Storage

Tinkering with the body’s fat storage system could be aproductive way to reduce fat supplies. Two strategiesunder consideration involve techniques to reduce adipose cell growth and promote cell death. One possibleway to induce these favorable changes in fat cells wouldbe to limit their blood supply via adipokines calledangiopoietins. Although theoretically reasonable, thisconcept may be impractical: it may be difficult to developa drug that could selectively target the appropriate fatcells and not cause other cells, such as those in the liver,to compensate by storing the additional calories. In thatcase, a patient could run the risk of developing the veryhealth problems (e.g., metabolic syndrome, diabetes, orheart disease) the treatment was designed to avoid.Moreover, too few fat cells themselves can cause seriousdiseases, such as liposystrophy, in certain individuals.The research on fat storage therapies is continuing.

What does all of this drug research mean for those whoare seriously overweight or obese? On one hand, muchrecent progress has been made in identifying new mechanisms involved in energy homeostasis, and these remain promising avenues of drug research anddevelopment. On the other, the body’s energy system is extremely complex; altering one part leads to compensatory changes in another, not to mention thepossible deleterious effects such alterations may have onother biological processes. Developing new drug treatments for obesity is a more complicated matter thanit might appear at first glance.

“Treating obesity is different from treating cancer,” Dr.Seeley indicates. “The body doesn’t want a tumor.However, it has been evolutionarily programmed to holdonto stored calories. Trying to take a finely designed system and upend it so that obese people lose weight iscounterintuitive. Our bodies simply were not built thatway. It’s hard to fool biology, although we continue to try.”


“Treating obesity is different from

treating cancer,” Dr. Seeley indicates.

“The body doesn’t want a tumor. However,

it has been evolutionarily programmed

to hold onto stored calories. Trying to

take a finely designed system and upend

it so that obese people lose weight is

counterintuitive. Our bodies simply were

not built that way. It’s hard to fool

biology, although we continue to try.”

Alteration of such control mechanisms could provide a novel

strategy for drug developers that could work hand in hand

with other techniques to multiply the long-term effect of

treatment. Indeed, such an integrated approach, which is

known as systems biology, has already proven useful in the

treatment of blood pressure and heart function.

Using systems biology for weight loss would require

identifying the most promising mechanisms involved in

energy maintenance and moving drug discovery toward

those compounds that could best affect it. “Our growing

understanding of the physiology and molecular biology of

obesity hopefully will identify new pathways and constituent

molecules that will be ‘drugable,’ generating a group of

agents that can be used in combination to address relevant

aspects of both energy intake and expenditure,” says Dr.

Leibel. Having a compendium of potential drug therapies that

address both sides of the energy equation will enable

physicians to address obesity in a more systematic fashion.

Indeed, this approach may have just produced its first

. Analyzing liver and fat tissue samples from mice, scientists

from Merck and Rosetta Inpharmatics have identified a

complex of core gene groups implicated in the onset of

obesity, diabetes, and heart disease (Telegraph 2008). Three

new genes, called Lpl, Pmp1l, and Lactb, appear to play an

important role in the onset of obesity. A second Merck

research team, working together with the Icelandic group

Decode Genetics, and the National University in Reykjavik,

Iceland, found a corresponding gene network in obese

humans. According to one of the lead researchers, Eric

Schadt, the fatty tissue of obese individuals displays a

typical pattern of genetic expression that is not visible by

blood-based diagnostic tools, which may explain why this

gene complex was unknown until now.

“These studies strongly support the theory that common

diseases such as obesity result from genetic and

environmental disturbances in entire networks of genes

rather than in a handful of genes,” Dr. Schadt says. “If

diseases like obesity are the result of complex networks of

genes, the accurate reconstruction of these networks will be

critical to identifying the best therapeutic targets.”

Alas, even a fully stocked medicine chest of complementary

anti-obesity drugs may not do the trick for some people. As

noted above, people eat for a variety of behavioral and social

reasons, and the only way to achieve lasting weight loss is to

alter lifestyle, by reducing the amount of food we eat and

drink, and increasing the exercise we get. Addressing a

chronic condition such as obesity will require a battery

of approaches, including behavioral counseling, drug

treatment, and changes in lifestyle, to achieve lasting results.

Short-term starvation, fitness programs, or even drug

therapy alone, simply will not do the trick.

“The goal of drug discovery and development is to give

physicians a bevy of different drugs so they can rationally

prescribe the best treatment for each individual patient,” Dr.

Seeley says. “Obesity is a serious dilemma for the public, but

over time, we hope to be able give patients a fighting

chance.”


