Obesity

AND NEW PHARMACEUTICAL

APPROACHES

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 HEALTH

1995 Broadway, 2nd Floor, New York, NY 10023-5860
Phone: (212) 362-7044 • Fax: (212) 362-4919
acsh.org •HealthFactsAndFears.com
E-mail: acsh@acsh.org
TH E FOLLOWI NG PEOPLE
R EVI EW E D TH I S P U B LICATION.

Nigel Bark, M.D.

Albert Einstein College of Medicine

Thomas G. Baumgartner, Pharm.D., M.Ed., FASHP,

BCNSP
University 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/N

East 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 the
public. The organization does not perform proprietary research, nor does it
accept support from individual corporations for specific research projects.
All contributions to ACSH—a publicly funded organization under Section
501(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 any
other means, without permission.
CONTE NT

CHAPTER PG

CHAPTER 1
Executive Summary 1

CHAPTER 2
Introduction 2

CHAPTER 3
What’s Under the Hood: How the Body Regulates the
Balance Between Food Intake and Energy Expenditure 4

CHAPTER 4
Current Treatments: How Effective Are They? 8

CHAPTER 5
New Approaches: Putting the Central and Peripheral
Mechanisms to Work 10

CHAPTER 6
Central Targets: The Role of the Hypothalamus 11
a. The Serotonin System: A Safer Redux?
b. Gut Hormones: Ensuring Fuel for the Short Trip

CHAPTER 7
Peripheral Mechanisms: Energy Expenditure 13
a. Metabolism
b. Fat Storage

CHAPTER 8
Toward the Future 15

CHAPTER 9
Conclusion 16

ACKNOWLEDGMENTS 17

REFERENCES 18
CHAPTE R

Executive Summar y

Obesity is a growing problem worldwide, with serious health and quality-

of-life implications.
Dietary and behavioral changes offer only limited The development of new drugs should focus on
help; although some people benefit from anti- helping patients eat less and better utilize what
obesity drugs, expectations are often unrealistic. they eat; thus far, drugs that stimulate the use
of existing fat stores are in the early stages of
The effectiveness of current treatments is limited; development.
for the morbidly obese, surgery is the most effective
option, although it is not risk-free. Pharmaceutical agents will not solve the obesity
problem by themselves; lifestyle adjustments will
Efforts to foster weight loss are countered by the likely always be necessary.
body’s inherent need to preserve weight.
For the immediate future, the most effective
Considerable progress has been made in treatment is likely to be a combination of drug and
identifying new means of treating obesity, behavioral therapy, along with changes in diet, rest,
particularly those that suppress appetite or restrict and exercise.
fat absorption.

The extremely complexity of the body’s energy

system means that altering one part affects others,
as well as other biological systems.

Obesity and New Pharmaceutical Approches / Chapter 1 / 1

CHAPTE R
Introduction
2
The endocrinologist David Ludwig calls his patients, the seven-member G
family, “a microcosm of 21st-century America.”
One of the parents is overweight and the other is obese,
wrote the Harvard Medical School professor and director
of the Optimal Weight for Life Clinic (Ludwig 2007). All
five of the children are even more severely obese, and
although they are still young, they already face the
prospect of lives limited by chronic medical
problems. One of the youngsters shows the first signs of
fatty liver, while another has high blood pressure. Three
have marked insulin resistance, the first sign of type-2
diabetes; four have abnormal cholesterol profiles, and
two complain of orthopedic problems. The children all
express serious emotional distress, stemming from their
obesity. Were the G family unusual, their health problems
could be written off as medical curiosities. Unfortunately,
families like that of Mr. and Mrs. G and their children are
becoming all too common in industrialized nations around
the world.
Today, about 66% of all Americans are overweight or
obese (Ogden 2006). Researchers from the Centers for
Disease Control and Prevention (CDC) report that since
1970, the number of overweight children and adolescents
between the ages of 6 and 19 years has tripled, meaning
that more than 9 million young Americans (or nearly one-
in-five) are at risk for a wide range of obesity-related
problems, including diabetes, hypertension, high choles-
terol, coronary artery disease, respiratory problems,
sleep apnea, gallbladder disease, osteoarthritis, and sev-
Obesity and New Pharmaceutical Approches
eral forms of cancer (Cooke 2006). These trends suggest
that the current generation of Americans may be the first
in the past 200 yeas to
have a shorter life expectancy than their parents had,
according to physicians at the University of Illinois
Medical Center in Chicago (Olshansky 2005). This is
hardly the definition of progress.
In addition to the health consequences, obesity also
entails substantial economic and social costs. An obese
worker 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 health
policy 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 also
been suggestions of bias in adoption proceedings, jury
selection, housing, and other areas of public life,
according to Yale University investigators (Puhl 2001).
Obesity is now the nation’s second-biggest public health
problem, right after smoking. Although lifestyle changes,
/ Chapter 2 / 2
most notably dietary adjustments and increased
physical activity, can help people lose weight and stave
off obesity, many find it difficult to comply with such
weight-loss regimens. Shedding surplus pounds is
frequently a struggle, but for many people, it's a battle
they are genetically programmed to lose. (Later on, we’ll
learn just why this is so.) For this reason, a great deal of
interest – and hope – rests on the potential effectiveness
of pharmaceutical therapies for obesity.

