Leptin as a Therapeutic Agent—Trials and Tribulations

Christos S. Mantzoros and Jeffrey S. Flier

Division of Endocrinology and Metabolism Department of Internal Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts 02215

Address correspondence and requests for reprints to: Christos S. Mantzoros, M.D., D.Sc., Division of Endocrinology, RN 325, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, Massachusetts 02215.


    Introduction
 Top
 Introduction
 References
 
Obesity is a prevalent condition that is reaching epidemic proportions in the United States. Sixty-three percent of men and 55% of women are overweight [body mass index (BMI) of 25 kg/m2 or higher], whereas 22% of the United States adult population is obese (BMI of 30 kg/m2 or higher) (1). More importantly, the prevalence of obesity has almost doubled in the past decade (1). The consequences of obesity are serious. Approximately 80% of obese adults have at least one and 40% have two or more comorbidities, which include diabetes, hyperlipidemia, hypertension, cardiovascular disease, gallbladder disease, osteoarthritis, and certain cancers (1, 2). The number of deaths directly attributable to obesity, approximately 300,000 annually in the United States, is second only to smoking in its contribution to total mortality rates (2). The direct and indirect costs of obesity have been estimated to account for 10% of the national health care budget. Thus, it is evident that obesity is a major medical and public health problem.

Obesity results from storage of excess energy as fat during periods when energy intake exceeds energy expenditure. Our understanding of the specific mechanisms underlying the regulation of energy homeostasis has been greatly advanced by research that followed the discovery of leptin 5 yr ago (3, 4, 5). Leptin, the product of the ob gene, is mainly produced by adipocytes, and its circulating levels reflect the amount of energy stored in adipose tissue (3, 4, 5). Although body fat accounts for approximately 50–60% of leptin’s variability, other factors such as age, gender, diurnal variation, and hormonal (mainly insulin) and cytokine levels also contribute to the regulation of leptin levels. Leptin acts by binding to specific receptors and activating the JAK STAT system for signal transduction (reviewed in Refs. 3, 4). Leptin has pleiotropic actions, but its main target is considered to be the central nervous system. In the hypothalamus, leptin increases energy expenditure and inhibits appetite and weight gain by decreasing the expression of orexigenic neuropeptides such as NPY and AgRP, and by increasing the expression of anorexigenic neuropeptides such as a-MSH, CRH, and CART (reviewed in Refs. 3, 4, 5). The discovery of leptin 5 yr ago triggered renewed enthusiasm for obesity research and has reinforced the view that obesity is a disease with strong biological basis. It has also accelerated research aimed at delineating the molecular pathways regulating energy homeostasis.

Will leptin be an effective treatment for obesity in humans? Although leptin-deficient animals and humans are extremely obese, the vast majority of obese humans have high circulating leptin concentrations indicating that obesity is a leptin-resistant state in humans (3, 4, 5). This concept of leptin resistance remains poorly understood, and the mechanisms underlying its development are just now being elucidated. One of these mechanisms may be impaired leptin transport into the brain. New Zealand obese mice and mice with obesity induced by high fat diet are resistant to peripheral leptin administration but respond to leptin when injected intracerebroventricularly (5). The ratio of CSF to serum leptin levels is relatively lower in obese subjects. Thus, suboptimal leptin transport through the blood brain barrier may be one factor that underlies the development of leptin resistance in humans (5). However, preliminary evidence suggests that peripheral leptin administration in very high doses can override the saturable leptin transport system and result in higher CSF leptin levels, probably through a mechanism independent of the saturable leptin transport system (6). Additional sites for leptin resistance include abnormalities of leptin receptors or impairment of leptin signaling. Although leptin receptor mutations are an extremely rare cause of leptin resistance in humans, several intracellular molecules that could inhibit leptin’s actions have been identified (5). For example, a member of the suppressors of the cytokine signaling family (SOCS-3) is induced by leptin and potently inhibits leptin signaling. The existence of leptin resistance creates doubt about the ability of exogenously administered leptin to overcome leptin resistance and effectively reduce body weight in obese humans.

