Leptin: What ‘Fat Rats’ Have Taught Us

By Michael D. Myers, MD, Los Alamitos, California
Reprinted from Eating Disorders Review
September/October 2003 Volume 13, Number 5
©2002 Gürze Books

We now know that the brain and adipose tissue form an integrated communications network.

Scientists have postulated for many years that adipose tissue must have some function beyond just “hanging out” awaiting the next famine, and that it must be regulated by the central nervous system. In the late 1950s Hervey’s parabiosis experiments (surgically connecting two animals to understand physiologic functions) showed that a humoral factor was involved in regulating weight. However, exactly what this factor was and how it functioned was unknown.

One such factor, subsequently named leptin (from the Greek leptos, or thin), was not discovered until almost three and a half decades later. Leptin is the only protein product of the “ob” gene that is composed of 146 amino acids. Leptin also is a hormone found only in mammals.

When leptin was first discovered, researchers thought that the “magic bullet” for obesity treatment was at hand. After all, mice bred with severe obesity (the ob/ob mouse) that did not produce any leptin had low metabolic rates, were infertile, and were hyperphagic, which led to severe obesity. When these mice were given leptin, their food intake decreased, their metabolic rate increased, and they lost a significant amount of weight.

Thus, researchers assumed that obese individuals must be like the ob/ob mice and either lacked leptin or had such low levels as to not protect against obesity. As a result, “leptimania,” with its wildly optimistic expectations of a cure for obesity, was born. However, like most manias, it ended in disappointment. When researchers measured the leptin levels in obese individuals, they were surprised to find high levels instead of the low levels they had anticipated. What was going on?

Humans and Leptin

To understand the function of leptin in humans, it is helpful to understand some of leptin’s basic physiology. Leptin is produced primarily by white adipose tissue (“fat”). There are many factors involved in the regulation of its production, with significant variations between individuals. Some of the more significant factors are as follows:

Hormonal factors. Several hormones increase leptin production, including insulin (which is generally elevated in obesity) and cortisol. Cortisol is frequently elevated with stress (physiologic or psychologic) and in many mood disorders. Additionally, there is sexual dimorphism, and women generally have much higher leptin levels than men of the same weight (corrected for body fatness). Estrogen appears to stimulate leptin production.

Obesity factors: Obese individuals produce much more leptin than non-obese individuals. This results from the following mechanisms:

1. Obese individuals have larger fat cells than those of nonobese individuals, and larger fat cells produce disproportionately more leptin than smaller cells.

2. Significantly obese individuals frequently have hyperplasia (an increased number of fat cells) compared to their leaner counterparts. Thus they have an increase in the number of leptin-producing cells.

Since leptin is produced primarily by fat cells, higher serum leptin levels are indicative of larger fat stores. Leptin reflects body stores in a steady state condition but it also reflects recent nutritional status. For example, in 1996 Kolacynski noted a 40% increase in leptin levels within 5 hours of overfeeding. Other studies show a greater than 50% decease in leptin after a 24-hour fast. Once produced, leptin enters the circulation and exhibits its greatest effects in the central nervous system, specifically acting on neurons in the hypothalamus. Leptin binds to leptin receptors that affect the secretion of two other neuropeptides, neuropeptide Y (NPY) and pro-opiomelanocortin (POMC). Leptin causes increased synthesis and secretion of POMC and decreased synthesis and secretion of NPY in the hypothalamus.

NPY has been identified as one of the most potent stimulators of food intake. In mice, NPY leads to increased food-seeking behavior and reduces metabolic rate. Within increasing (physiologic) leptin concentrations, the secretion of NPY is diminished. POMC has the opposite effect by increasing metabolic rate and decreasing feeding behavior through its effects on other neurotransmitters. Researchers are still studying the exact actions of POMC in humans.

In the ob/ob mouse, a genetic defect prevents leptin production. When leptin fails to signal the hypothalamus, the brain cannot sense the more-than-adequate nutritional status (fat stores) of the mouse. Thus, the mouse continues to conserve energy by minimizing its metabolic rate and continues to eat in an effort to compensate for what it believes are inadequate energy stores.

Human Obesity

Human obesity (with extremely rare exceptions) doesn’t result from the lack of leptin. In fact, obese individuals have leptin levels that are sometimes as much as two to seven times higher than those of normal-weight persons. Unfortunately, leptin levels above a “normal” amount appear to have minimal effects on reducing food intake or increasing metabolism. This is not to say that leptin is not important in metabolic disorders or dysregulated appetite. Although leptin’s role in metabolic disorders is fascinating, it is far beyond the scope of this brief review.

Leptin and Appetite

Appetite regulation in humans is extremely complicated and requires integration at three levels. The first level is socially or psychologically based, such as hunger perception and the behavioral effects that follow (such as consuming a meal). The second level comes from the periphery and involves metabolic factors (such as glucose levels, amino acid levels, and hormones produced in the periphery). The third level is the central nervous system, which involves the integration of the psychological and metabolic factors with various neurotransmitters, including leptin.

It appears that in many obese individuals, this third level of integration is overwhelmed by dysregulation of psychological and/or peripheral physiological factors. The higher levels of leptin found in obesity fail to increase metabolic rate or decrease appetite enough to prevent or reverse weight gain.

Leptin and Bulimia Nervosa

Bulimia nervosa is characterized by recurrent episodes of binge eating combined with inappropriate compensatory mechanisms (such as vomiting postprandially or the use of laxatives) in an attempt to prevent weight gain. Some studies suggest this is caused by impaired post-ingestive satiation with diminished responsiveness of serotonin-mediated pathways. One group of women with bulimia nervosa showed decreased leptin levels as compared to age- and weight-matched controls, with a tendency toward an inverse relationship between frequency of binge-eating episodes with leptin levels. The degree to which leptin contributes to the abnormalities in eating and satiation in bulimia nervosa is not yet fully understood, but there is significant evidence to suggest a major direct or indirect effect.

Anorexia Nervosa and Leptin

Anorexia nervosa is the most serious of the eating disorders, and is characterized by a body mass index (BMI) of less than 17.5, compared with a “normal” BMI of 18.5 to 25. Since adipose tissue is depleted in anorexia nervosa, the levels of leptin are low, as would be expected. However, in some studies, weight regain in individuals with anorexia nervosa increased leptin concentrations much more rapidly than in weight-matched controls, which may contribute to early satiation and a possibly increased metabolic rate. If this is confirmed in future studies, it may be one of the factors that frustrate attempts to achieve and maintain a more normal weight in individuals afflicted with anorexia nervosa.

Conclusion

Although leptin has not been the long-anticipated silver bullet for obesity treatment as initially hoped, it has helped clarify the biological basis of not only obesity, but also of eating disorders and other metabolic disorders. Although this is far from certain, leptin may play a role in helping obese individuals maintain a reduced obese state, and may be helpful in the dysregulated appetite and satiation seen in the major eating disorders.

Suggest Reading

Blundell JE, Goodson S, Halford JC. Regulation of appetite: role of leptin in signaling systems for drive and satiety. J Obes Relat Metab Disord 2001;May; 25; S29.

Fried SK, Ricci MR, Russell CD, et al. Regulation of leptin production in humans. J Nutr 2000;130:3127S.

Kim S, Moustaid-Moussa N. Secretory, endocrine and autocrine/paracrine function of the adipocyte. J Nutr 2000; 130:3110S.

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Michael D. Myers, MD

Los Alamitos, California

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