- Email: [email protected]
Leptin and the neurobiology of eating disorders
EDITORIAL Leptin and the neurobiology of eating disorders
A
norexia nervosa and bulimia nervosa are major psychiatric disorders characterized by abnormal eating patterns and preoccupation with body shape and weight.1 These disorders are associated with substantial psychosocial morbidity, and nutritional deficits and recurrent purging behaviors can result in potentially severe medical complications.2,3 The pathogenesis of these eating disorders is unknown, although studies of their genetic epidemiology suggest a significant biologic contribution. Research on these disorders is an important priority, given that current treatments for anorexia nervosa have limited efficacy, and patients with both disorders frequently experience chronic and recurrent symptoms. Clinical investigations on the role of neurobiologic factors in eating disorders have commonly been guided by systematic studies of symptom patterns. Thus analysis of eating behavior in patients with bulimia nervosa in laboratory settings has demonstrated impaired postingestive satiety, a probable factor in the characteristically large size of binge meals. This observation directed research attention toward serotonin and cholecystokinin, two neurochemical mediators of satiety. Bulimia nervosa does appear to be associated with decreased responsiveness in serotonergic and cholecystokinin pathways.4,5 Although research probes of serotonin function in low-weight anorexic patients have also shown diminished responses, other studies suggest that individuals susceptible to anorexia nervosa may actually have increased activity in central nervous system serotonergic pathways.6 In the current issue of the Journal, Frederich et al7 provide a clear and concise summary of the rapidly advancing field of research on leptin regulation in eating disorders. Leptin, the protein product of the ob gene, plays an important role in the central nervous system and peripheral systems involved in the modulation of food intake and energy metabolism.8 As reviewed by Frederich et al, circulating leptin concentrations are markedly reduced in low-weight anorexic patients in
J Lab Clin Med 2002;70-1. Copyright © 2002 by Mosby, Inc. 0022-2143/2002 $35.00 + 0 5/1/121013 doi:10.1067/mlc.2002.121013 70
comparison with values for normal-weight healthy control subjects. As anorexic patients gain weight during treatment, serum leptin levels return to a normal range, possibly at an accelerated rate that may interfere with stable weight restoration.9 Also reviewed are recent reports indicating that serum leptin levels in normalweight patients with bulimia nervosa, although not as low as those in anorexia nervosa, are significantly below control levels and appear to remain low after remission of bulimic episodes.10 Investigators studying anorexia nervosa face inherent difficulties when measuring biologic variables— such as catecholamines, thyroid hormones, and leptin— that are influenced by nutritional state and body weight. Given the absence of weight-matched healthy control subjects, a common approach is to identify a regression relationship between the biologic variable of interest and adjusted body weight (eg, body mass index). Measurements in the anorexic patient can then be compared with estimated normal values by extending the regression curve to the appropriate low body mass index. This approach has been applied, for example, to assessment of metabolic rate in anorexia nervosa.11 The authors summarize data from their laboratory indicating that leptin levels are higher in anorexia nervosa than would be expected when adjusting for percent ideal body weight,7 and they consider factors that could contribute to variable results from other investigators. Given that serum leptin levels in anorexia nervosa can be quite low, one source of variability could be differences in assay techniques across laboratories. In their report, the authors present very useful data showing robust consistency for results obtained with three commercial kits based on radioimmunoassay and enzyme-linked immunosorbent assay methods. These findings support the authors’ conclusion that assay differences are not likely to be a critical factor contributing to variable results in previous clinical studies. As highlighted by these authors and others, refinements in clinical aspects of study methodology will be important in future research on leptin regulation in eating disorders. Assessing the effects of illness phase and current treatment on caloric intake during the days before the study may be helpful.12 Conversely, it may
J Lab Clin Med Volume 139, Number 2
