UAMS Researcher Finds Genetic Link to Obesity
| LITTLE ROCK – What began as a study at the University of Arkansas for Medical Sciences (UAMS) of puberty and reproduction has resulted in the discovery of one possible genetic trigger for adult onset obesity.
The serendipitous discovery by Gwen V. Childs, Ph.D., has led to a $1.7 million federal grant and an article published by Endocrinology online on Nov. 18. It also will appear in the publication’s January 2011 printed edition.
UAMS coauthors of the study are Helen Benes, Ph.D., Noor Akhter, Ph.D., Mohsin Syed, Ph.D., Dana Gaddy, Ph.D. and Larry Suva, Ph.D.
“We’ve often heard that weight problems are caused by defective genes, and now we’re beginning to assemble evidence that shows how important genes in the pituitary gland are to maintaining optimal weight,” said Childs, who also is a professor and chair of the Department of Neurobiology and Developmental Sciences in the UAMS College of Medicine.
Childs’ discovery has to do with leptin, a hormone that’s known to control appetite by acting on specific neurons in the brain. Past studies of leptin have focused on leptin’s function within the brain. Childs’ study focused on leptin receptors that are on growth hormone cells in the pituitary, which, in addition to stimulating growth of bones and muscle, play a key role in breaking down fat.
In Childs’ study, the leptin receptor gene in growth hormone cells was removed in mice. The original purpose was to observe the effects on reproduction, because both leptin and growth hormone are known to be involved in the timing of puberty. However, Childs noticed that whereas puberty was normal, the male mice were becoming overweight as they reached adulthood and the female mice became overweight several months later.
“Tests of serum leptin and leptin receptor levels in the brain suggested that normal leptin is available to effectively control their appetite, and yet they still are gaining weight,” Childs said of the genetically altered mice.
She concluded that the obesity was caused by removing the leptin receptor on the mice’s growth hormone cells (pituitary somatotropes).
“This is very new; everyone had thought that leptin’s most important functions were in the brain to control appetite,” she said.
The overweight mice had 60 percent fewer growth hormone cells than the control mice, which means they did not produce enough growth hormone to break down fat as effectively as the control mice. This shows how important leptin is to the maintenance of a normal population of growth hormone cells. It also shows how important growth hormone is to the optimization of body composition including fat.
The discovery relates to the syndrome of adult onset obesity in people, which also is associated with low levels of growth hormone, Childs said. Often obesity in adults causes resistance to leptin, which results in low growth hormone. However, in Childs’ study, the low growth hormone was seen before the mice became obese, which points to a possible role for leptin in growth hormone cell development.
“It’s a significant issue; in cases of adult onset growth hormone deficiency, people become obese and develop full-blown metabolic syndrome (high blood pressure, cholesterol and triglyceride levels) and insulin resistance,” Childs said. “Not all the cases of growth hormone deficiency may be due to the lack of a leptin receptor on the growth hormone, however there is no question that obesity leads to leptin resistance, which will result in lower numbers of growth hormone cells and prevent their recovery.”
Childs is in the early stages of a five-year grant from the National Institute for Child Health and Human Development in the National Institutes of Health. Her research is continuing on the link between the genetically altered mice and their obesity, and she also is studying its potential reproductive toll.
She noted that the growing rise in obesity is also bad for reproduction and that some of the genetically altered females are sterile or have fewer pups, even before they become obese. Scientists don’t know all the reasons for that, but Childs said they’re working on possible roles for growth hormone and leptin, because unexplained infertility is a significant societal problem.
“There are many factors that are important to healthy reproduction, including ones’ metabolic status, and we are trying to find out what they all are,” she said. “I’m studying the leptin-driven circuits that may be responsible for unexplained infertility, and at the end of five years I would like to have found roles for leptin in regulatory circuits that allow for reproductive competence.”
UAMS is the state’s only comprehensive academic health center, with colleges of Medicine, Nursing, Pharmacy, Health Related Professions and Public Health; a graduate school; a 540,000-square-foot hospital; a statewide network of regional centers; and six institutes: the Winthrop P. Rockefeller Cancer Institute, the Jackson T. Stephens Spine & Neurosciences Institute, the Myeloma Institute for Research and Therapy, the Harvey & Bernice Jones Eye Institute, the Psychiatric Research Institute and the Donald W. Reynolds Institute on Aging. It is the only adult Level 1 trauma center in the state. UAMS has 2,836 students and 761 medical residents. It is the state’s largest public employer with more than 10,000 employees, including nearly 1,150 physicians who provide medical care to patients at UAMS, Arkansas Children’s Hospital, the VA Medical Center and UAMS’ Area Health Education Centers throughout the state. Visit www.uams.edu or uamshealth.com.
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