Pharmacological Therapy of Obesity: Past, Present, and Future

David S. Weigle

University of Washington School of Medicine and Harborview Medical Center, Seattle, Washington 98104

Address all correspondence and requests for reprints to: David S. Weigle, M.D., Endocrinology, Box 359757, Harborview Medical Center, 325 Ninth Avenue, Seattle, Washington 98104. E-mail: weigle{at}u.washington.edu.


    Introduction
 Top
 Introduction
 The past
 The present
 The future
 Conclusions
 References
 
There is probably no medical condition for which a safe and effective form of pharmacotherapy is more highly desired than obesity. Neither is there a condition for which effective treatment would spare so much suffering for so many individuals. There is abundant evidence from epidemiological and interventional studies to suggest that morbidity from diabetes, cardiovascular disease, cerebrovascular disease, osteoarthritis, sleep apnea, and certain cancers could all be reduced in proportion to a reduction in body fat content. Past forms of pharmacotherapy for obesity have often been misguided, and currently available drugs are less effective than we would like them to be. However, our growing understanding of peripheral signals and central nervous system (CNS) pathways involved in the regulation of adiposity makes it very likely that effective new drugs will become available to treat obesity in the near future. This review will provide a brief history of obesity pharmacotherapy, discuss the status of currently available obesity drugs, and outline the major physiological pathways that will form the targets for future drug development.


    The past
 Top
 Introduction
 The past
 The present
 The future
 Conclusions
 References
 
Thyroid hormone was the first drug to be used in the treatment of obesity, perhaps due to the mistaken impression that excessive deposition of body fat was a manifestation of subtle hypothyroidism (1). Although exogenous T4 or T3 produces rapid weight loss, as much as 80% of the lost weight is lean body tissue, and marked increases in both urinary nitrogen and calcium excretion occur. Weight is rapidly regained after discontinuation of therapy, in part due to the thyroid atrophy that accompanies prolonged ingestion of thyroid hormone (2). The most serious consequences of excessive thyroid hormone use for obesity are tachycardia, cardiac arrhythmias, and sudden death (3). In view of these complications, it is surprising that thyroid hormone was widely used in the treatment of obesity until the 1980s.

Dinitrophenol, a respiratory poison that uncouples oxidative phosphorylation and increases metabolic rate, was introduced for the treatment of obesity in 1933 (4). Used either as a single agent or in combination with thyroid hormone (5), dinitrophenol produced rapid weight loss accompanied by sensations of increased warmth, perspiration, or the development of a fever. It is estimated that as many as 100,000 persons may have been treated with this drug (6). Severe toxicities of dinitrophenol, including dermatitis, agranulocytosis, hepatotoxicity, visual impairment, and death, led to discontinuation of its use (6). Amphetamine, which was introduced in 1938, rapidly replaced dinitrophenol as the most widely used treatment for obesity (7). Amphetamine and related drugs have anorectic, sympathomimetic, and CNS-stimulant effects that effectively promote weight loss. Combinations of amphetamine with thyroid hormone, digitalis, and diuretics were prescribed from the 1940s through the 1960s as "Rainbow Pills" (8, 9, 10). This approach to the treatment of obesity caused addiction, hypertension, severe myocardial toxicity, and sudden death (11). Aminorex, an amphetamine-like sympathomimetic drug with anorectic properties, was introduced in Europe in 1965 for the treatment of obesity. An epidemic of chronic pulmonary hypertension caused by precapillary vascular obstruction among users of aminorex was recognized in 1967 and persisted until 1972. Although the drug was withdrawn from the market in 1968, the mortality rate among affected individuals was 50% (12).

