Identifying Genetic Markers In Overweight Newborns Could Prevent Obesity In Later Life

Similar genetic variations occur in both overweight newborns and obese adults, a large study finds. The results were presented at The Endocrine Society's 95th Annual Meeting in San Francisco.

"Our data suggest that adult obesity and newborn adiposity share, in part, a common genetic background," said study lead author Reeti Chawla, MD, fellow in pediatric endocrinology at Ann & Robert H. Lurie Children's Hospital of Chicago and the Northwestern University Feinberg School of Medicine, in Chicago, IL. "Allowing earlier identification of high-risk newborns may allow for earlier interventions to take place to possibly prevent obesity later in life. "

Obesity has become an epidemic worldwide. In the United States alone, more than one-third of adults are obese, according to the Centers for Disease Control and Prevention. Excess weight and obesity are related to numerous health problems, including heart disease, type 2 diabetes, stroke and some cancers. Since being obese in childhood increases the risk of adult obesity, medical researchers are interested in identifying early risk factors, or genetic markers, to help predict who is at greater risk for weight gain.

One of these genetic markers is called a single nucleotide polymorphism, or SNP, which is a naturally occurring genetic variant within the general population. In this case, investigators used SNPs related to adult obesity to identify genetic markers associated with higher newborn weight and skinfold thickness.

Investigators were able to identify 144 SNPs associated with birth weight or skinfold thickness. Since some of these 144 SNPs are closely linked and inherited together, they then narrowed the group down to 45 SNPs that are related to higher fat among newborns.

Investigators obtained the genetic data of 4,465 newborns from a large, multi-ethnic study examining the association between maternal blood-sugar levels and risk of poor pregnancy outcome. The study, called the Hyperglycemia and Adverse Pregnancy Outcomes, or HAPO, comprised mothers and infants from diverse ethnic backgrounds, including 1,095 Afro-Caribbean, 1,363 European, 616 Mexican-American and 1,207 of Thai descent.

Chawla said that she and her team now are using the 45 SNPs identified in this study to develop a genetic risk score "to determine whether bearing a large number of these SNPs predicts which newborns are at risk for increased fat at birth and, potentially, obesity later in life."

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Fat Tissues In Sheep Affected By Prenatal Exposure To BPA

New research suggests that fetal exposure to the common environmental chemical bisphenol A, or BPA, causes increased inflammation in fat tissues after birth, which can lead to obesity and metabolic syndrome. Results of the animal study were presented at The Endocrine Society's 95th Annual Meeting in San Francisco.

Found in plastic water bottles, older baby bottles and many other consumer products, BPA is a known hormone disrupter with estrogen-like properties. Prior research has linked BPA in both animals and humans to obesity and the metabolic syndrome, which is a cluster of metabolic risk factors that increase the chance of later developing diabetes, heart disease and stroke.

"This research is the first study to show that prenatal exposure to BPA increases postnatal fat tissue inflammation, a condition that underlies the onset of metabolic diseases such as obesity, diabetes and cardiovascular disease," said the study's lead author, Almudena Veiga-Lopez, DVM, PhD, a research investigator at the University of Michigan, Ann Arbor.

She said the study, which examines the effects of BPA on sheep, improves the understanding of how prenatal BPA exposure regulates the inflammatory response in offspring in the tissues that are relevant to development of metabolic disease. The study was conducted in the laboratory of Vasantha Padmanabhan, MS, PhD, Professor at the University of Michigan, Ann Arbor, with funding from the National Institutes of Health's National Institutes of Environmental Health Sciences. Veiga-Lopez said sheep have similar body fat to that in humans, including visceral (deep belly) fat and subcutaneous fat, which is directly below the skin.