be beneficial to characterize control groups with respect to their dietary intake, perhaps including a separate comparison group of individuals with restrained eating patterns. Additional studies of the effects of psychotropic medications, exercise, and menstrual cycle phase on leptin levels will be useful. Controlled laboratory studies are needed to provide guidance regarding the implications of altered serum leptin levels for symptom patterns in patients with eating disorders. Thus it will be useful to evaluate the threshold at which leptin alterations are associated with significant changes in eating behavior. With respect to findings in anorexia nervosa, it will be important to clarify the behavioral and physiologic consequences of a below-normal leptin level that is higher than would be expected based on degree of weight loss. For example, in considering the possible role of leptin alteration in the amenorrhea of anorexia nervosa,13 additional data are needed to clarify the relative importance of absolute leptin level versus the relative level based on adjustment for body weight. The timely report by Frederich et al7 in this issue of the Journal highlights the promising potential for followup studies of leptin regulation in eating disorders. This research will undoubtedly include measurement of circulating leptin-binding protein concentrations and development of indirect measures of leptin receptor function. An important future direction for translational research is likely to include assessment of interactions between leptin-modulated pathways and related neurochemical messengers such as the catecholamines, serotonin, neuropeptide Y, and the melanocortins. DAVID C. JIMERSON, MD Professor of Psychiatry Beth Israel Deaconess Medical Center Harvard Medical School 330 Brookline Ave Boston, MA 02215
Editorial
71
REFERENCES
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 2. American Psychiatric Association Workgroup on Eating Disorders. Practice guideline for the treatment of patients with eating disorders [revision]. Am J Psychiatr 2000;157:1-39. 3. Wolfe BE, Metzger ED, Levine JM, Jimerson DC. Laboratory screening for electrolyte abnormalities and anemia in bulimia nervosa: a controlled study. Int J Eat Disord 2001;30: 288-93. 4. Geracioti TD Jr, Liddle RA. Impaired cholecystokinin secretion in bulimia nervosa. N Engl J Med 1988;319:683-8. 5. Wolfe BE, Metzger E, Jimerson DC. Research update on serotonin function in bulimia nervosa and anorexia nervosa. Psychopharmacol Bull 1997;33:345-54. 6. Kaye WH. Anorexia nervosa, obsessional behavior, and serotonin. Psychopharmacol Bull 1997;33:335-44. 7. Frederich R, Shousheng H, Raymond N, Pomeroy C. Leptin in anorexia nervosa and bulimia nervosa: importance of assay technique and method of interpretation. J Lab Clin Med 2002;139:72-9. 8. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763-70. 9. Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC. Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain. J Clin Endocrinol Metab 1997;82:1845-51. 10. Jimerson DC, Mantzoros C, Wolfe BE, Metzger ED. Decreased serum leptin in bulimia nervosa. J Clin Endocrinol Metab 2000;85:4511-4. 11. Obarzanek E, Lesem MD, Jimerson DC. Resting metabolic rate of anorexia nervosa patients during weight gain. Am J Clin Nutr 1994;60:666-75. 12. Chin-Chance C, Polonsky KS, Schoeller DA. Twenty-fourhour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake. J Clin Endocrinol Metab 2000;85:2685-91. 13. Flier JS. Clinical review 94: What’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab 1998;83: 1407-413.
A
norexia nervosa and bulimia nervosa are major psychiatric disorders characterized by abnormal eating patterns and preoccupation with body shape and weight.1 These disorders are associated with substantial psychosocial morbidity, and nutritional deficits and recurrent purging behaviors can result in potentially severe medical complications.2,3 The pathogenesis of these eating disorders is unknown, although studies of their genetic epidemiology suggest a significant biologic contribution. Research on these disorders is an important priority, given that current treatments for anorexia nervosa have limited efficacy, and patients with both disorders frequently experience chronic and recurrent symptoms. Clinical investigations on the role of neurobiologic factors in eating disorders have commonly been guided by systematic studies of symptom patterns. Thus analysis of eating behavior in patients with bulimia nervosa in laboratory settings has demonstrated impaired postingestive satiety, a probable factor in the characteristically large size of binge meals. This observation directed research attention toward serotonin and cholecystokinin, two neurochemical mediators of satiety. Bulimia nervosa does appear to be associated with decreased responsiveness in serotonergic and cholecystokinin pathways.4,5 Although research probes of serotonin function in low-weight anorexic patients have also shown diminished responses, other studies suggest that individuals susceptible to anorexia nervosa may actually have increased activity in central nervous system serotonergic pathways.6 In the current issue of the Journal, Frederich et al7 provide a clear and concise summary of the rapidly advancing field of research on leptin regulation in eating disorders. Leptin, the protein product of the ob gene, plays an important role in the central nervous system and peripheral systems involved in the modulation of food intake and energy metabolism.8 As reviewed by Frederich et al, circulating leptin concentrations are markedly reduced in low-weight anorexic patients in
J Lab Clin Med 2002;70-1. Copyright © 2002 by Mosby, Inc. 0022-2143/2002 $35.00 + 0 5/1/121013 doi:10.1067/mlc.2002.121013 70