C H A P T E R

Toward the Future

Despite the physiological mechanisms that are activated during periods ofrestrictive dieting to reduce the body’s metabolic rate, there are signs that thedevelopment of drugs to produce a persistent change in metabolic rate maybe possible.

8

Nevertheless, obesity is a condition rife with therapeuticpossibilities. Our knowledge of the mechanisms involvedin energy homeostasis has grown enormously in the pastdecade, providing obesity researchers inside and outsidethe pharmaceutical industry with many potential drug targets to test. Although the future introduction of a magicpill that will help obese people shed fifty or one hundredpounds painlessly and safely is highly unlikely, a combination of multiple drugs, behavioral therapy, andlifestyle changes should enable patients and their doctorsto address the many health and quality-of-life issuesassociated with this intractable condition.


C H A P T E R

Conclusion

Obesity is a growing public health problem with serious medical and quality-of-life implications. Although several drug treatments are available, their use-fulness is limited, at best, and patients are often disappointed in the results.

9

In preparing the sections on anti-obesity drug

research and development, I benefited immensely

from the excellent reviews written by Karl G.

Hofbauer, Janet R. Nicholson, and Olivier Boss

(Ann Rev Pharmacol Toxicol. 2007;47:565-92) and

Dunstan Cooke and Steve Bloom (Nature Rev.

2006;6:919-31). All of the errors are my own. I also

would like to thank David H. Weinberg, Ph.D., for his

invaluable insights and support.

Obesity and New Pharmaceutical Approches / Acknowledgments / 17

A C K N O W L E D G M E N T S

Bauditz K, Norman J, Biering H et al. Severe weight loss caused by chewinggum. BMJ. 2008;336:9607.

British Broadcasting Corporation. Key to Way Stomach Expands Found. BBCNews. Avaliable at: http://news.bbc.co.uk/2/hi/health/7274820.stm.Accessed March 4, 2008.

Cooke D, Bloom S.The obesity pipeline: current strategies in the develop-ment of antiobesity drugs. Nature Rev. 2006;6:919-31.

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Harper J. Obese workers cost employers. Washington Times. January 15,2008:A3

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Hofbauer KG, Nicholson J, Boss O. The obesity epidemic: current and futurepharmacological treatments. Ann Rev Pharmacol Toxicol.2007;47:565-92.

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Olshansky SJ, Passaro DJ, Hershow RC et al. A potential decline in lifeexpectancy in the United States in the 21st century. N Engl J Med.2005;352:1138-45.

Puhl R, Brownell KD. Bias, discrimination, and obesity. Obes Res.2001;9:788-805.

Spiegelman B.The skinny fat. The Scientist.com. Available at: http://www.the-scientist.com/article/display/54033/. Accessed January 20, 2008.

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Reneé M. Goodrich, Ph.D.University of Florida

Frederick K. Goodwin, M.D.The George Washington University MedicalCenter

Timothy N. Gorski, M.D., F.A.C.O.G.University of North Texas

Ronald E. Gots, M.D., Ph.D.International Center for Toxicology andMedicine

Henry G. Grabowski, Ph.D.Duke University

James Ian Gray, Ph.D.Michigan State University

William W. Greaves, M.D., M.S.P.H.Medical College of Wisconsin

Kenneth Green, D.Env.American Interprise Institute

Laura C. Green, Ph.D., D.A.B.T.Cambridge Environmental, Inc.

Richard A. Greenberg, Ph.D.Hinsdale, IL

Sander Greenland, Dr.P.H., M.S., M.A.UCLA School of Public Health

Gordon W. Gribble, Ph.D.Dartmouth College

William Grierson, Ph.D.University of Florida

Lester Grinspoon, M.D.Harvard Medical School

F. Peter Guengerich, Ph.D.Vanderbilt University School of Medicine

Caryl J. Guth, M.D.Advance, NC

Philip S. Guzelian, M.D.University of Colorado

Terryl J. Hartman, Ph.D., M.P.H., R.D.The Pennsylvania State University

Clare M. Hasler, Ph.D.The Robert Mondavi Institute of Wine andFood Science, University of California,Davis