Fenfluramine is a drug that both stimulates release and inhibits presynaptic reuptake of serotonin without sympathomimetic or CNS-stimulant activity. The combination of fenfluramine with the sympathomimetic agent phentermine was introduced in 1992 as an effective chronic therapy for obesity that was free of serious side effects (13). Although the "fen-phen" approach was valuable in demonstrating that long-term drug administration is necessary to effectively treat obesity, problems with these agents became evident as early as 1996. In that year, a cluster of cases of primary pulmonary hypertension was linked to use of fenfluramine derivatives in western Europe (14). In the following year, a similar case was reported in a patient in the United States who had used fenfluramine and phentermine for only 23 d (15). This recapitulation of the aminorex experience was not surprising in view of the structural similarity among these anorexic drugs (Fig. 1Go). Of even greater concern was a report in 1997 linking the use of fenfluramine to valvular heart disease (16). This report, which was subsequently confirmed by additional studies (17, 18, 19), led the manufacturer to voluntarily remove both fenfluramine and dexfenfluramine from the market in September 1997.



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Figure 1. Chemical structures of related anorexic drugs. [Reprinted with permission from E. J. Mark et al.: N Engl J Med 337:602–606, 1997 (15 )].

 
The mitral and aortic lesions caused by fenfluramine resembled the valvular abnormalities observed in carcinoid syndrome, another state of serotonin excess. An early Food and Drug Administration (FDA) series found abnormal echocardiograms in 92 of 291 patients (32%) treated with either fenfluramine or dexfenfluramine for up to 24 months (20). However, subsequent studies of patients who underwent echocardiography both before and after medication use suggested a 4.3–16.5% incidence of new cases of valvular regurgitation, most of which were asymptomatic (21, 22). The incidence of valvular lesions in patients treated for less than 3 months was found to be less than 3% (17). Echocardiograms obtained in patients with valvular lesions 6–24 months after discontinuation of fenfluramine or dexfenfluramine therapy have generally shown stability or improvement of regurgitation (23, 24).

Phenylpropanolamine, a sympathomimetic drug found in numerous appetite suppressants and cough or cold remedies, is the most recent weight control drug to be removed from the market due to its association with hemorrhagic stroke. A study of 702 men and women 18–49 yr of age found an odds ratio of 16.58 for the association of phenylpropanolamine-containing appetite suppressants and hemorrhagic stroke in women (25). An odds ratio of 3.13 was found for the first use of a cough or cold remedy containing phenylpropanolamine and hemorrhagic stroke in women (25). Although they have not yet been removed from the market, dietary weight control supplements containing ephedra alkaloids have been associated with hypertension, tachycardia, stroke, seizures, and death (26). Ephedrine itself is not approved for the treatment of obesity in the United States.


    The present
 Top
 Introduction
 The past
 The present
 The future
 Conclusions
 References
 
Medications currently approved by the FDA for treatment of obesity in the United States have been succinctly reviewed by Yanovski and Yanovski (27) and are summarized in Table 1Go. Available agents either promote anorexia by potentiating the CNS effect of norepinephrine or both norepinephrine and serotonin or decrease absorption of fat from the gastrointestinal tract. Selective noradrenergic drugs generally produce a 3–8% weight loss compared with placebo and may cause palpitations, tachycardia, insomnia, hypertension, and dry mouth. These drugs have not been independently associated with pulmonary hypertension or valvular heart disease. Although phendimetrazine and benzphetamine have greater abuse potential than phentermine and diethylpropion, administration of any of these agents for more than 12 wk is not approved. Selective serotonin-reuptake inhibitors including fluoxetine and sertraline have weak and nonsustained weight-reducing effects when given at doses higher than those normally used in the treatment of depression. Only sibutramine and orlistat are approved by the FDA for the long-term treatment of obesity in the United States.


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Table 1. Drugs currently approved for treating obesity

 
Sibutramine.

Sibutramine blocks the presynaptic reuptake of both norepinephrine and serotonin, thereby potentiating the anorexic effect of these two neurotransmitters in the CNS. Unlike fenfluramine and dexfenfluramine, which also release serotonin from presynaptic sites, sibutramine did not cause valvular heart disease in 133 patients treated for a mean of 7.6 months (28). Sibutramine given at 2–5 times the therapeutic dose was found to lack acute abuse potential in comparison with 20 mg of D-amphetamine (29).

