The only known adults in the world who possess a rare genetic mutation that prevents their bodies from producing leptin may open the door to a new way of fighting fat. After injections with leptin -- a human hormone linked to appetite control -- the adults dramatic weight loss suggests that leptin offers significant promise for treating obesity.
Dr. Julio Licinio, professor of medicine at the David Geffen School of Medicine at UCLA, flew three cousins -- two women and one man -- from a tiny village in Turkey to UCLA Medical Center last September for clinical research treatment with leptin. Ranging in age from the late 20s to 40, all of the cousins were severely obese and one was still prepubescent.
"We hypothesized that leptin deficiency may lead to obesity and, in some cases, delay sexual and psychological maturity," explained Licinio, also a professor of psychiatry and biobehavioral sciences at the UCLA Neuropsychiatric Institute. "Although this is a small study, it produced striking results."
Ten months after the study began, the three adults have lost half of their body weight -- more than 150 pounds each. But the leptin therapy resulted in dramatic outcomes beyond their weight loss, including physiological and personality changes.
After receiving leptin injections, the prepubescent adult began experiencing a wide range of physiological changes associated with adolescence and rapidly reached sexual maturity. In addition, UCLA researchers observed neurological growth in all three participants.
"At the end of the study, we measured the subjects brains with MRI and discovered that the organs had expanded a small but significant amount," Licinio said. "While the relevance of this outcome is currently unclear, it poses the first known instance of brain growth in adults."
Earlier research conducted on laboratory animals born without the ability to make leptin showed that they possessed brains 30 percent smaller than their normal counterparts. Until now, however, scientists had never studied the effect of leptin deficiency and replacement in humans.
The cousins dispositions also altered. Within two weeks of leptin therapy, they grew noticeably more assertive and independent.
"The subjects personality changes suggest that there is a relationship between fat and how we feel," Licinio said. "We plan to explore leptins link to mood disorders in the future."
Manufactured in the fat cells, leptin plays three important roles in the human body. First, the hormone signals fullness, controls the appetite and tells the brain to stop eating. Second, it is triggered by puberty and regulates sexual development. And third, it helps the immune system fight off diseases -- a critical weapon in staving off childhood diseases.
According to Licinio, science originally considered leptin a gold mine for weight control. Later, however, researchers discovered that obese people produced too much of the hormone and their bodies simply stopped responding to its appetite cues.
In rare cases, though, some people -- like the adults in Licinios study -- become obese because they manufacture too little leptin. Licinio decided to study the cousins in order to better understand the role that leptin plays in normal human biology.
The only side effect of the leptin replacement therapy was a minor rash at the injection site that lasted briefly in one patient.
Licinio is a member of the Brain Research Institute, director of the UCLA Pharmacogenetics and Pharmacogenomics Research Group, and founding editor-in-chief for The Pharmacogenomics Journal and Molecular Psychiatry.
The UCLA study was funded by the National Institute of Diabetes, Digestive and Kidney Diseases and the National Center for Research Resources. Licinios colleagues at the UCLA Neuropsychiatric Institute included Dr. Ma-Li Wong, Dr. Edythe London, Dr. Sinan Caglayan, and Dr. Bulent Yildez. Licinio also collaborated with Dr. Metin Ozata at the Gulhane School of Medicine in Turkey.
The Thousand Oaks-based pharmaceutical firm Amgen supplied the UCLA researchers with complimentary leptin for the duration of the study and paid $7,500 to Licinio for patient recruitment.
Future UCLA projects will explore the interactions of leptin and other hormones in the elderly, how leptin replacement influences the human endocrine system, and the effect of a single mutation in one of the two genes that encode for human leptin.
Elaine Schmidt | EurekAlert
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