In this issue of the journal, Hukshorn et al. (7) present data from a Phase I–II clinical trial designed to assess the safety of pegylated recombinant native human leptin (PEG-OB). Pegylation [i.e. covalent linkage of proteins to amphiphilic polymers of ethylene glycol (PEG)] results in increased serum half-life and reduced immunogenicity for several proteins, including leptin (7). The authors studied 30 obese men randomized to a double-blind treatment with either SC injections of 20 mg PEG-OB or placebo in addition to a hypocaloric diet (500 kcal less than the daily requirement) for 12 weeks (7). PEG-OB was well tolerated and safe, with no adverse events observed. PEG-OB treatment produced significant suppression of appetite, as measured by eating/hunger questionnaires and a significant correlation of weight loss with percent change in serum triglycerides. No significant changes in body weight or metabolic parameters were observed, but circulating leptin levels in the actively treated group were not significantly elevated, with the exception of only two time points over the 12-week study period. The power of this study to assess changes of body weight was clearly suboptimal. Thus, it remains possible that increasing the dose and/or changing the dose schedule to achieve significantly higher circulating leptin levels could result in significant reductions of body fat and body weight and potentially greater changes in metabolic parameters in future larger trials of PEG-OB.

In addition to this study, which assessed the safety of a long-acting leptin compound, two additional studies have evaluated the safety and efficacy of recombinant human methionyl leptin (met-leptin) administration. The first was an uncontrolled study involving leptin administration to a limited number of leptin-deficient subjects (8), and the second was a double-blind, placebo-controlled, escalating dose cohort trial in 54 lean and 73 obese subjects (9). In the first study, low doses of met-leptin, calculated to raise circulating leptin levels to 10% of that predicted based on body fat, were administered to subjects with congenital leptin deficiency. Leptin was well tolerated and resulted in a dramatic reduction of appetite, food intake, and body weight (8). After 12 months of treatment, body weight of a leptin-deficient girl was decreased by 16.4 kg, 95% of which was adipose tissue, but metabolic rate and lipid profile were not affected. In the second study, higher doses of met-leptin, ranging from 0.01–0.3 mg/kg daily, were administered for 4–24 weeks. These doses were also well tolerated by lean and obese humans (9). Met-leptin treatment resulted in significant dose-dependent weight loss ranging from -1.3 kg in the placebo group and -1.4 kg in the 0.03 mg/kg group to -7.1 kg in the 0.30 mg/kg group over a 24-week period (9). Importantly, the loss of fat mass accounted for more than 95% of the weight loss achieved in the two highest dose cohorts, whereas changes in fat free mass were not significant (9). These findings suggest that relative leptin resistance can, in some cases, be overcome by high enough leptin concentrations. As in rodents, leptin may have a selective effect to preferentially decrease adipose tissue mass (3, 4). Because variability in the amount of weight lost by individual subjects was considerable, these data suggest that leptin may only be effective in a subset of leptin-resistant obese subjects. In summary, these three studies provide reassuring data regarding the safety and tolerability of the compounds used. The therapeutic potential of met-leptin or PEG-OB in obesity cannot be determined from these early phase clinical trials because they were not specifically designed or powered to assess efficacy in terms of weight reduction or improvement of comorbidities.

The first large study aimed at evaluating both safety and efficacy of another long-acting leptin molecule (A-200) was recently presented in abstract form (10). Two hundred seventy obese subjects (BMI, 90 ± 13 kg) were enrolled in a 24-week randomized, placebo-controlled pilot study with minimal dietary intervention (500 kcal less than the daily requirement). Subcutaneous administration of A-200 was reported to be safe, well tolerated, and resulted in a statistically significant reduction in body weight and fat mass. The weight lost was predominantly adipose tissue and was in the same order of magnitude as that produced by currently approved medications for the treatment of obesity (see below) (11). Because abdominal fat is preferentially decreased earlier in response to weight loss, it remains possible that leptin treatment may affect not only body composition but also body fat distribution. This remains to be addressed by careful studies that should also assess its effect on metabolic parameters that are more closely associated with abdominal than total fat.