The longest randomized, double-blind trial of sibutramine published to date involved 605 obese subjects recruited from 8 European centers (30). After being treated for 6 months with a hypocaloric diet and 10 mg/d of sibutramine, 467 subjects achieving more than 5% weight loss were randomized to 18 months of further treatment with 10–20 mg/d of sibutramine (n = 352) or placebo (n = 115). Forty-two percent of subjects in the sibutramine group and 50% in the placebo group dropped out. Of subjects completing the trial, 43% in the sibutramine group as compared with 16% in the placebo group maintained 80% or more of their original weight loss. An absolute weight loss of 8.9 kg from baseline was achieved in the sibutramine group (Fig. 2Go). The proportion of subjects maintaining at least 5% and 10% weight loss from baseline is shown in Fig. 3Go. Allowing for dropouts and nonresponders, one of five subjects who received sibutramine for the entire 24 months of the study maintained 80% or more of their original weight loss.



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Figure 2. Mean body weight changes in 204 subjects completing 24 months of study on sibutramine and 57 subjects completing 24 months of study on placebo. Data for both sexes are combined. Of 605 subjects enrolled, 467 subjects achieved sufficient weight loss (5%) on sibutramine plus a hypocaloric diet to continue in the trial, and 352 of these were assigned to sibutramine. [Reprinted with permission from W. P. T. James et al.: Lancet 356:2119–2125, 2000 (30 )].

 


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Figure 3. Proportion of subjects on sibutramine and placebo maintaining at least 5% and 10% weight loss. Data for both sexes are combined. [Reprinted with permission from James WPT, Astrup A, Hilsted J, Kopelman P, Rossner S, Saris WHM, Van Gaal LF: Lancet 356:2119–2125, 2000 (30 )].

 
In a number of studies lasting up to 1 yr, weight loss with a hypocaloric diet and 10–20 mg/d of sibutramine ranged from 4.7–7.3% of baseline, or about 2–3 times that observed in placebo-treated control subjects (31, 32, 33, 34, 35). The decline in fasting triglyceride levels ranged from 4.5–42 mg/dl (0.051–0.47 mmol/liter), the increase in high-density lipoprotein cholesterol ranged from 3–9 mg/dl (0.078 to 0.23 mmol/liter), and the change in low-density lipoprotein cholesterol was small and variable. Consistent side effects of sibutramine therapy included a 0.3–2.7 mm Hg increase in systolic blood pressure, a 1.6–3.4 mm Hg increase in diastolic blood pressure, and a 2–5 beat per minute increase in resting heart rate. Other side effects included headache, insomnia, dry mouth, and constipation. One study found that the frequency of adverse events could be reduced without sacrificing efficacy if sibutramine was given intermittently as 12 wk of active drug alternating with 7 wk of placebo over a 44-wk period (36).

Orlistat.

Orlistat is the only approved inhibitor of the gastrointestinal lipases, predominantly pancreatic lipase, necessary for the hydrolysis of triglyceride to free fatty acids in the lumen of the gut. Because this agent can reduce the absorption of dietary fat by up to 30%, it produces weight loss comparable to or greater than that obtained by placing an individual on a fat-restricted diet. Although there are no systemic side effects of orlistat due to its lack of absorption, supplementation of fat-soluble vitamins may be prudent to prevent the development of vitamin deficiency syndromes.

In a representative 2-yr study, 1187 obese adult subjects were placed on a hypocaloric diet for 4 wk (37). Of this group, 892 subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 wk. At the end of this period, the orlistat group was again randomized to receive either placebo, orlistat 60 mg, or orlistat 120 mg 3 times a day for an additional 52 wk. During the first year, orlistat-treated subjects lost more weight than placebo-treated subjects (8.76 vs. 5.81 kg; P < 0.001). During the second year, subjects treated with orlistat 120 mg 3 times a day regained 35.2% of lost weight; subjects treated with orlistat 60 mg 3 times a day regained 51.3% of lost weight; and subjects treated with placebo regained 63.4% of lost weight (Fig. 4Go).