Davis Virgil W. Hays, Ph.D.University of Kentucky

Cheryl G. Healton, Dr.PH.Mailman School of Public Health ofColumbia University

Clark W. Heath, Jr., M.D.American Cancer Society

Dwight B. Heath, Ph.D.Brown University

Robert Heimer, Ph.D.Yale School of Public Health

Robert B. Helms, Ph.D.American Enterprise Institute

Zane R. Helsel, Ph.D.Rutgers University, Cook College

James D. Herbert, Ph.D.Drexel University

Gene M. Heyman, Ph.D.McLean Hospital/Harvard Medical School

Richard M. Hoar, Ph.D.Williamstown, MA

Theodore R. Holford, Ph.D.Yale University School of Medicine

Robert M. Hollingworth, Ph.D.Michigan State University

Edward S. Horton, M.D.Joslin Diabetes Center/Harvard MedicalSchool

Joseph H. Hotchkiss, Ph.D.Cornell University

Steve E. Hrudey, Ph.D.University of Alberta

Clifford A. Hudis, M.D.Memorial Sloan-Kettering Cancer Center

Peter Barton Hutt, Esq.Covington & Burling, LLP

Susanne L. Huttner, Ph.D.University of California, Berkeley

Lucien R. Jacobs, M.D.University of California, Los Angeles

Alejandro R. Jadad, M.D., D.Phil.,F.R.C.P.C.University of Toronto

Rudolph J. Jaeger, Ph.D.Environmental Medicine, Inc.

William T. Jarvis, Ph.D.Loma Linda University

Elizabeth H. Jeffery, Ph.D.University of Illinois, Urbana

Geoffrey C. Kabat, Ph.D., M.S.Albert Einstein College of Medicine

Michael Kamrin, Ph.D.Michigan State University

John B. Kaneene, D.V.M., M.P.H., Ph.D.Michigan State University

P. Andrew Karam, Ph.D., CHPMJW Corporation

Kathryn E. Kelly, Dr.P.H.Delta Toxicology

George R. Kerr, M.D.University of Texas, Houston

George A. Keyworth II, Ph.D.Progress and Freedom Foundation

F. Scott Kieff, J.D.Washington University School of Law

Michael Kirsch, M.D.Highland Heights, OH

John C. Kirschman, Ph.D.Allentown, PA

William M. P. Klein, Ph.D.University of Pittsburgh

Ronald E. Kleinman, M.D.Massachusetts General Hospital/Harvard Medical School

Leslie M. Klevay, M.D., S.D. in Hyg.University of North Dakota School ofMedicine and Health Sciences

David M. Klurfeld, Ph.D.U.S. Department of Agriculture

Kathryn M. Kolasa, Ph.D., R.D.East Carolina University

James S. Koopman, M.D, M.P.H.University of Michigan School of PublicHealth

Alan R. Kristal, Dr.P.H.Fred Hutchinson Cancer Research Center

Stephen B. Kritchevsky, Ph.D.Wake Forest University Baptist MedicalCenter

Mitzi R. Krockover, M.D.SSB Solutions

Manfred Kroger, Ph.D.Pennsylvania State University

Sandford F. Kuvin, M.D.University of Miami School of Medicine/Hebrew University of Jerusalem

Carolyn J. Lackey, Ph.D., R.D.North Carolina State University

J. Clayburn LaForce, Ph.D.University of California, Los Angeles

Robert G. Lahita, M.D., Ph.D.Mount Sinai School of Medicine

James C. Lamb, IV, Ph.D., J.D., D.A.B.T.The Weinberg Group

Lawrence E. Lamb, M.D.San Antonio, TX

William E. M. Lands, Ph.D.College Park, MD

Lillian Langseth, Dr.P.H.Lyda Associates, Inc.

Brian A. Larkins, Ph.D.University of Arizona

Larry Laudan, Ph.D.National Autonomous University of Mexico

Tom B. Leamon, Ph.D.Liberty Mutual Insurance Company

Jay H. Lehr, PH.D.Environmental Education Enterprises, Inc.