Taken together, data from these studies indicate that leptin treatment is safe, well tolerated (6, 7, 8, 9, 10), and clearly effective in subjects with congenital leptin deficiency (8). In some subjects with common obesity, leptin may reduce appetite in low doses (7, 9, 10), and body weight and body fat at the maximal doses studied (9, 10), but this needs to be confirmed by future studies. These studies also raise several intriguing questions that need to be addressed by well-designed studies in the future.

Although all leptin-deficient subjects are expected to respond dramatically to administration of low leptin doses, "leptin-resistant" obese subjects required higher doses, and their responses were highly variable. Are there any specific phenotypic characteristics or laboratory tests that could predict response to leptin treatment? Baseline serum leptin levels do not seem to be such a predictor based on data provided by one of these studies (9). Can markers be developed that will predict response to leptin treatment? Will response at an early time point be a predictor of long-term response, as is the case with orlistat treatment? These important questions remain to be clarified in future large leptin trials.

Additional questions can be raised. Would leptin treatment of obese subjects be more effective if the caloric restriction accompanying leptin administration had been higher than 500 kcal daily? Could leptin treatment play a role in the long-term maintenance of weight loss achieved by other means? Achieving and maintaining a reduced weight is made difficult by the reduction in energy expenditure and increased appetite that are induced by weight loss. Maintenance of body weight at 10% below the baseline in obese subjects has been associated with approximately an 8-kcal/kg reduction in total energy expenditure (11). Are decreasing leptin levels in response to weight loss responsible for the observed decrease in total energy expenditure and/or increased appetite, and would exogenously administered leptin be able to prevent metabolic rate and appetite adaptations that tend to restore body weight to baseline? Falling leptin levels regulate the neuroendocrine response to food deprivation, and, in addition, hypothalamic orexigenic and anorexigenic neuropeptides are more responsive to leptin during fasting than in the obese state in rodents (5, 12). If this is also the case in humans, leptin administration might be more effective as a weight-reducing treatment when administered together with very low calorie diets, or as a maintenance treatment after a significant weight loss has been achieved using other, medical, or surgical treatments.

A third question that will be raised by current and future studies is how these initial data regarding leptin’s efficacy compare with those of currently approved medications for long-term treatment of obesity. Administration of the highest dose of met-leptin resulted in a weight reduction to approximately 8% below baseline or 6% below the levels achieved by the placebo-treated group, whereas 95% of this weight reduction was due to fat loss (8, 9). Administration of the long-acting leptin analog decreased body weight by approximately 3% and body fat by approximately 6.5% below baseline or 2% and 5% below the levels achieved by the placebo-treated group, respectively (10). It has previously been shown that 24 weeks of treatment with either orlistat or sibutramine result in a decrease of body weight by 3–3.6% and 5–6% beyond that of the placebo-treated group, respectively (11). Because drug therapy for obesity needs to be administered continuously over a prolonged period of time like drug therapy for any other chronic disease, not only efficacy, but also safety, tolerability, and compliance are issues of paramount importance and need to be assessed in future long-term cost effectiveness and cost efficacy studies.

The fourth question raised by these preliminary leptin trials is whether leptin administration has additional effects in humans. Although leptin was originally viewed as an antiobesity hormone, it is now evident that may have more pleiotropic actions. Experiments in rodents have shown that leptin activates the sympathetic nervous system, is involved in regulation of blood pressure, hematopoiesis, immune function, angiogenesis, and brain and bone development, as well as the regulation of glucose metabolism, lipid oxidation, substrate partitioning, and adipocyte apoptosis (3, 4). Biological effects expected based on observations in rodents, such as changes in energy expenditure and lipid profile, have so far not been seen in initial studies in humans. Neither of the above studies that reported data on these parameters was adequately powered to assess changes in insulin resistance and lipid profile, however. Moreover, the methods used to assess insulin resistance in study participants were limited, and only one unpublished study included overtly diabetic subjects. Furthermore, none of these trials specifically assessed the role of leptin in activation of the sympathetic nervous system, regulation of blood pressure, neuroendocrine function, hematopoiesis, immune function, or angiogenesis.