Americans currently spend more than $33 billion a year

on 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 can
be disappointing for even those treatments that have
value. Nonetheless, the pharmaceutical industry has
invested enormous capital in the search for effective and
safe weight-loss drugs that target the body’s intricate
energy-regulation mechanisms. The research and
development continues today.

Obesity and New Pharmaceutical Approches / Chapter 2 / 3

CHAPTE R
3
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 excessive
accumulation of body fat.
It can be determined using a variety of means, including
underwater weighing, CT scans, and bioelectric
impedance analysis, an exam in which a low-voltage
electric current is used to determine lean body mass – the
more fat a body has, the more resistant it is to the current.
Many of these tests are not easy to perform, and some
require sophistcated technology. To overcome these
limitations, the U.S. Government in the late 1990sbegan
to use a simpler, actuarial-based measure of obesity, the
“Body Mass Index” (BMI). BMI is the ratio of weight to
height (kg/m2, or pounds/in2) (Table 1). People are said
to 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 pounds
for a 5 foot 4 inch person.
Several caveats are in order when interpreting BMI.
The index is an initial warning that an individual might be
carrying excess body fat. It is most accurate for people
who 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 excess
abdominal fat, a condition associated with an increased
risk of metabolic syndrome, diabetes, and cardiovascular
disease. Tests of blood glucose (for incipient diabetes)
and lipids (for coronary artery disease) also might be
ordered. On the other hand, a BMI of 31 in a body builder,
tennis player, or other well-trained athlete would not be
cause for concern. Excessive body fat is not an issue for
Obesity and New Pharmaceutical Approches
people who have increased muscle mass. In other
words, BMI is helpful to identify those at risk for serious
obesity-related diseases, although its utility as an
indicator of health status and risk is limited. (For more on
the use of BMI, see, “Are Our Athletes Really Fat?” at
www.acsh.org/factsfears/ newsID.517/news_detail.asp.)
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.
Perhaps a more useful way to consider the problem of
excessive fat is to examine the physiology of weight gain.
In this regard, 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. However, the two sides of the
equation are not quite equal; in fact, many obesity experts
now 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 of
obesity, the lack of exercise is now understood to be at
least as important. As the Harvard cell biologist Bruce
Spiegelman says, “The precise contribution of overeating
to obesity is unclear. Studying diet in obese patients
/ Chapter 3 / 4
 Body Mass Index Table

Normal Overweight Obese Extreme Obesity

BMI 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

Height
(inches) Body Weight (pounds)

58 91 96 100 105 110 115 119 124 129 134 138 143 148 153 158 162 167 172 177 181 186 191 196 201 205 210 215 220 224 229 234 239 244 248 253 258

