obesity and new pharmaceutical approaches

8/8/2019 Obesity and New Pharmaceutical Approaches

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AND NEW PHARMACEUTICALAPPROACHES

Obesity

American Council on Science and Health


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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: [email protected]


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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 the

public. The organization does not perform proprietary research, nor does it

accept support from individual corporations for specific research projects.

All contributions to ACSHa publicly funded organization under Section

501(c)(3) of the Internal Revenue Codeare 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.

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 .


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CHAPTER 1

Executive Summary

CHAPTER 2

Introduction

CHAPTER 3

Whats Under the Hood: How the Body Regulates theBalance Between Food Intake and Energy Expenditure

CHAPTER 4

Current Treatments: How Effective Are They?

CHAPTER 5

New Approaches: Putting the Central and PeripheralMechanisms to Work

CHAPTER 6

Central Targets: The Role of the Hypothalamusa. The Serotonin System: A Safer Redux?

b. Gut Hormones: Ensuring Fuel for the Short Trip

CHAPTER 7

Peripheral Mechanisms: Energy Expenditurea. Metabolismb. Fat Storage

CHAPTER 8

Toward the Future

CHAPTER 9

Conclusion

ACKNOWLEDGMENTS

REFERENCES

1

2

4

8

10

11

13

15

16

17

18

CHAPTER PG

C O N T E N T


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Dietary and behavioral changes offer only limited

help; 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 effective

option, although it is not risk-free.

Efforts to foster weight loss are countered by the

bodys inherent need to preserve weight.

Considerable progress has been made in

identifying new means of treating obesity,

particularly those that suppress appetite or restrict

fat absorption.

The extremely complexity of the bodys energy

system means that altering one part affects others,

as well as other biological systems.

The development of new drugs should focus on

helping 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 of

development.

Pharmaceutical agents will not solve the obesity

problem by themselves; lifestyle adjustments will

likely always be necessary.

For the immediate future, the most effective

treatment is likely to be a combination of drug and

behavioral 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.


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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, meaningthat 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-

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 nations 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, juryselection, housing, and other areas of public life,

according to Yale University investigators (Puhl 2001).

Obesity is now the nations second-biggest public health

problem, right after smoking. Although lifestyle changes,


C H A P T E R

Introduction

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

2


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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, well

learn just why this is so.) For this reason, a great deal ofinterest 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 bodys intricate

energy-regulation mechanisms. The research anddevelopment continues today.



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9/26


BMI

19

20

21

222

3

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)

BodyWeight(pounds)

58

91

96

100

105

110

115

119

124

129

134

138

143

148

15

3

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

15

8

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

16

3

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

16

9

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

17

5

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

18

0

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

18

6

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

19

2

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

19

8

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

20

4

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

21

0

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

21

6

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

22

2

229

236

243

250

257

264

271

278

285

292

299

306

313

320

327

334

341

348

355

362

369

376

71

136

143

150

157

165

172

179

186

193

200

208

215

222

22

9

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

23

5

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

24

2

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

24

9

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

25

6

264

272

279

287

295

303

311

319

327

335

343

351

359

367

375

383

391

399

407

415

423

431

76

156

164

172

180

189

197

205

213

221

230

238

246

254

26

3

271

279

287

295

304

312

320

328

336

344

353

361

369

377

385

394

402

410

418

426

435

443

Source:Adaptedfrom

ClinicalGuidelinesontheIdentification

,Evaluation

,andTreatmentofOverweight

andObesityinAdults:TheEvidenceReport.

BodyMassIndexTable

Normal

Overweight

Obese

ExtremeObesity


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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

individuals energy expenditure (Spiegelman 2007). Thisobservation 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.

Under normal conditions, the bodys 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% (Hofbauer2007). 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

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 ourbodies 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.

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.


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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 useand 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 hormonaldata relating to the bodys 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), andfat absorption, and to elevate energy expenditure by

boosting 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, energy

use, 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


12/26

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 thebeginning 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


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. Dont 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 doctors

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 oraspirin, 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


13/26

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 inlight 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

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 aredesigned 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.