The researchers fed two groups of pregnant sheep corn oil, either with nothing added to it or with added BPA at a dose needed to achieve BPA levels similar to those seen in human cord blood in the umbilical cord blood of the sheep offspring. Of the female offspring from the sheep, half from each group were overfed at approximately 6 weeks of age. All female offspring then were divided into four groups of nine to 12 animals each: (1) non-BPA-exposed controls that received a normal diet, (2) BPA-exposed offspring that received a normal diet, (3) overfed, obese controls and (4) overfed, obese BPA-exposed offspring.

At 15 months of age, sheep underwent a glucose tolerance test, to measure their insulin and blood sugar levels. Seven months later, the researchers collected samples of the animals' visceral and subcutaneous fat tissues to evaluate levels of two biological markers of inflammation. These biomarkers were CD68, a marker for inflammatory cells, and adiponectin, a molecule with a known role in the development of metabolic syndrome. When the adiponectin level decreases or CD68 expression increases, inflammation is worse, according to Veiga-Lopez.

Adiponectin was decreased and CD68 expression was raised in the visceral fat of both obese groups, and CD68 expression also was raised in the subcutaneous fat in normal weight, BPA-exposed female offspring, Veiga-Lopez reported. She said these results suggest that "prenatal BPA exposure and postnatal diet may interact to modulate inflammatory mechanisms in fat deposits."

Both obese groups had hyperinsulinemia, or high insulin levels, a precursor to insulin resistance, which is a prediabetic state, Veiga-Lopez reported. However, she said prenatal exposure to BPA did not lead to insulin resistance in sheep, as was true in a previous mouse study. She speculated that the hyperinsulinemia in obese offspring stems from changes that occurred in the two inflammatory markers in the visceral fat deposit.

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Research Breakthrough Of Essential Molecule Reveals Important Targets In Diabetes And Obesity

Insulin is the most potent physiological anabolic agent for tissue-building and energy storage, promoting the storage and synthesis of lipids, protein and carbohydrates, and inhibiting their breakdown and release into the circulatory system. It also plays a major role in stimulating glucose entry into muscle tissue, where the glucose is metabolized and removed from the blood following meals. But gaps exist in understanding the precise molecular mechanisms by which insulin regulates glucose uptake in fat and muscle cells.

A research team led by Assia Shisheva, Ph.D., professor of physiology in Wayne State University's School of Medicine, has made breakthrough advancements on a molecule that may provide more answers to this mystery.

The conserved phospholipid enzyme, PIKfyve, was discovered in Shisheva's lab in 1999. Based on studies in cultured cells, the lab has implicated PIKfyve in the insulin-regulated glucose transport activation, which led to the development of a unique mouse model with PIKfyve ablation, or removal, in muscle (MPlfKO), the tissue responsible for the majority of postprandial glucose disposal.

In Shisheva's recent paper, "Muscle-specific PIKfyve gene distribution causes glucose intolerance, insulin resistance, adiposity and hyperinsulinemia but not muscle fiber-type switching," published online in the American Journal of Physiology - Endocrinology and Metabolism, Shisheva and her research team characterize whether this new model exhibits metabolic defects.

"Our team found a striking metabolic phenotype in the MPIfKO mice consisting of glucose intolerance and insulin resistance at an early age and on a normal diet," said Shisheva, a resident of Royal Oak. "We also revealed that PIKfyve is essential for normal insulin signaling to GLUT4/glucose transport in muscle and provided the first in vivo evidence for the central role of PIKfyve in the mechanisms regulating healthy blood glucose levels, or glucose homeostasis."

In addition, the research team found that these metabolic disturbances were followed by increased animal fat (adiposity) and elevated levels of insulin (hyperinsulinemia), but not abnormal amounts of lipids or cholesterol in the blood (dyslipidemia).

"The combined phenotype manifested by the MPlfKO mouse closely recapitulates the cluster of typical features in human prediabetes including systemic glucose intolerance and insulin resistance, hyperinsulinemia and increased visceral obesity without dyslipidemia," said Shisheva.

"Therefore, our mouse model, in addition to providing novel mechanisms of insulin resistance, represents a valuable tool for exploring new preclinical strategies to improve treatments in individuals with prediabetes."

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