59 94 99 104 109 114 119 124 128 133 138 143 148 153 158 163 168 173 178 183 188 193 198 203 208 212 217 222 227 232 237 242 247 252 257 262 267
60 97 102 107 112 118 123 128 133 138 143 148 153 158 163 168 174 179 184 189 194 199 204 209 215 220 225 230 235 240 245 250 255 261 266 271 276

61 100 106 111 116 122 127 132 137 143 148 153 158 164 169 174 180 185 190 195 201 206 211 217 222 227 232 238 243 248 254 259 264 269 275 280 285
62 104 109 115 120 126 131 136 142 147 153 158 164 169 175 180 186 191 196 202 207 213 218 224 229 235 240 246 251 256 262 267 273 278 284 289 295
63 107 113 118 124 130 135 141 146 152 158 163 169 175 180 186 191 197 203 208 214 220 225 231 237 242 248 254 259 265 270 278 282 287 293 299 304

64 110 116 122 128 134 140 145 151 157 163 169 174 180 186 192 197 204 209 215 221 227 232 238 244 250 256 262 267 273 279 285 291 296 302 308 314
65 114 120 126 132 138 144 150 156 162 168 174 180 186 192 198 204 210 216 222 228 234 240 246 252 258 264 270 276 282 288 294 300 306 312 318 324
66 118 124 130 136 142 148 155 161 167 173 179 186 192 198 204 210 216 223 229 235 241 247 253 260 266 272 278 284 291 297 303 309 315 322 328 334
67 121 127 134 140 146 153 159 166 172 178 185 191 198 204 211 217 223 230 236 242 249 255 261 268 274 280 287 293 299 306 312 319 325 331 338 344
68 125 131 138 144 151 158 164 171 177 184 190 197 203 210 216 223 230 236 243 249 256 262 269 276 282 289 295 302 308 315 322 328 335 341 348 354

69 128 135 142 149 155 162 169 176 182 189 196 203 209 216 223 230 236 243 250 257 263 270 277 284 291 297 304 311 318 324 331 338 345 351 358 365
70 132 139 146 153 160 167 174 181 188 195 202 209 216 222 229 236 243 250 257 264 271 278 285 292 299 306 313 320 327 334 341 348 355 362 369 376

Obesity and New Pharmaceutical Approches

71 136 143 150 157 165 172 179 186 193 200 208 215 222 229 236 243 250 257 265 272 279 286 293 301 308 315 322 329 338 343 351 358 365 372 379 386

/
72 140 147 154 162 169 177 184 191 199 206 213 221 228 235 242 250 258 265 272 279 287 294 302 309 316 324 331 338 346 353 361 368 375 383 390 397
73 144 151 159 166 174 182 189 197 204 212 219 227 235 242 250 257 265 272 280 288 295 302 310 318 325 333 340 348 355 363 371 378 386 393 401 408

74 148 155 163 171 179 186 194 202 210 218 225 233 241 249 256 264 272 280 287 295 303 311 319 326 334 342 350 358 365 373 381 389 396 404 412 420
75 152 160 168 176 184 192 200 208 216 224 232 240 248 256 264 272 279 287 295 303 311 319 327 335 343 351 359 367 375 383 391 399 407 415 423 431

Chapter 3
76 156 164 172 180 189 197 205 213 221 230 238 246 254 263 271 279 287 295 304 312 320 328 336 344 353 361 369 377 385 394 402 410 418 426 435 443

/
Source: Adapted from Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report.

5
 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.
Under normal conditions, the body’s energy balance
is strictly regulated and controlled. Consider that most
people consume about 700,000 calories each year; even
so, body weight usually does not vary by more than 1
kilogram 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% (Hofbauer
2007). The bad news for those trying to lose weight is that
fewer than 20 excess calories a day over the course of a
year will put on 1 pound of fat.
“That the body can regulate such a small amount of
overeating – 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 the

is confounded by the fact that these patients tend to
under-report their food intake by as much as 30%.
Overeating can be gauged only in relation to that
individual’s energy expenditure (Spiegelman 2007).” This
observation means that people who follow a regular
exercise regime and do not overeat routinely tend to
maintain their weight. However, even small changes in
diet or in the amount of physical activity can affect
body weight when the changes extend over a long period
of time.
University of Cincinnati, in a telephone interview.
Evolutionary pressures, which required prehistoric man to
maintain his energy reserves in the face of a harsh
environment and limited food supplies, predispose our
bodies to prevent weight loss more strongly than weight
gain. Our energy regulatory system contains many
redundant mechanisms to keep us from starving.“Our
bodies were not designed to restrict our intake of food but
to help us survive,” Dr. Seeley added. Although cavemen
struggled 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.