Brian C. Lentle, MD., FRCPC, DMRDUniversity of British Columbia

Scott O. Lilienfeld, Ph.D.Emory University

Floy Lilley, J.D.Fernandina Beach, FL

Paul J. Lioy, Ph.D.UMDNJ-Robert Wood Johnson MedicalSchool

William M. London, Ed.D., M.P.H.California State University, Los Angeles

Frank C. Lu, M.D., BCFEMiami, FL

William M. Lunch, Ph.D.Oregon State University

Daryl B. Lund, Ph.D.University of Wisconsin-Madison

John R. Lupien, M.Sc.University of Massachusetts

Howard D. Maccabee, Ph.D., M.D.Alamo, CA

Janet E. Macheledt, M.D., M.S., M.P.H.Houston, TX

Henry G. Manne, J.S.D.George Mason University Law School

Karl Maramorosch, Ph.D.Rutgers University, Cook College

Judith A. Marlett, Ph.D., R.D.University of Wisconsin, Madison

Lawrence J. Marnett, Ph.D. Vanderbilt University

James R. Marshall, Ph.D.Roswell Park Cancer Institute

Roger O. McClellan, D.V.M., M.M.S., DABT,DABVT, FATSToxicology and Risk Analysis

Mary H. McGrath, M.D., M.P.H.University of California, San Francisco

Alan G. McHughen, D.Phil.University of California, Riverside

James D. McKean, D.V.M., J.D.Iowa State University

Joseph P. McMenamin, M.D., J.D.McGuireWoods, LLP

Patrick J. Michaels, Ph.D.University of Virginia

Thomas H. Milby, M.D., M.P.H.Walnut Creek, CA

Joseph M. Miller, M.D., M.P.H.Durham, NH

Richard A. Miller, M.D.Pharmacyclics, Inc.

Richard K. Miller, Ph.D.University of Rochester

William J. Miller, Ph.D.University of Georgia

Grace P. Monaco, J.D.Medical Care Ombudsman Program

Brian E. Mondell, M.D.Baltimore Headache Institute

John W. Morgan, Dr.P.H.California Cancer Registry

Stephen J. Moss, D.D.S., M.S.New York University College of Dentistry/Health Education Enterprises, Inc.

Brooke T. Mossman, Ph.D.University of Vermont College of Medicine

Allison A. Muller, Pharm.DThe Children’s Hospital of Philadelphia

Ian C. Munro, F.A.T.S., Ph.D., FRCPathCantox Health Sciences International

Harris M. Nagler, M.D.Beth Israel Medical Center/ Albert Einstein College of Medicine