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 patientexpectations 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.

Its 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 arent 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 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 remainsthe objective of current pharmaceutical research and

development.


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.


14/26

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 were 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, somepharmaceutical researchers believe, is that the bodys most importantregulators 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 ifsuccessful, it could prove to be a way to achieve

to the benefits of these surgical interventions

without incurring the risks.

BARIATRIC SURGERY

A WAY TO BYPASS GASTRIC BYPASS?


15/26

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 bodys 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 mostimportant 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

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 FDAapproved 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 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,


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


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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 involves

melanin-concentrating hormone (MCH). This hormone isproduced by neurons in the hypothalamus and acts on

specific receptors in the brain that control our desire for

food. Several different MCH drugs are also now in the

early 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 bodys long-term energy

supply. In contrast, neural and hormonal messages from

the gastrointestinal system contain information about the

status of immediately available energy stores. Importantgut 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.

One difficulty facing scientists working on the design of a

practicable peptide YY obesity therapy is the chemical

composition of the hormone itself: its complex structure

makes a pill formulation difficult, if not impossible, to

create. Consequently, a nasal spray is being studied,

although this route may reduce the drugs potential

effectiveness. In addition, some patients in clinicalstudies developed nausea and vomiting, raising concerns

about 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 their

appetite, 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 be

proven in the lab and clinic.



17/26


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 hormona l, 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.


18/26

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 thatDr. 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).

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 cellmessengers, called adipokines, which are essential to

many of the bodys 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.

Fat Storage

Tinkering with the bodys 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 wouldbe 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 bodys 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 doesnt 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. Its hard to fool biology, although we continue to try.


Treating obesity is different from

treating cancer, Dr. Seeley indicates.

The body doesnt 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. Its hard to fool

biology, although we continue to try.


19/26

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 acomplex 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 drugtherapy 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 bodys metabolic rate, there are signs that thedevelopment of drugs to produce a persistent change in metabolic rate maybe possible.

8


20/26

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.


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


21/26

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


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R E F E R E N C E S


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A C S H B O A R D O F T R U S T E E S

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Norman E. Borlaug, Ph.D.Texas A&M University

Michael B. Bracken, Ph.D., M.P.HYale University School of Medicine

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Hon. Bruce S. GelbNew York, NY

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Emeritus

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Elizabeth RoseAim High Productions

Lee M. Silver, Ph.D.Princeton University

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

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Elizabeth M. Whelan, Sc.D., M.P.H.ACSH

C H A I R M A N V I C E C H A I R M A N P R E S I D E N T

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Gary R. Acuff, Ph.D.Texas A&M University

Casimir C. Akoh, Ph.D.University of Georgia

Peter C. Albertsen, M.D.University of Connecticut

Julie A. Albrecht, Ph.D.University of Nebraska, Lincoln

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Blaine L. Blad, Ph.D.Kanosh, UT

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William G. Gaines, Jr., M.D., M.P.H.College Station, TX

Charles O. Gallina, Ph.D.Professional Nuclear Associates

Raymond Gambino, M.D.Quest Diagnostics Incorporated

Randy R. Gaugler, Ph.D.Rutgers University

J. Bernard L. Gee, M.D.Yale University School of Medicine

K. H. Ginzel, M.D.University of Arkansas for Medical Science

William Paul Glezen, M.D.Baylor College of Medicine

Jay A. Gold, M.D., J.D., M.P.H.Medical College of Wisconsin

Roger E. Gold, Ph.D.Texas A&M University

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

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

Center

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

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James Ian Gray, Ph.D.Michigan State University

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

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Lester Grinspoon, M.D.Harvard Medical School

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

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

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Davis

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

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Columbia 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 Medical

School

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 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, 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 Medical

School

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-MadisonJohn 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


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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 Childrens 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 Childrens Hospital of Philadelphia

John Patrick OGrady, 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 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 SchoolStanley 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 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., FRCPKings 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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obesity and new pharmaceutical approaches

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