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UB "Pup in a Cup" Study Finds Early Nutritional Modification Permanently Programs Metabolism, Predisposes to Obesity

High carbohydrate diet led to changes in islet cells, overproduction of insulin

By Lois Baker

Release Date: April 23, 2002

NEW ORLEANS -- Consuming a milk formula high in carbohydrates during the critical early weeks of postnatal life causes permanent changes in pancreatic islets and leads to overproduction of insulin and development of obesity in adulthood, University at Buffalo biochemists, working with rats, have found.

Furthermore, this "metabolic programming" carries through to the next generation. Offspring of first-generation high-carbohydrate-fed (HC) female rats developed hyperinsulinemia (high insulin levels) and obesity without any dietary modification.

Mulchand Patel, Ph.D., UB professor of biochemistry and senior author on the study, presented results of his research here today (April 23) at the Experimental Biology 2002 meeting.

The study provides a new perspective on obesity, according to Patel.

"We are always looking at what happens later in life. Maybe we should be looking at the role of early metabolic programming," he said.

"The results from this study involving the high-carbohydrate-fed rat model suggest that what foods human babies are fed as newborns may contribute to metabolic programming, leading to adult-onset diseases such as obesity and diabetes," Patel said.

"Overfeeding of formula and early introduction of supplemental weaning foods such as cereals, fruits and juices that are high in carbohydrates may be the culprits."

Metabolic programming, sometimes called dietary patterning, isn't a new phenomenon. Epidemiologic studies of malnourished mothers, which showed that their babies often were underweight and at increased risk for several chronic diseases as adults, led to the public health emphasis on adequate nutrition during pregnancy. Several animal studies on maternal protein malnourishment or caloric restriction have shown that pre- and immediate postnatal nutritional modifications have long-term consequences on adult-onset diseases.

"Metabolic signals are reset in response to a high carbohydrate diet, which induces permanent changes at the molecular level in our rat model," Patel said. "The HC phenotype is transferred from cell to cell, is expressed for life and is transmitted to succeeding generations."

Patel and colleagues were the first to manipulate the composition of the diet -- the percentages of carbohydrates and fat while keeping calories constant -- in order to study the metabolic programming effect. Milk produced by the rat mother is composed of 8 percent carbohydrate, 68 percent fat and 24 percent protein; the modified milk formula fed to the rat pups in the UB study was composed of 56 percent carbohydrate, 20 percent fat and 24 percent protein.

The animals were raised for the first 24 days -- the natural suckling period -- using a technique dubbed "pup in a cup," which involved placing 4-day-old rat pups in Styrofoam cups floating in a temperature-controlled water bath and delivering the modified formula directly into the stomach. Rat pups reared in this manner receiving a formula comparable in calories to mother's milk, and rat pups nursed by their mothers served as controls.

The high-carbohydrate pups developed high insulin levels within 24 hours and these levels persisted throughout adulthood, even after the rats were weaned onto rat chow, Patel said. The researchers found alterations in the insulin secretory pathway of pancreatic islet cells and molecular changes that induced increased expression of preproinsulin, a precursor of insulin. At two months, the HC rats started gaining weight and eventually became obese.

What happened with the offspring of HC rats was not expected, however, Patel said. The second generation HC rats developed hyperinsulinemia without receiving the high carbohydrate diet and became obese in adult life. Only the HC females transmit these traits to their progeny, he said, suggesting that the intrauterine experience may be essential for transmission of the metabolic programming.

A parallel situation may exist with the overfeeding of human babies, he noted.

"Babies who were formula-fed when it was popular in the 1950s and '60s may have developed obesity as adults and may have passed on this trait to their children. With breast feeding, the mother produces an adequate amount of milk naturally. With formula feeding, the tendency is to finish the bottle, and this may result in overfeeding," Patel said.

"It's evident from our studies with rats that the composition and the timing of the dietary treatment programs the onset of pathological conditions in the adults that mimic major metabolic diseases noted in humans, such as obesity and type 2 diabetes."

The newly emerging field of metabolic programming offers an additional route to examine the development of chronic diseases of adulthood, he noted. The researchers' long-term goal is to determine the mechanisms causing the hyperinsulinemic phenotype to be expressed for life in the first generation, and what factors in the mother are responsible for spontaneous transmission of this trait to the offspring.

Malathi Srinivasan, Ph.D.; Ravikumar Aalinkeel, Ph.D., and Fei Song, Ph.D., from Patel's lab, and Suzanne Laychock, Ph.D., of the UB Department of Pharmacology and Toxicology, also contributed to the study, as well as Satish Kalhan, M.D., of Case Western Reserve University, and David Hill, Ph.D., of Lawson Research Institute, London, Ontario.

The research was supported by grants from the National Institutes of Health.

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