High-Fat Diet in Pregnancy Linked to Brain Inflammation in Offspring, Animal Study Suggests

Irreversible Effects Stretch Into Adulthood, Affecting Immune Function and Behavior

Kate Johnson

December 07, 2010

December 7, 2010 (Miami Beach, Florida) — A high-fat diet in pregnant rats is linked to irreversible negative brain changes in offspring, according to research presented at the American College of Neuropsychopharmacology 49th Annual Meeting.

"This is a first look at the effects of mothers' obesity on the fetal brain," said Staci Bilbo, PhD, lead author of the study and assistant professor of psychology and neuroscience at Duke University, Durham, North Carolina.

"Previous research has shown a link between obesity and inflammation in the body — outside of the brain — but little is known about whether obesity in a pregnant mother can affect the way the brain develops in her offspring."

The study involved feeding female rats 1 of 3 diets for a month before conception and throughout pregnancy and lactation (FASEB J. 2010;24[6]:2104-2115).

The first diet was high in saturated fat, the second was high in unsaturated or "trans" fat, and the third was a control low-fat diet.

Both high-fat diets contained 60% fat and the low-fat diet contained 10% fat, but all other elements, including macronutrients and micronutrients, were the same.

Long-Term Impact

As expected, compared with the low-fat diet, both high-fat diets resulted in significant weight gain and increased leptin levels in the mothers.

Offspring of these mothers were born at normal weight, but by weaning, which was on postnatal day 21, they were overweight compared with the control offspring.

Similarly, even though all offspring were fed a low-fat diet after weaning, the male offspring of high-fat fed mothers continued to be overweight into adulthood, explained Dr. Bilbo.

Brain samples and peripheral tissues were collected from a subset of pups at 1 day after birth, from a second set of pups just before weaning, and from a third set of pups in early adulthood.

"We saw clear evidence of inflammation primarily within the hippocampus of the pups born to the mothers on high-fat diets," she said.

This increase in microglial activation markers was seen immediately after birth and maintained into adulthood despite no direct exposure to a high-fat diet, she continued.

Immune response was also negatively affected by exposure to a high-fat diet. When exposed to a bacterial challenge or "simulated infection," the young-adult offspring of obese mothers "had a greatly exaggerated inflammatory response within the brain compared to low-fat controls," she explained.

"Inflammation is good in the short term because it can aid in healing, alert us to tissue damage, but in the long run, constant inflammation can be damaging to neurons and brain function."

Surprising Effect

Anxiety was also significantly increased in fat-exposed offspring — particularly males — with a surprising effect on learning, said Dr. Bilbo.

"The high-fat groups actually learned faster than the low fat controls, contrary to our expectations," she said in an interview. "But we think it is because they were more anxious and therefore more motivated to escape the maze.  There were no differences in memory or other aspects of cognition, just the learning part — and once the low-fat rats learned it, they were just as good at remembering."

The male and female offspring responded equally badly to the high-fat diet early on, "but after weaning we started to see a separation," she said. "The males continued to have an exaggerated inflammatory response within the brain...but the females were actually protected, they had a blunted response. This occurred after puberty, so we think there may be a protective role of estrogen."

The findings suggest that maternal diet can program brain changes that begin before birth and cannot be reversed with diet.

"We have definitely demonstrated that the mothers' diet during pregnancy clearly determines a lifelong inflammatory condition for the fetus that cannot be reversed with a low-fat diet, and the next step will be to look at the success of reversing the impact of the maternal diet on these inflammatory changes through interventions that target the fetal immune response," she concluded.

Asked about teasing out the different effects of maternal diet and obesity from offspring obesity, Dr. Bilbo agreed that it is hard.

"Right now we don't know how much of this is due to the pups themselves starting off heavier in life or some component of the maternal diet itself," she said.

"However, the day after birth we already saw evidence of inflammation within the brain in the pups from high-fat moms — so at least we know that the immune changes were not dependent on an increase in body weight.  

"My hunch is that all of the enduring changes that we see are due to how immune cells are becoming activated; that is, we know that both saturated and trans fats can activate immune cells via the Toll-like receptors and that this activation is linked to the adverse metabolic changes you see in obesity."

Findings 'Very Concerning'

Kevin L. Grove, MD, senior scientist at the Oregon National Primate Research Center, Oregon Health & Sciences University, in Beaverton, has recently published similar findings in primates — specifically an increased rate of behavioral disorders and anxiety in the offspring of mothers who were fed high-fat diets (J Neurosci. 2010;30[10]:3826-3830).

Reached for comment, Dr. Grove said the most interesting and important finding from Dr. Bilbo's study is that offspring of mothers who eat a high-fat diet continue to display a hypersensitive inflammatory response into adulthood, even when eating a low-fat diet themselves.

"This means that the offspring are essentially permanently susceptible to any infectious disease," he told Medscape Medical News.  "This includes a potential increased severity and sensitivity to flu virus and decreased wound healing or susceptibility to infections.  All of these issues have been associated with obesity itself, but Dr. Bilibo's work points toward an increased risk simply from the high-fat diet exposure during pregnancy.  This is very concerning."

Dr. Bilbo has disclosed no relevant financial relationships.

American College of Neuropsychopharmacology (ACNP) 49th Annual Meeting. Presented December 7, 2010.

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