Obesity and New Pharmaceutical Approches / Chapter 3 / 6

 AREAS OF
AREAS OF INVESTIGATION DRUGS NOW IN USE
CURRENT RESEARCH

Leptin
Melanocortin system
Serotonin system
Loracaserin Meridia
Melanin-concentrating hormone Sympatomimetics
Central (appetite, satiation, Cannabinoid receptors Phentermine
metabolism) Zimulti* Phendimetrazie
Gut hormones Benzphetamine
Peptide YY Glucophage and Sandostatin†
Cholecystokinin
Ghrelin
Synthetic GLP-1

Uncoupling proteins
Peripheral (metabolism, energy Xenical
Adipokines
use, fatnstorage) Alli (OTC)
Adiponectin

* Currently in final clinical studies prior to FDA review

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

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. In other words,
getting fat is easy for most people, but losing weight can
be 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 few
calories burned off can lead to overweight, and in time,
obesity. This simple equation explains why understanding
the connection between energy intake and expenditure is
so important. The balance between the two is regulated
by 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 use
and respond to signals from the body that contain
information about energy stores and availability, much as
a warehouse manager keeps track of inventory.
Peripheral mechanisms include hormonal signals from
the gastrointestinal tract, as well as from fat cells to such
organs as the liver and pancreas, skeletal muscle, and
even disease-fighting immune cells that carry out various
metabolic (biochemical) functions important to energy
regulation (Hofbauer 2007) (see Figure 1). These are the
orders the warehouse must fill, sometimes immediately
and other times later in the day.
Here is how the two mechanisms work. First, feelings of
hunger cause one to fix a sandwich or grab an apple.
Eating triggers the process of digestion, and then signals
emanating from the stomach tell the brain you are
satisfied and have had enough to eat. The brain gathers
this information, along with other neuronal and hormonal
data 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 of
Washington and an obesity investigator at the Howard
Hughes Medical Institute (personal communication).
Ongoing obesity drug research has targeted both central
and peripheral mechanisms in the search for safe and
effective treatments (Table 2). This research investigates
strategies to reduce food intake by altering appetite,
feelings of satiety (i.e., fullness or satisfaction), and
fat absorption, and to elevate energy expenditure by
boosting metabolism.