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Figure 4. Mean body weight changes in subjects during a 2 yr study of orlistat vs. placebo. Data for both sexes are combined. [Adapted with permission from M. H. Davidson et al.: JAMA 281:235–242, 1999 (37 )].

 
Other studies of orlistat lasting from 1–2 yr have demonstrated mean weight losses of 5.9–10.0% in comparison with weight losses of 4.6–6.4% in placebo-treated subjects (38, 39, 40). Orlistat has also been shown to reduce regain of weight after 6 months of an energy-restricted diet (41) and to reduce the percentage of subjects with impaired glucose tolerance who progress to develop overt diabetes mellitus (42). In contrast to sibutramine, orlistat causes significant reductions in total and low-density lipoprotein cholesterol and in systolic and diastolic blood pressure. Gastrointestinal side effects of orlistat, including loose stools, increased defecation, fecal urgency, and oily discharge, are significantly more common than observed with placebo and may lead to discontinuation of the drug. One study found that concomitant use of natural fiber (psyllium mucilloid) may reduce the incidence of these gastrointestinal side effects (43).

Because their mechanisms of action differ, it is reasonable to ask whether combined therapy with orlistat plus sibutramine might produce a greater degree of weight loss than is achievable with either agent alone. One study of 34 obese women addressed this issue (44). Subjects were treated with sibutramine for 1 yr and achieved a mean weight loss of 11.6% of initial weight. They were then randomly assigned in a double-blind fashion to 16 additional wk of treatment with either sibutramine plus placebo or sibutramine plus orlistat. The study demonstrated that addition of orlistat produced no additional weight loss during the 16 wk of combined therapy. This finding suggests that weight loss with currently available agents may be limited to about 10% of starting weight. Only 20–30% of unselected individuals will come close to this degree of weight loss, and as shown in Figs. 2Go and 4Go, body weight begins to rise again after 12–18 months of treatment. The possibility of long-term failure of these agents must be born in mind, and drug therapy should be discontinued if significant weight regain occurs.

Guidelines for use of weight control medications.

A useful algorithm for incorporating weight loss medications into the overall treatment plan for overweight and obese individuals has been formulated by the National Institutes of Health (45). It is recommended that all individuals initiate treatment with diet modification, exercise, and behavioral therapy. If these lifestyle changes do not promote a weight loss equivalent to 10% of initial weight or at least 0.5 kg/wk over 6 months, then pharmacotherapy may be considered. Pharmacotherapy should be restricted to individuals with a body mass index (BMI) greater than 30 kg/m2 if there are no obesity-related risk factors present, or a BMI greater than 27 kg/m2 if the patient has hypertension, dyslipidemia, coronary artery disease, type 2 diabetes mellitus, or sleep apnea. If the patient does not lose at least 2 kg in the first 4 wk after initiating therapy, then the likelihood of a response to that medication is low, and consideration should be given to adjusting the dose, discontinuing the drug, or substituting a different medication. If significant weight loss occurs on a medication or the initial weight loss is maintained, then the medication may be continued as long as it remains effective and the side effects are tolerable. Because obesity is a chronic condition, drugs restricted by the FDA for use up to a maximum period of 12 wk should probably not be administered outside the setting of a clinical trial. Sibutramine should be avoided in patients with uncontrolled hypertension or coronary artery disease.

Effects of psychotropic drugs on body weight.