comparison with values for normal-weight healthy control subjects. As anorexic patients gain weight during treatment, serum leptin levels return to a normal range, possibly at an accelerated rate that may interfere with stable weight restoration.9 Also reviewed are recent reports indicating that serum leptin levels in normalweight patients with bulimia nervosa, although not as low as those in anorexia nervosa, are significantly below control levels and appear to remain low after remission of bulimic episodes.10 Investigators studying anorexia nervosa face inherent difficulties when measuring biologic variables— such as catecholamines, thyroid hormones, and leptin— that are influenced by nutritional state and body weight. Given the absence of weight-matched healthy control subjects, a common approach is to identify a regression relationship between the biologic variable of interest and adjusted body weight (eg, body mass index). Measurements in the anorexic patient can then be compared with estimated normal values by extending the regression curve to the appropriate low body mass index. This approach has been applied, for example, to assessment of metabolic rate in anorexia nervosa.11 The authors summarize data from their laboratory indicating that leptin levels are higher in anorexia nervosa than would be expected when adjusting for percent ideal body weight,7 and they consider factors that could contribute to variable results from other investigators. Given that serum leptin levels in anorexia nervosa can be quite low, one source of variability could be differences in assay techniques across laboratories. In their report, the authors present very useful data showing robust consistency for results obtained with three commercial kits based on radioimmunoassay and enzyme-linked immunosorbent assay methods. These findings support the authors’ conclusion that assay differences are not likely to be a critical factor contributing to variable results in previous clinical studies. As highlighted by these authors and others, refinements in clinical aspects of study methodology will be important in future research on leptin regulation in eating disorders. Assessing the effects of illness phase and current treatment on caloric intake during the days before the study may be helpful.12 Conversely, it may
J Lab Clin Med Volume 139, Number 2
be beneficial to characterize control groups with respect to their dietary intake, perhaps including a separate comparison group of individuals with restrained eating patterns. Additional studies of the effects of psychotropic medications, exercise, and menstrual cycle phase on leptin levels will be useful. Controlled laboratory studies are needed to provide guidance regarding the implications of altered serum leptin levels for symptom patterns in patients with eating disorders. Thus it will be useful to evaluate the threshold at which leptin alterations are associated with significant changes in eating behavior. With respect to findings in anorexia nervosa, it will be important to clarify the behavioral and physiologic consequences of a below-normal leptin level that is higher than would be expected based on degree of weight loss. For example, in considering the possible role of leptin alteration in the amenorrhea of anorexia nervosa,13 additional data are needed to clarify the relative importance of absolute leptin level versus the relative level based on adjustment for body weight. The timely report by Frederich et al7 in this issue of the Journal highlights the promising potential for followup studies of leptin regulation in eating disorders. This research will undoubtedly include measurement of circulating leptin-binding protein concentrations and development of indirect measures of leptin receptor function. An important future direction for translational research is likely to include assessment of interactions between leptin-modulated pathways and related neurochemical messengers such as the catecholamines, serotonin, neuropeptide Y, and the melanocortins. DAVID C. JIMERSON, MD Professor of Psychiatry Beth Israel Deaconess Medical Center Harvard Medical School 330 Brookline Ave Boston, MA 02215
Editorial
71
REFERENCES
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 2. American Psychiatric Association Workgroup on Eating Disorders. Practice guideline for the treatment of patients with eating disorders [revision]. Am J Psychiatr 2000;157:1-39. 3. Wolfe BE, Metzger ED, Levine JM, Jimerson DC. Laboratory screening for electrolyte abnormalities and anemia in bulimia nervosa: a controlled study. Int J Eat Disord 2001;30: 288-93. 4. Geracioti TD Jr, Liddle RA. Impaired cholecystokinin secretion in bulimia nervosa. N Engl J Med 1988;319:683-8. 5. Wolfe BE, Metzger E, Jimerson DC. Research update on serotonin function in bulimia nervosa and anorexia nervosa. Psychopharmacol Bull 1997;33:345-54. 6. Kaye WH. Anorexia nervosa, obsessional behavior, and serotonin. Psychopharmacol Bull 1997;33:335-44. 7. Frederich R, Shousheng H, Raymond N, Pomeroy C. Leptin in anorexia nervosa and bulimia nervosa: importance of assay technique and method of interpretation. J Lab Clin Med 2002;139:72-9. 8. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763-70. 9. Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC. Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain. J Clin Endocrinol Metab 1997;82:1845-51. 10. Jimerson DC, Mantzoros C, Wolfe BE, Metzger ED. Decreased serum leptin in bulimia nervosa. J Clin Endocrinol Metab 2000;85:4511-4. 11. Obarzanek E, Lesem MD, Jimerson DC. Resting metabolic rate of anorexia nervosa patients during weight gain. Am J Clin Nutr 1994;60:666-75. 12. Chin-Chance C, Polonsky KS, Schoeller DA. Twenty-fourhour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake. J Clin Endocrinol Metab 2000;85:2685-91. 13. Flier JS. Clinical review 94: What’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab 1998;83: 1407-413.