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Overfeeding normal infant rats affects three generations: changes basic metabolism, interferes with reproduction

NEW ORLEANS -- Some women who become glucose intolerant late in pregnancy may develop gestational diabetes and give birth to larger than normal babies with a tendency to become obese. Now a new study of genetically normal rats indicates that the effect of overfeeding extends for at least three generations and may explain health trends beginning to be seen in human populations in the American Southwest, Japan, Australia and some Pacific islands. The fact that the overfed animals were genetically normal is important because it shows that conditions during development can have consequences several generations later, even in the absence of genetic abnormalities, emphasized a University of Washington researcher reporting on new work here today at the Society for Neuroscience's annual meeting. The newborn rats were overfed to duplicate nutritional conditions during late human pregnancy that often affect the babies of diabetic mothers, according to Elsie Taylor, a recent Ph.D. graduate in psychology and UW researcher. Gestational diabetes occurs in 2 to 3 percent of otherwise normal human pregnancies. A mother's system regulates the amount of nutrients fed to her developing baby through the bloodstream, but pregnancy can produce a stress on the pancreas. When this happens, the pancreas sometimes can't produce enough insulin, a hormone that allows the body to use carbohydrates, triggering gestational diabetes. Taylor says newborn rats are immature at birth so their first three weeks of life correspond to that of a human fetus in the final trimester before birth in terms of metabolic and brain development. "Newborn rats are God's gift to developmental science," says Jaime Diaz, a UW psychology professor and Taylor's collaborator on the study. "We can study a newborn rat and learn much about maturational events which occur during late human pregnancy. Our experiments show that a brief period of overfeeding made one group of rats and their descendants strikingly different from their siblings and their descendants. "Our findings demonstrate that many effects seen in the descendants of diabetics can be caused by alterations in the developmental environment independent of genetic effects." "So what is happening from overfeeding or diabetes is more or less imprinting a baby for life," adds Taylor. Taylor and Diaz only used female rats in their study because the research was focused on the effects of overfeeding on the maternal environment provided to subsequent generations. The rats used in the study were Long-Evans hooded rats, a spotted black and white strain often used in laboratories, not the more familiar white rats. The first generation consisted of normal sister rats randomly assigned to one of three groups when they were 5 days old. One group was fed by mother rats. A second group was fed formula through stomach tubes to match the growth rate of the mother-reared rats. The third or experimental group also was fed through a stomach tube, but these animals were given 150 percent the amount of food consumed by the other groups. At age 15 days both groups of stomach tube-fed rats were returned to nursing mothers. A week later all groups were weaned, fed laboratory chow and treated identically. The overfed rats were 20 percent heavier than the other rats at age 15 days, but then their weight dropped to normal after being returned to their mothers, Taylor said. However, at puberty their growth rate accelerated again and they were 12 percent larger than the controls when they were bred to normal males at 4 months of age. Many of the overfed first generation had difficulty with their ensuing pregnancies and their birth rate was 70 percent of normal rats. The weight pattern reversed itself in the second generation and the experimental rats were significantly smaller than the controls, even though the two groups were raised identically. "These rats were 5 percent smaller at birth and remained consistently smaller throughout their lifetime," said Taylor. In addition, reproductive problems persisted. When this generation of experimental rats were bred, their birth rate was only 57 percent of the controls. In the third generation, both groups weighed the same at birth, but the descendants of the original overfed group had an accelerated growth spurt around the ninth day after birth, and by 3 weeks of age were 15 percent bigger. Taylor says this third-generation effect is highly significant and was replicated in a second breeding. Taylor now hopes to explore the metabolic status of overfed rats at several periods, particularly during pregnancy, and study how regulatory mechanisms may have been altered, including brain changes in the hormones insulin and leptin. The work has broad clinical application in understanding and improving the outcome of diabetic pregnancies and in dealing with an epidemic increase in obesity and non- insulin-dependent diabetes that has been documented among the Pima Indians of Arizona, Australian aboriginals and other human populations. The Pima, whose diet changed when they were put on a reservation at the turn of the last century, have the world's highest rate of non-insulin-dependent diabetes. According to Taylor, 50 percent of the Pima have the disease by age 35, which has changed the tribe's basic body type from thin to obese in a century. Taylor and Diaz' study was supported by the University of Washington's Royalty Research Fund, which gets its money from licensed technology developed by UW researchers. ### For more information contact Taylor at (206) 523-0463 or or Diaz at (206) 543-2546 or Taylor will be in New Orleans Oct. 27-30 and is staying at the Doubletree Hotel New Orleans Lakeside (504) 836-5253.