A number of drugs commonly used in the treatment of psychosis, depression, and epilepsy cause marked weight gain that may either diminish patient compliance or increase the risk of an adverse health outcome. Fortunately, newer drugs that cause less weight gain or even promote weight loss are becoming available to treat these conditions. Awareness of the effects of these agents on body weight may allow modification of a patient’s regimen to avoid excessive weight gain. Among the antipsychotics, risperidone, sertindole, olanzapine, and clozapine were found to cause weight gains ranging from 2.1–4.5 kg over the course of 10 wk of treatment, whereas ziprasidone caused a weight gain of only 0.04 kg, which did not differ from placebo (46). Among the antidepressants, the risk for significant weight gain was highest for tricyclic drugs, nonselective monoamine oxidase inhibitors, and the novel agent mirtazapine (47, 48). In contrast, nefazodone appeared to be weight neutral, and bupropion produced modest weight losses that increased with increasing baseline body weight (49). Among the antiepileptics, valproate (50) and gabapentin (51) have been found to cause extreme weight gain in some individuals. Lamotrigine is felt to be weight neutral and in one 32-wk study caused a mean weight gain of only 0.6 kg compared with a weight gain of 5.8 kg in subjects on valproate (52). Topiramate is unique among the antiepileptics in its tendency to cause weight loss. In one study lasting 1 yr, 8 obese subjects treated with topiramate lost an average of 11% of initial weight, and 26 nonobese subjects lost an average of 6.3% of initial weight (53). It is clear that choices made among these agents can have a major impact on the success of a patient’s weight control efforts (Table 2Go).


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Table 2. Psychotropic drugs causing weight gain and alternatives

 

    The future
 Top
 Introduction
 The past
 The present
 The future
 Conclusions
 References
 
The maximal weight loss achievable with any current dietary or pharmacological strategy for treating obesity varies with the individual but appears to be no more than 10% of initial weight. As this threshold is approached, or perhaps as the time spent below initial weight increases, physiological mechanisms acting to preserve body fat mass cause a progressive increase in appetite and decrease in energy expenditure. These regulatory responses prevent further weight loss and make maintenance of achieved weight loss difficult. It is now appreciated that the long-term regulation of adiposity involves both peripheral signals that relay information about adipose tissue mass to the CNS and opposing circuits in the hypothalamus that regulate appetite and energy expenditure (54). To improve the pharmacological options for treating obesity, it will be necessary to intervene at key points within this regulatory network.

Peripheral signals that regulate appetite include both short-acting humoral and neural signals, generated by the gastrointestinal tract in response to a meal, and long-acting hormonal signals that reflect adipose tissue mass (Fig. 5Go). The short-acting signals function largely to terminate individual meals and include fuel molecules, gut polypeptides such as cholecystokinin, and vagal afferent input to the CNS. Augmentation of these meal termination signals has not been an effective strategy for reducing body fat content in either animals or humans. In contrast, the long-acting hormonal adiposity signals affect overall energy balance by modulating both energy intake and energy expenditure and provide good targets for the development of novel antiobesity drugs (54). The dominant adiposity signals acting to reduce energy intake include leptin, which is produced by adipocytes, and insulin, which is produced by pancreatic ß-cells. Both of these hormones circulate at higher levels with increasing adipose mass and interact specifically with receptors in areas of the hypothalamus affecting energy balance. Leptin engages several postreceptor signaling pathways, one of which, the Janus kinase-signaling transducer and activator of transcription (JAK-STAT) pathway, is also used by proinflammatory cytokines that produce anorexia, and another of which, the insulin receptor substrate-phosphoinositol 3-kinase [IRS-PI(3)K] pathway, is also used by insulin in the CNS and in peripheral tissues (55). A more recently described putative adiposity signal acting to increase energy intake is ghrelin, which is produced largely by cells in the oxyntic glands of the stomach. Plasma ghrelin levels rise before a meal and fall immediately after a meal, suggesting that ghrelin may be a physiological stimulus for meal initiation (56). Integrated plasma ghrelin levels are inversely related to adipose mass and increase with various interventions that cause weight loss (57, 58, 59, 60). Thus, ghrelin seems to play a role complementary to leptin and insulin in bringing about changes in energy intake to compensate for changes in adipose mass.



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Figure 5. Peripheral signals regulating appetite.