Daniel J. Ncayiyana, M.D.Benguela Health

Philip E. Nelson, Ph.D.Purdue University

Joyce A. Nettleton, D.Sc., R.D.Denver, CO

John S. Neuberger, Dr.P.H.University of Kansas School of Medicine

Gordon W. Newell, Ph.D., M.S., F.-A.T.S.Cupertino, CA

Thomas J. Nicholson, Ph.D., M.P.H.Western Kentucky University

Robert J. Nicolosi, Ph.D.University of Massachusetts, Lowell

Steven P. Novella, M.D.Yale University School of Medicine

James L. Oblinger, Ph.D.North Carolina State University

Paul A. Offit, M.D.The Children’s Hospital of Philadelphia

John Patrick O’Grady, M.D.Tufts University School of Medicine

James E. Oldfield, Ph.D.Oregon State University

Stanley T. Omaye, Ph.D., F.-A.T.S., F.ACN,C.N.S.University of Nevada, Reno

Michael T. Osterholm, Ph.D., M.P.H.University of Minnesota

Michael W. Pariza, Ph.D.University of Wisconsin, Madison

Stuart Patton, Ph.D.Pennsylvania State University

James Marc Perrin, M.D.Mass General Hospital for Children

Jay Phelan, M.D.Wyle Integrated Science and EngineeringGroup

Timothy Dukes Phillips, Ph.D.Texas A&M University

Mary Frances Picciano, Ph.D.National Institutes of Health

David R. Pike, Ph.D.University of Illinois, Urbana-Champaign

Steven Pinker, Ph.D.Harvard University

Henry C. Pitot, M.D., Ph.D.University of Wisconsin-Madison

Thomas T. Poleman, Ph.D.Cornell University

Gary P. Posner, M.D.Tampa, FL

John J. Powers, Ph.D.University of Georgia

William D. Powrie, Ph.D.University of British Columbia

C.S. Prakash, Ph.D.Tuskegee University

Marvin P. Pritts, Ph.D.Cornell University

Daniel J. Raiten, Ph.D.National Institute of Health

David W. Ramey, D.V.M.Ramey Equine Group

R.T. Ravenholt, M.D., M.P.H.Population Health Imperatives

Russel J. Reiter, Ph.D.University of Texas, San Antonio

William O. Robertson, M.D.University of Washington School ofMedicine

J. D. Robinson, M.D.Georgetown University School of Medicine

Brad Rodu, D.D.S.University of Louisville

Bill D. Roebuck, Ph.D., D.A.B.T.Dartmouth Medical School

David B. Roll, Ph.D.The United States Pharmacopeia

Dale R. Romsos, Ph.D.Michigan State University

Joseph D. Rosen, Ph.D.Cook College, Rutgers University

Steven T. Rosen, M.D.Northwestern University Medical School

Stanley Rothman, Ph.D.Smith College

Stephen H. Safe, D.Phil.Texas A&M University

Wallace I. Sampson, M.D.Stanford University School of Medicine

Harold H. Sandstead, M.D.University of Texas Medical Branch

Charles R. Santerre, Ph.D.Purdue University

Sally L. Satel, M.D.American Enterprise Institute

Lowell D. Satterlee, Ph.D.Vergas, MN

Mark V. Sauer, M.D.Columbia University

Jeffrey W. SavellTexas A&M University

Marvin J. Schissel, D.D.S.Roslyn Heights, NY

Edgar J. Schoen, M.D.Kaiser Permanente Medical Center

David Schottenfeld, M.D., M.Sc.University of Michigan

Joel M. Schwartz, M.S.American Enterprise Institute

David E. Seidemann, Ph.D.Brooklyn College

David A. Shaywitz, M.D., Ph.D.The Boston Consulting Group

Patrick J. Shea, Ph.D.University of Nebraska, Lincoln

Michael B. Shermer, Ph.D.Skeptic Magazine

Sidney Shindell, M.D., LL.B.Medical College of Wisconsin

Sarah Short, Ph.D., Ed.D., R.D.Syracuse University

A. J. Siedler, Ph.D.University of Illinois, Urbana-Champaign

Marc K. Siegel, M.D.New York University School of Medicine

Michael Siegel, M.D., M.P.H.Boston University School of Public Health

Michael S. Simon, M.D., M.P.H.Wayne State University

S. Fred Singer, Ph.D.Science & Environmental Policy Project

Robert B. Sklaroff, M.D.Elkins Park, PA

Anne M. Smith, Ph.D., R.D., L.D.Ohio State University

Gary C. Smith, Ph.D.Colorado State University

John N. Sofos, Ph.D.Colorado State University

Laszlo P. Somogyi, Ph.D.SRI International (ret.)

Roy F. Spalding, Ph.D.University of Nebraska, Lincoln

Leonard T. Sperry, M.D., Ph.D.Florida Atlantic University

Robert A. Squire, D.V.M., Ph.D.Johns Hopkins University

Ronald T. Stanko, M.D.University of Pittsburgh Medical Center

James H. Steele, D.V.M., M.P.H.University of Texas, Houston

Robert D. Steele, Ph.D.Pennsylvania State University

Daniel T. Stein, M.D.Albert Einstein College of Medicine

Judith S. Stern, Sc.D., R.D.University of California, Davis

Ronald D. Stewart, O.C., M.D., FRCPCDalhousie University

Martha Barnes Stone, Ph.D.Colorado State University

Jon A. Story, Ph.D.Purdue University

Sita R. Tatini, Ph.D.University of Minnesota

Dick TaverneHouse of Lords, UK

Steve L. Taylor, Ph.D.University of Nebraska, Lincoln

Andrea D. Tiglio, Ph.D., J.D.Townsend and Townsend and Crew, LLP

James W. Tillotson, Ph.D., M.B.A.Tufts University

Dimitrios Trichopoulos, M.D.Harvard School of Public Health

Murray M. Tuckerman, Ph.D.Winchendon, MA

Robert P. Upchurch, Ph.D.University of Arizona

Mark J. Utell, M.D.University of Rochester Medical Center

Shashi B. Verma, Ph.D.University of Nebraska, Lincoln

Willard J. Visek, M.D., Ph.D.University of Illinois College of Medicine

Lynn Waishwell, Ph.D., C.H.E.S.University of Medicine and Dentistry ofNew Jersey, School of Public Health

Brian Wansink, Ph.D.Cornell University

Miles Weinberger, M.D.University of Iowa Hospitals and Clinics

John Weisburger, Ph.D.New York Medical College

Janet S. Weiss, M.D.The ToxDoc

Simon Wessley, M.D., FRCPKing’s College London and Institute ofPsychiatry

Steven D. Wexner, M.D.Cleveland Clinic Florida

Joel Elliot White, M.D., F.A.C.R.Danville, CA

John S. White, Ph.D.White Technical Research

Kenneth L. White, Ph.D.Utah State University

Carol Whitlock, Ph.D., R.D.Rochester Institute of Technology

Christopher F. Wilkinson, Ph.D.Wilmington, NC

Mark L. Willenbring, M.D., Ph.D.National Institute on Alcohol Abuse andAlcoholism

Carl K. Winter, Ph.D.University of California, Davis

James J. Worman, Ph.D.Rochester Institute of Technology

Russell S. Worrall, O.D.University of California, Berkeley

S. Stanley Young, Ph.D.National Institute of Statistical Science

Steven H. Zeisel, M.D., Ph.D.University of North Carolina

Michael B. Zemel, Ph.D.Nutrition Institute, University of Tennessee

Ekhard E. Ziegler, M.D.University of Iowa

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