Obesity and New Pharmaceutical Approches / Chapter 3 / 7

CHAPTE R
4
Current Treatments:
How Effective Are They?
The Food and Drug Administration (FDA) has approved three drugs for the
long-term treatment of obesity, Meridia (sibutramine), Xenical (orlistat), and
Alli, an over-the-counter (OTC) version of Xenica. Each primarily addresses
one of the two mechanisms described above.
Centrally acting Meridia blocks the action of several important
chemicals involved mainly in promoting hunger and, to a lesser
degree, food intake. In the clinical trials of Meridia, patients lost about
3% to 4% of their body weight, most of which occurred during the first
six months of treatment. Continued use of the drug helped maintain
the weight loss. Patients also experienced reductions in triglyceride
levels and increases in good (HDL) cholesterol, which could help
prevent the development of metabolic syndrome, diabetes, and heart
disease. However, this benefit was counterbalanced by a slight
increase in blood pressure and heart rate. As a result, for patients with
hypertension or who have had an excessively rapid heart beat in the
past, the use of Meridia may require regular monitoring. The drug did
not affect bad (LDL) cholesterol.
In contrast, Xenical and Alli work on the gastrointestinal system,
where they prevent the absorption of fat. People using these drugs
lose 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 that
stem from their special mechanism of action: the fat that is not
absorbed remains in the gut, where it can contribute to flatulence and
the 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, especially
when fat intake is reduced.
A fourth drug, Zimulti/Accomplia (rimonabant), is in late clinical
development and should also be noted. Researchers were prompted
to study the effects of Zimulti and sister drugs on appetite suppression
because cannabis (the active ingredient in marijuana) has long been
known to promote feelings of hunger, the so-called “munchies.” This
Obesity and New Pharmaceutical Approches
BUYER BEWARE
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.
/ Chapter 4 / 8
drug blocks a class of receptors in the brain that respond
to cannabis (cannabinoid receptors), which, in theory,
should reduce the desire to overeat. In clinical trials,
weight loss achieved with Zimulti had positive effects on
a number of risk factors for heart disease, including
cholesterol and triglyceride levels and insulin resistance.
Blood pressure was not affected, which was surprising in
light of the fact that patients taking Zimulti also lost about
3% to 5% of their weight and therefore should have expe-
rienced a reduction in blood pressure. Nearly 20
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.
countries around the world have approved this
medication for use. However, in 2007, the FDA rejected
Zimulti because of the risk of psychiatric side effects,
including depression, anxiety, and loss of sleep. The
manufacturer plans to conduct additional studies and
then resubmit Zimulti for approval.
In addition to Meridia, Xenical, and Alli, which are
designed and approved for chronic therapy, the FDA also
has approved several other drugs for short-term use.
Phentermine, phendimetrazine, and benzphetamine all
belong 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 the
treatment of obesity can serve as helpful adjuncts to a
regimen of diet and exercise. Because these drugs can
be habit-forming and may cause serious side effects,
including high blood pressure, agitation, depression, and
even psychoses, physicians limit their use to two to three
weeks. (See “The Serotonin System: A Safer Redux”
section in Chapter 6.) The sympathomimetics are not
recommended for children and adolescents because of
the potential for abuse and adverse events.
Obesity and New Pharmaceutical Approches
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. A 1997 study examined patient
expectations for obesity drugs and produced startling
results. Obese patients indicated that they hoped to lose
from 31% to 38% of their weight. Twenty-five percent was
deemed 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 scientifically
rational treatments that produce the kind of weight loss
that people want,” says Dr. Seeley. “As things now stand,
our treatments aren’t even effective enough to be
disappointing!” More important, maintaining even the
modest reduction in weight requires life-long treatment.
“There is a common misconception that any effective
obesity drug can be used for a limited time – until the
desired weight loss is achieved – and then stopped,” says
Rudolph Leibel, MD, professor of molecular genetics at
Columbia University and co-director of the Naomi Berrie
Diabetes Center, in an interview. “In this respect, treating
obesity is no different from treating hypertension or high
cholesterol. Any successful drug or combination of drugs
will probably have to be taken indefinitely.” The hope is
that, in the future, doctors will have a wider range of drug
therapies that they will be able to use selectively on the
patients best able to benefit from them. That remains
the objective of current pharmaceutical research and
development.
/ Chapter 4 / 9
CHAPTE R
New Approaches:
5
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.
The available therapies only address those mechanisms that