 
After being transported through the blood-brain barrier (a process that may be sensitive to dietary fat levels in the case of leptin), leptin, insulin, and ghrelin bind specifically to receptors in the arcuate nucleus and other areas of the hypothalamus and hindbrain. Two specific populations of neurons within the arcuate nucleus appear to be critical in translating information conveyed by peripheral adiposity signals into the subjective experience of hunger (54). One population of neurons makes neurotransmitters named neuropeptide Y (NPY) and agouti-related protein (AgRP). The other population of arcuate neurons critical to body weight regulation makes proopiomelanocortin (POMC) which is processed into the neurotransmitter {alpha} melanocyte-stimulating hormone ({alpha} MSH). Experimental administration of NPY into the hypothalamus of animals strongly stimulates feeding by its interaction with the Y1 receptor. In contrast, administration of {alpha} MSH inhibits feeding by its interaction with the melanocortin 4 receptor (MC4r). AgRP antagonizes the binding of {alpha} MSH to MC4r and, therefore, promotes feeding.

A portion of the hypothalamic circuitry that processes peripheral adiposity signals is diagrammed in Fig. 6Go. Leptin and insulin, both of which increase with expansion of adipose tissue, stimulate the activity of POMC neurons and inhibit the activity of NPY/AgRP neurons in the arcuate nucleus. Axons of these neurons project to the paraventricular nucleus and other nuclei of the hypothalamus, which express both Y1 and MC4 receptors. Second-order neurons in these locations integrate POMC and NPY/AgRP input and send projections to other brain areas including the hindbrain and cerebral cortex. When plasma leptin and insulin levels increase, reflecting increased adipose tissue mass, POMC activity exceeds NPY/AgRP activity, and output from the second-order neurons elicits anorexia. When plasma leptin and insulin levels decrease, reflecting decreased adipose tissue mass, NPY/AgRP activity exceeds POMC activity, and output from the second-order neurons elicits hunger. Available evidence suggests that integrated plasma ghrelin levels increase as adipose mass falls (57, 58, 59, 60). This increase should also elicit an increase in appetite by virtue of the ability of ghrelin to stimulate arcuate NPY/AgRP neurons (61).



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Figure 6. A portion of the hypothalamic circuitry regulating energy balance in response to peripheral adiposity signals.

 
There is compelling evidence from very rare single gene mutations associated with obesity in humans that these peripheral signals and CNS pathways are critical in determining body weight and are the correct targets for development of new antiobesity drugs. Inactivating mutations of both the leptin gene (62) and the leptin receptor gene (63) produce morbid obesity, and leptin replacement eliminates the obesity caused by leptin deficiency (64). Similarly, interference with POMC signaling at the level of POMC gene expression (65), POMC posttranslational processing (66), or {alpha} MSH binding to MC4r (67, 68) all cause obesity. Thus, agents that augment leptin signaling or enhance the central effects of {alpha} MSH would appear to be particularly good candidates for antiobesity drugs.

The effects of recombinant leptin have been studied in both lean and obese genetically uncharacterized human subjects. Daily sc injection of leptin in obese volunteers for 24 wk produced a variable degree of weight loss, with a mean change of -7.1 kg at a dose of 0.3 mg/kg, the highest dose studied (69). Although the average effect of leptin at intermediate doses was modest, the data from this study suggested the existence of both leptin responders and nonresponders. Weekly administration of pegylated recombinant human leptin for 12 wk was without effect on body weight or sleeping metabolic rate in obese men (70), and daily administration of leptin at a dose of 0.3 mg/kg produced no changes in autonomic nervous system activity or resting metabolic rate in lean men (71). The generally disappointing outcome of these leptin trials has been ascribed to the existence of leptin resistance in subjects at their baseline weight. More recently, twice-daily low dose leptin administration to four subjects was found to reverse the reductions in circulating thyroid hormone levels and nonresting energy expenditure caused by prior diet-induced weight loss (72). This finding suggests that it may be more appropriate to use leptin as an agent to reduce regain of weight lost by other strategies. Efforts are under way to find molecules that may bypass leptin resistance by activating the leptin signaling cascade distal to the leptin receptor. One such agent appears to be ciliary neurotrophic factor, a cytokine that can activate the STAT 3 signaling pathway in hypothalamic neurons through a receptor distinct from the leptin receptor (73). Ciliary neurotrophic factor has been shown to produce rapid weight loss in obese animal models of leptin resistance (74), humans being treated for amyotrophic lateral sclerosis (75), and obese humans with BMI values of 35–50 kg/m2 (76).

