The Leptin Era: New Insight Into the Mechanisms of Body Weight Homeostasis

IMPORTANCE OF BODY WEIGHT HOMEOSTASIS The relationship between health and body weight has long been recognized, but until recently the specific mechanisms controlling body weight have been poorly understood. Sparked by the cloning of the obese gene and its protein product leptin, and fueled by the increasing understanding of the health risks associated with obesity, research into the homeostatic control of body weight has been advancing rapidly. These advances promise new insight, not only into the physiologic basis of obesity, but also into the mechanisms underlying diseases of underweight. Importance of Obesity as a Public Health Problem Obesity affects more than one fourth of all adults in the United States and an increasing number of children. Its prevalence is increasing rapidly in most age and ethnic groups (1,2), and similar trends are seen in many industrialized nations in Europe and Asia (3-5). Excess body fat is associated with substantially increased risks for a variety of diseases, including type II diabetes mellitus, hypertension, dyslipidemia, obstructive sleep apnea, and ischemic heart disease (6-8), which in turn confer increased morbidity, mortality, and medical costs on the obese population (8-11). As a result, obesity is now recognized as a critically important public health problem, estimated to be the second leading cause of preventable death in the United States today (12). Although most of the complications of obesity occur during adulthood, significant morbidity and mortality attend childhood obesity. The most obvious complications are orthopedic sequelae, including genu varum, valgus deformities, and slipped capital femoral epiphysis and genu. Obesity is a predisposing factor in approximately 60% of cases of slipped capital femoral epiphysis; the majority of such patients have bilateral disease (13). Pseudotumor cerebri appears to be associated with obesity in adolescent children (14,15), as it is in adults, but there is no clear association between these conditions in preadolescent children (16). Obstructive sleep apnea is potentially the most life-threatening complication in the pediatric age range. Its incidence is difficult to estimate, because the disorder is probably underrecognized. In one study, investigators reported polysomnographic abnormalities in approximately 7% of a group of obese children (17). Tonsillar and adenoidal hypertrophy are important risk factors for obstructive sleep apnea in children, but obesity is also an important contributor, as it is in adults (18). Polysomnographic abnormalities in most obese children are mild, and many improve with adenoidectomy, but coma and deaths have been reported, particularly in patients with Prader-Willi syndrome. Thus, patients with significant obesity and sleep disturbances or daytime somnolence should be further evaluated for obesity-hypoventilation syndrome. Type II diabetes mellitus in children and adolescents, often termed maturity-onset diabetes of youth, is increasing in incidence, coincident with the increasing prevalence of obesity in this population. In a large midwestern diabetes clinic, the percentage of diabetic children with maturity-onset diabetes rose from 4% to 16% during a 12-year period (19). Obesity-associated diabetes most commonly occurs in early puberty, in children 12 to 14 years of age, and genetic risk factors are similar to those in adults, with particularly high incidence in Pima Indian, African American, and Mexican American children (19). Acanthosis nigricans is an important sign of early insulin resistance. Juvenile-onset obesity is also associated with steatohepatitis. Similar to maturity-onset diabetes of youth, obesity-associated steatohepatitis is most commonly found in early puberty. In a group of Japanese children, steatohepatitis was more closely associated with insulin resistance than with the degree of obesity per se(20). The natural history of the disease is not known, but the presence of fibrosis in some biopsy specimens suggests that significant liver injury can occur. Weight loss can reverse the clinical and many of the associated histologic abnormalities (21). The relationship between obesity-associated steatohepatitis in children and nonalcoholic steatohepatitis in adults is not clear. However, it is troubling that nonalcoholic steatohepatitis is an increasingly important cause of cirrhosis and of the need for orthotopic liver transplantation in adults. Psychosocial consequences of obesity are more difficult to measure than the medical sequelae, but substantial morbidity is suggested by the lower rates of school achievement, marriage, and income among obese young adults. Many of these effects can be attributed to discrimination against the obese, rather than to decreases in self-esteem or underlying mental illness (22). Other Disorders of Body Weight Homeostasis Although obesity is the most prevalent disorder of body weight homeostasis, other disorders affecting body weight are also seen in childhood. Several chronic diseases, including inflammatory bowel disease, cystic fibrosis, and acquired immune deficiency syndrome, are often associated with underweight and growth failure. In these disorders, appetite varies, but energy intake is often below ideal needs, even when there is little or no evidence of malabsorption (23-25). These observations imply that there is dysregulation of the homeostatic controls of appetite and energy metabolism in these chronic diseases. However, the cause of the relative anorexia associated with these disorders is unknown. Numerous cytokines and other regulatory factors are elaborated during the course of these disease, but the circulating levels of these mediators are not consistently elevated and do not correlate well with the degree of anorexia. As in other states of malnutrition, including anorexia nervosa, a variety of endocrine disturbances are seen, including low levels of insulin-like growth factor I, but these changes are consistent with the state of low body fat and are therefore more apt to be a consequence of malnutrition than a primary cause of anorexia (26,27). Developmental Regulation of Body Fat Alterations in body fat homeostasis occur during normal physiologic development. Dramatic changes in the amount and distribution of body fat in women occur during puberty and after menopause, suggesting that variations in gonadal hormones strongly regulate adipose stores (28,29). This hypothesis is supported by the finding that ovariectomy or castration in animals or humans is associated with the development of obesity (30). Although estrogens and progestins are known to participate in regulating appetite and energy expenditure, the mechanisms through which they act are unknown (31). These varied disorders in which the homeostatic control of body weight is disturbed call for a broader understanding of the control elements involved. During the past 4 years, substantial progress has been made in defining a complex neuroendocrine system that influences appetite and energy metabolism and interacts with systems controlling reproductive and immune function. Much of this research was sparked by the discovery of leptin, a protein that acts as a signal of fat stores. Together with its downstream mediators, leptin contributes to a tightly regulated system for body fat homeostasis. Understanding this control system will ultimately provide an explanation for the loss of homeostatic control over body weight associated with obesity and many other clinical disorders. LIPOSTAT HYPOTHESIS Tight Regulation of Body Weight Over Time Considerable clinical and experimental evidence points to the existence of sensitive systems for controlling body weight in animals and humans. In the absence of developmental changes or disease, most people exhibit remarkable stability in body weight over time within a given environment, despite considerable variability in meal size, content, and frequency. Obese humans are resistant to changes in body weight, as manifested by the poor success of dietary changes in achieving long-term weight loss (2-5% success over 5 years) (32,33). 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