fine-tune the energy balance. As one investigator commented, “There
are lots of new targets under evaluation, and we hope that some of
them 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.”
Obesity and New Pharmaceutical Approches
BARIATRIC SURGERY
A WAY TO BYPASS GASTRIC BYPASS?
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.
/ Chapter 5 / 10
CHAPTE R
Central Targets:
6
The Role of the Hypothalamus
As noted above, the hypothalamus serves as the central caretaker of energy
homeostasis. Our understanding of the myriad pathways involved in this
process took a giant leap forward in 1994 when a hormone called leptin was
identified.
Hormones are signaling agents produced by various
tissues in the body. Scientists discovered that leptin is
released from fat cells to inform the brain about the state
of the body’s energy supply. We now know that leptin
circulates in the blood to the hypothalamus, providing
information about the number and size of adipose (fat)
cells in the body – the greater the amount of body fat, the
more leptin a person produces, the greater the amount of
body fat. In theory, administration of leptin to obese
people would signal the brain that fat stores were
abundant, thereby reducing food intake. However, early
studies using a genetically engineered form of the
hormone proved to be disappointing: daily injections of
leptin helped only a small percentage of obese subjects
lose weight. This finding led researchers to hypothesize
that 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 may
prove useful in the regulation of food intake and energy
expenditure include those in the melanocortin system.
The central melanocortin system is arguably the most
important neuronal pathway involved in the regulation of
energy homeostasis; it also is active in a wide array of
other processes, including erectile function, blood
pressure, and steroid production. Although obesity
research on melanocortin pharmaceuticals continues,
progress has been stymied by the fact that the these
drugs also produce undesirable effects on the other
biological activities, altering blood pressure and causing
Obesity and New Pharmaceutical Approches
unwanted erections, for example. In addition, there are
several different kinds of melanocortin receptors, two of
which are abundant in the brain, and it is not entirely clear
what the role of each one is. Thus, it is not yet known
whether 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 investigation
involves the serotonin system. This neurotransmitter
helps control appetite – when serotonin levels are low,
people feel hungry. Preventing the re-uptake of serotonin
in the brain – keeping levels high, in other words – is the
means by which such antidepressants as Paxil and
Prozac work, and this approach also may help control
weight. The first such serotonin re-uptake blocker,
fenfluramine, was used along with the appetite
suppressant phentermine in the mid-1990s as a popular
anti-obesity regimen. Early in 1996, the FDA approved an
updated 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 heart
valve 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,
/ Chapter 6 / 11
is now undergoing clinical trials, as is tesofensine, a One difficulty facing scientists working on the design of a
compound that inhibits serotonin, noradrenaline, practicable peptide YY obesity therapy is the chemical
and dopamine. composition of the hormone itself: its complex structure
makes a pill formulation difficult, if not impossible, to
In addition to the serotonin system, another central create. Consequently, a nasal spray is being studied,
mechanism that could help lower appetite involves although this route may reduce the drug’s potential
melanin-concentrating hormone (MCH). This hormone is effectiveness. In addition, some patients in clinical
produced by neurons in the hypothalamus and acts on studies developed nausea and vomiting, raising concerns
specific receptors in the brain that control our desire for about the potential safety of this approach. Those
food. Several different MCH drugs are also now in the working on a ghrelin blocker face a different obstacle.
early stages of development. Although such a drug could help obese people cut their
appetite, the treatment would have to be given any time
Gut Hormones: a person wanted to eat, a potentially costly and
Ensuring Fuel for the Short Trip inconvenient approach. Thus, notwithstanding the
intriguing hypotheses underlying the research on gut
Signals from fat cells (such as leptin) seem to be hormones, the viability of these concepts still must be
responsible for maintaining the body’s long-term energy proven in the lab and clinic.
supply. In contrast, neural and hormonal messages from
the gastrointestinal system contain information about the
status of immediately available energy stores. Important
gut hormones include appetite suppressants such as
peptide YY and cholecystokinin (CCK), as well as
appetite stimulants such as ghrelin. Another gut
hormone that helps reduce the desire for food in diabetic
patients is synthetic glucagon-like peptide 1 (GLP-1).
The first GLP-1 activator, Byetta, is now available, and
others are in the final stages of clinical development.
These medications, which produce weight loss in many
diabetics, are under consideration as anti-obesity
therapies.

