A new mouse model for a genetic cause of obesity has been developed by scientists at the Stanford University School of Medicine and Lucile Packard Children's Hospital.
The researchers hope that learning more about the mice, which overeat but do not gain weight, will help them develop new therapies for people with Prader-Willi syndrome, a rare genetic condition that triggers uncontrollable eating.
“Although these mice exhibit many aspects of Prader-Willi syndrome, they somehow use their food fuel in a different way, ” said Packard Children's geneticist Uta Francke, MD, whose lab conducted the research.
“ It's not that they exercise more, they are just able to eat more without getting fat, ” said Francke, who is also professor of genetics and of pediatrics at the medical school. One reason the mice eat more, the researchers believe, is that they lack a “ meal-termination mechanism ” that signals most of us first to slow, then to stop eating. But, unlike humans, the mice stay lean.
The similarities and the differences between the mice and human patients provide tantalizing clues into the cause, and possible treatments, of the disorder.
The research will be published in the March 5 issue of Public Library of Science-ONE.
About one in every 10,000 to 20,000 people is born with Prader-Willi syndrome. Although the mice developed in Francke's lab weren't obese, they shared many other traits with Prader-Willi patients, including early-onset growth deficiency, adult-onset overeating, motor learning deficits and increased anxiety. Babies with the syndrome are initially weak and floppy and have trouble eating. As toddlers they develop an insatiable desire for food that persists throughout their lifetime; family members and caregivers often resort to keeping all food under lock and key in an attempt to prevent the morbid obesity that shortens patients' lives. Other symptoms include short stature, cognitive defects and behavioral abnormalities.
Prader-Willi syndrome is the result of a phenomenon known as genomic imprinting. Although we all inherit two copies of nearly every gene - one from our fathers and one from our mothers - we sometimes utilize only one. The region of chromosome 15 involved in Prader-Willi syndrome is always expressed from the paternally derived chromosome; the mother's genes in that region are inactivated. Problems arise when the father's contribution is missing, either because the region is removed from the chromosome or the chromosomes don't partition themselves correctly when the sperm and egg are formed or when the imprinting process itself goes awry.
Members of Francke's lab have been homing in on the genetic culprits for Prader-Willi syndrome for years. Although they knew the general area, no one had yet been able to pick the perpetrators out of the lineup of genes found in that stretch of chromosome 15. Knocking out the expression of fairly large portions of the region was known to result in mice that died soon after birth.
One of the local inhabitants of the suspect region is a type of molecule known as a small nucleolar RNA, or snoRNA. The snoRNAs function as floor managers for the workforce of small, noncoding RNA molecules - directing the placement of chemical tags on the workers to control their function and expression. The gene for a particular snoRNA, known as SNORD116, occurs more than 40 times in the suspect region.
In this study, lead author Feng Ding, PhD, knocked out the expression of all copies of SNORD116. Ding, a former postdoctoral scholar in Francke's lab, found that, like humans with Prader-Willi syndrome, these mice experience a growth delay after birth but then grow up to be adults that eat about 30 percent more food than control mice. They also have threefold higher circulating levels of the hunger-triggering hormone ghrelin. They are more anxious, as evidenced by their tendency to spend more time in the safer-feeling “ closed ” arms of a standard maze test. They were also less able to learn how best to cling to a rotating rod, indicating a severe deficit in motor learning.