Augmentation of {alpha} MSH signaling in the hypothalamus poses a greater challenge because of the difficulty in delivering small peptides to their site of action within the brain. One approach to this problem may be to administer active fragments of the POMC molecule by the intranasal route (77). In a study of 36 lean human subjects, MSH/ACTH4–10 and placebo were given intranasally for 6 wk to assess effects on body composition and plasma hormone concentrations (78). Subjects on active treatment experienced a significant 1.68-kg reduction in body fat mass, a 24% decrease in plasma leptin levels, and a 20% decrease in plasma insulin levels. These results, although preliminary, suggest that peptide or small molecule agonists for the MC4 receptor may eventually prove to be effective agents for treating obesity.

Another promising approach for treating obesity may be to block the action of ghrelin in the CNS. In support of this approach, gastric bypass surgery, a uniquely effective intervention to control obesity, has been shown to suppress plasma ghrelin to nearly undetectable levels (60). Other conditions that produce weight loss, including chronic heart failure (57), anorexia nervosa (58, 59), and dietary energy restriction (60), result in elevated ghrelin levels. In addition, one of the most extreme forms of human obesity, the Prader-Willi syndrome, has recently been associated with ghrelin levels 4.5-fold higher than in equally obese controls (79). It is tempting to speculate that extremely high ghrelin levels may drive the excessive food intake observed in this condition and that suppression of ghrelin action could be an effective treatment for affected individuals.

Numerous other targets for the development of antiobesity drugs exist within and outside the central nervous system. Examples include the receptor for melanin-concentrating hormone, a potent orexigenic neurotransmitter produced in the lateral hypothalamus (80); the cannabinoid receptor (81); and 11-ß hydroxysteroid dehydrogenase type 1, an enzyme that metabolizes inactive cortisone into cortisol within adipose tissue and liver (82, 83). Research is being actively pursued on these and other systems both in academic laboratories and the private sector (84). However, the concern has been raised that the hypothalamic and peripheral systems that evolved to regulate body fat content may be more efficient in preventing loss of fat stores than excess accumulation of adipose tissue (85). If this is true, drugs that target some of these systems may be less effective than anticipated. Obviously, a great deal more basic and human research will be required to determine which of these targets provides the most useful strategy for treating obesity.


    Conclusions
 Top
 Introduction
 The past
 The present
 The future
 Conclusions
 References
 
Medications used in the past to treat obesity have caused unacceptable morbidity and mortality. Sibutramine and orlistat, the only agents currently approved for long-term treatment of obesity, may cause up to a 10% weight loss when used in combination with dietary, behavioral, and exercise therapy. Although this degree of weight loss may have a salutary effect on medical comorbidities, there is a need for more effective and better tolerated antiobesity drugs. Our growing understanding of the complex and highly redundant physiological mechanisms regulating body fat content will allow the development of such drugs. The redundancy of this regulatory system underscores the evolutionary importance of regulating total body energy stores and suggests that normalization of body weight may require the simultaneous administration of drugs targeting several peripheral or CNS-signaling molecules.


    Footnotes
 
This work was supported by National Institutes of Health Grants DK55460 and DK02860.

Abbreviations: AgRP, Agouti-related protein; BMI, body mass index; CNS, central nervous system; MC4r, melanocortin 4 receptor; {alpha} MSH, {alpha} melanocyte-stimulating hormone; NPY, neuropeptide Y; POMC, proopiomelanocortin.

Received January 30, 2003.

Accepted March 5, 2003.


    References
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 Introduction
 The past
 The present
 The future
 Conclusions
 References
 

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