Obesity and New Pharmaceutical Approches / Chapter 6 / 12

CHAPTE R

7
Peripheral Mechanisms:
Energy Expenditure

Uncoupling proteins (UCPs) are specialized substances contained within the

inner layer of mitochondria, the cell powerhouse that helps the body produce
energy. Investigations in animals show that increasing levels of UCPs raises
body temperature.

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.

Obesity and New Pharmaceutical Approches / Chapter 7 / 13

Unfortunately, early human studies have not been
successful, as mitochondria-rich brown fat cells, which
express UCP1 and play an important role in temperature
regulation in animals, disappear in humans after birth.
Ongoing studies are attempting to find triggers of brown
fat/UCP1 in adults, as well as other genes involved in
energy use. The promise of this science is so great that
Dr. Spiegelman at Harvard has written that he is “betting”
this line of research will lead to treatments that have a
noticeable effect on obesity (Spiegelman 2007).
“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.”
Metabolism
Contrary to popular perception, fat is more than lumpy
tissue that makes the wearing of horizontal stripes a dicey
matter. We now know that adipose tissue is metabolically
active, and its cells are key sources of certain cell
messengers, called adipokines, which are essential to
many of the body’s most important functions, including
those in the brain, liver, skeletal muscles, pancreas, and
the immune system (see Figure 2). Research has shown
that 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 respond
to insulin and thus are unable to process or store glucose.
In addition to blocking cannabinoid receptors, Zimulti also
stimulates the production of adiponectin; so do such
diabetes drugs as Avandia and Actos. Scientists are now
working on a range of potential chemical approaches to
reduce insulin resistance, including drugs that may
increase adiponectin or target other adipokines that
affect metabolism.
Obesity and New Pharmaceutical Approches
Fat Storage
Tinkering with the body’s fat storage system could be a
productive way to reduce fat supplies. Two strategies
under consideration involve techniques to reduce
adipose cell growth and promote cell death. One possible
way to induce these favorable changes in fat cells would
be to limit their blood supply via adipokines called
angiopoietins. Although theoretically reasonable, this
concept may be impractical: it may be difficult to develop
a drug that could selectively target the appropriate fat
cells and not cause other cells, such as those in the liver,
to compensate by storing the additional calories. In that
case, a patient could run the risk of developing the very
health problems (e.g., metabolic syndrome, diabetes, or
heart disease) the treatment was designed to avoid.
Moreover, too few fat cells themselves can cause serious
diseases, such as liposystrophy, in certain individuals.
The research on fat storage therapies is continuing.
What does all of this drug research mean for those who
are seriously overweight or obese? On one hand, much
recent progress has been made in identifying new
mechanisms involved in energy homeostasis, and
these remain promising avenues of drug research and
development. On the other, the body’s energy system
is extremely complex; altering one part leads to
compensatory changes in another, not to mention the
possible deleterious effects such alterations may have on
other biological processes. Developing new drug
treatments for obesity is a more complicated matter than
it 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 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.”
/ Chapter 7 / 14
CHAPTE R

Toward the Future

8
Despite the physiological mechanisms that are activated during periods of
restrictive dieting to reduce the body’s metabolic rate, there are signs that the
development of drugs to produce a persistent change in metabolic rate may
be possible.
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.”

Obesity and New Pharmaceutical Approches / Chapter 8 / 15

CHAPTE R

Conclusion
9
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.
Nevertheless, obesity is a condition rife with therapeutic
possibilities. Our knowledge of the mechanisms involved
in energy homeostasis has grown enormously in the past
decade, providing obesity researchers inside and outside
the pharmaceutical industry with many potential drug
targets to test. Although the future introduction of a magic
pill that will help obese people shed fifty or one hundred
pounds painlessly and safely is highly unlikely, a
combination of multiple drugs, behavioral therapy, and
lifestyle changes should enable patients and their doctors
to address the many health and quality-of-life issues
associated with this intractable condition.

Obesity and New Pharmaceutical Approches / Chapter 9 / 16

ACKNOWLE DG M E NTS

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

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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., CHP
MJW 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 of
Medicine 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 Public
Health
Alan R. Kristal, Dr.P.H.
Fred Hutchinson Cancer Research Center
Stephen B. Kritchevsky, Ph.D.
Wake Forest University Baptist Medical
Center
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, DMRD
University 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 Medical
School
William M. London, Ed.D., M.P.H.
California State University, Los Angeles
Frank C. Lu, M.D., BCFE
Miami, 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, FATS
Toxicology 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.D
The Children’s Hospital of Philadelphia
Ian C. Munro, F.A.T.S., Ph.D., FRCPath
Cantox 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 Engineering
Group
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 of
Medicine
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. Savell
Texas 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., FRCPC
Dalhousie 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 Taverne
House 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 of
New 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., FRCP
King’s College London and Institute of
Psychiatry
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 and
Alcoholism
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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