Leptin

Biology

Anatomy or system affected: All

Definition: A protein hormone involved in regulation of food intake and obesity, with secondary effects on immunity, reproduction, and heart disease

Structure and Functions

Leptin (from the Greek leptos, meaning “thin”) is a protein hormone with important roles in regulating body weight, metabolism, and reproductive function. It is the product of the LEP gene, the human analogue of the ob (short for "obese") gene in mice, located at 7q32.1 on the human chromosome. Leptin is produced primarily by white adipocytes (fat cells). It is also produced by brown adipocytes, bone marrow, and epithelial cells of the stomach and the placenta, among other organs. As adipocytes increase in size because of accumulation of triglycerides (fat molecules), they synthesize more and more leptin. The mechanism by which leptin production is controlled is not fully understood, but a number of hormones are known to modulate leptin output, including insulin and melatonin.

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 due to 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 have shown that leptin's roles and mechanisms of action are more complex than previously believed. 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 is limited. If leptin levels are high, appetite is reduced and energy use is stimulated. In the hypothalamus, leptin counteracts the effects of neuropeptide Y and anandamide, both potent hunger stimulators, in the lateral hypothalamus and promotes production of α-melanocyte-stimulating hormone (α-MSH), a hunger suppressant, in the medial hypothalamus, among other actions.

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. Since most obese individuals have plenty of leptin available, additional leptin will have no effect. It is believed that sustained elevated levels of leptin in obese individuals lead to leptin resistance, similar to how elevated levels of insulin can lead to insulin resistance.

In 2014, the US Food and Drug Administration (FDA) approved metreleptin (trade name Myalept), a synthetic analog of leptin, for the treatment of leptin deficiency in patients with congenital or acquired lipodystrophy. In 2019, England's National Health Service also approved the drug for such use. Further research in the early 2020s found potential for the drug to treat anorexia nervosa, but such use was not yet approved by the FDA as of mid-2023.

Bibliography

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