Interventional studies using leptin administration to humans are absolutely necessary. These studies are expected to contribute greatly to our knowledge of energy homeostasis and, on this basis, may lead to the development of novel therapeutic approaches to obesity. In addition, leptin sensitizers or leptin analogs that are smaller, more potent, and better absorbed need to be developed and carefully studied in comparison to first and second generation leptin molecules. Finally, downstream effectors of leptin signaling that can bypass loci responsible for leptin resistance, such as melanocortin agonists, also need to be studied in future clinical trials.

In the United States, nearly one half of women and more than one third of men report they are attempting to lose weight at any given time. Although short-term weight loss is often possible, durable weight loss is not often attained. Despite initial hopes, results from recent trials suggest the notion that leptin will not be a "magic bullet" for the treatment of obesity. The pattern of weight loss typically seen with existing antiobesity treatments is an initial decline, followed by a slower decrease until the 24th week, after which a plateau is reached. This suggests that any drugs used to treat obesity activate compensatory mechanisms that limit further decreases in body weight. Effective treatment of severe obesity may, therefore, require the simultaneous targeting of more than one pathway in the complex and redundant system that controls energy homeostasis (3, 4, 11). As leptin and compounds that activate the melanocortin pathway become available for clinical research studies, many new insights are sure to emerge with respect to the pathophysiology, prevention, and treatment of obesity and eating disorders. We have entered an exciting era in clinical research that is expected to give answers to many important questions. Although we are now at a very early stage, it seems likely that these efforts will eventually provide tangible benefits to obese persons who are striving unsuccessfully to control excessive body weight.


    Acknowledgments
 
Due to limitation in the number of references we were unable to cite many important original papers.

Received September 19, 2000.

Accepted September 19, 2000.


    References
 Top
 Introduction
 References
 

  1. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. 1999 The disease burden associated with overweight and obesity. J Am Med Assoc. 282:1523–1529.[Abstract/Free Full Text]
  2. Allison DB, Fontaine KR, Manson JE, Stevens J, VanItalie TB. 1999 Annual deaths attributable to obesity in the United States. J Am Med Assoc. 282:1530–1538.[Abstract/Free Full Text]
  3. Friedman JM, Halaas JL. 1998 Leptin and the regulation of body weight in mammals. Nature. 395:763–770.[CrossRef][Medline]
  4. Mantzoros CS. 1999 The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med. 130:671–680.[Abstract/Free Full Text]
  5. Ahima RS, Saper CB, Flier JS, Elmquist JK. 2000 Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 21:263–307.[CrossRef][Medline]
  6. Fujioka K, Patane J, Lubina J, Lau D. 1999 CSF leptin levels after exogenous administration of recombinant methionyl human leptin. J Am Med Assoc. 282:1517–1518.[Free Full Text]
  7. Hukshorn CJ, Saris WHM, Westerterp-Plantenga MS, Farid AR, Smith FJ, Campfield LA. 2000 Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. J Clin Endocrinol Metab. 85:4003–4009.[Abstract/Free Full Text]
  8. Farooqi IS, Jebb SA, Langmack G, et al. 1999 Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 341:879–884.[Free Full Text]
  9. Heymsfield SB, Greenberg AS, Fujioka K, et al. 1999 Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. J Am Med Assoc. 282:1568–1575.[Abstract/Free Full Text]
  10. Fujioka K, Murphy-Filkins R, Green D, DePaoli A, LeBel C. Significant body composition changes observed in obese subjects receiving chronic subcutaneous administration of a modified form of recombinant human leptin (Abstract). NAASO Annual Meeting, 2000.
  11. Bray GA, Tartaglia LA. 2000 Medicinal strategies in the treatment of obesity. Nature. 404:672–677.[CrossRef][Medline]
  12. Ahima RS, Prabakaran D, Mantzoros C, et al. 1996 Role of leptin in the neuroendocrine response to fasting. Nature. 382:250–252.[CrossRef][Medline]