What is leptin?

Structure and Functions

Leptin (from the Greek leptos, meaning “thin”) is a protein hormone with important effects in regulating body weight, metabolism, and reproductive function. It is the product of the obese (ob) gene occurring on chromosome 7 in the human. Leptin is produced primarily by adipocytes (white fat cells). It is also produced by cells of the epithelium of the stomach and in the placenta. It appears that as adipocytes increase in size because of accumulation of triglycerides (fat molecules), they synthesize more and more leptin. However, the mechanism by which leptin production is controlled is largely unknown. It is likely that a number of hormones modulate leptin output, including corticosteroids and insulin.

Disorders and Diseases

At first leptin was assumed to be simply a signaling molecule involved in limiting food intake and increasing energy expenditure. Studies published as early as 1994 showed a remarkable difference in weight gain in mice deficient in leptin (mice with a nonfunctional ob gene). Daily injections of leptin into these animals resulted in a reduction of food intake within a few days and a 50 percent decrease in body weight within a month.

More recent studies in the human have not been as promising. It appears that leptin’s effects on body weight are mediated through effects on hypothalamic (brain) centers that control feeding behavior and hunger, body temperature, and energy expenditure. If leptin levels are low, appetite is stimulated and use of energy limited. If leptin levels are high, appetite is reduced and energy use stimulated. The most likely target of leptin in the hypothalamus is inhibition of neuropeptide Y, a potent stimulator of food intake. However, this inhibition alone could not account for the effects seen, and studies looking at other hormones are under way.

Leptin also affects reproductive function in humans. It has long been known that very low body fat in human females is associated with cessation of menstrual cycles, and the onset of puberty is known to correlate with body composition (fat levels) as well as age. Several studies have suggested that leptin stimulates hypothalamic output of gonadotropin-releasing hormone, which in turn causes increases of luteinizing and follicle-stimulating hormones from the anterior pituitary gland. These hormones stimulate the onset of puberty. Prepubertal mice treated with leptin become thin and reach reproductive maturity earlier than control mice. One report has also indicated that humans with mutations in the ob gene that prevent them from producing leptin not only become obese but also fail to achieve puberty.

Leptin has been identified in placental tissues; newborn babies show higher levels than those found in their mothers. Leptin has also been found in human breast milk. Together, these findings suggest that leptin aids in intrauterine and neonatal growth and development, as well as in regulation of neonatal food intake.

Finally, leptin appears to have a role in immune system function. Studies have suggested a role for leptin in production of white blood cells and in the control of macrophage function. Mice that lack leptin have depressed immune systems, but the mechanisms for this remain unclear.

Perspective and Prospects

Although early reports claimed that leptin could be useful in treating human obesity, clinical reports to date have not looked promising. It appears that deficiencies in leptin production are a rare cause of human obesity. However, since most obese individuals have plenty of leptin available, additional leptin will have no effect. In those individuals with a genetic deficiency of leptin, clinical use would require either daily injections of leptin or gene therapy. At this point neither of these options looks particularly promising.

Bibliography

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