Influence of prenatal nutrition and obesity on tissue specific fat mass and obesity-associated (FTO) gene expression

Abstract

The recent discovery of an association between body composition, energy intake and the fat mass and obesity-associated (FTO) gene represents a promising new therapeutic target in obesity prevention. In a well, pre-established large animal model, we investigated the regulation of FTO gene expression under conditions either leading to obesity or increased risk of obesity related disorders: i) a sedentary 'Western' lifestyle and ii) prenatal exposure to nutrient restriction. Pregnant sheep were either fed to fully meet their nutritional requirements throughout gestation or 50% of this amount from early-to-mid gestation. Following weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. A significant positive relationship between placental FTO gene expression and fetal weight was found at 110 days gestation. In both the newborn and adult offspring, the hypothalamus was the major site of FTO gene expression. Hypothalamic FTO gene expression was upregulated by obesity and was further increased by prenatal nutrient restriction. Importantly, we found a strong negative relationship between the hypothalamic FTO gene expression and food intake in lean animals only that may imply FTO as a novel controller of energy intake. In contrast, FTO gene expression in the heart was downregulated in obese offspring born to nutrient restricted mothers. In addition, FTO gene expression was unaffected by obesity or prenatal diet in insulin-dependent tissues, where it changed with age possibly reflecting adaptations in cellular energetic activity. These findings extend information gained from human epidemiology and provide new insights into the regulation of in vivo energy metabolism to prevent obesity.

Placental FTO expression relates to fetal growth

“…Data from a most recent manuscript in sheep give support to the results from our study by showing that FTO is highly expressed in placenta in late gestation and is positively related to fetal weight. 31 In conclusion, our data report for the first time on the role of the human placenta as a source of FTO in a representative sample of healthy pregnancies and indicate that placental FTO expression is associated with fetal and placental weight in a maternal parity-dependent manner.…”

Acute exercise increases insulin sensitivity in adult sheep: a new preclinical model

“…This increase in body weight probably largely reflects gain of fat tissue, because these sheep were mature adult ewes, that were transferred from paddock housing and pasture feeding into relatively sedentary conditions of pen housing with abundant nutrition ϳ2 wk prior to the first clamp, conditions shown to increase weight and fat deposition, even in young growing animals (47). The sheep in the present study were relatively insulin-resistant, with preexercise insulin sensitivity approximately three-fold and six-fold lower than we have observed previously in young adult sheep and in 1 mo-old lambs, respectively (16).…”

Maternal Nutrient Restriction During Late Gestation and Early Postnatal Growth in Sheep Differentially Reset the Control of Energy Metabolism in the Gastric Mucosa

“…Intriguingly, we found these transcriptional changes to be associated with dinucleotide methyl transferase type I and FTO , two factors that can regulate DNA methylation (53, 54). Furthermore, FTO has been established to encode a 2-oxoglutarate DNA demethylase and provides a link between energy-sensing pathways (55–57) that could include be further modulated by changes in short-chain fatty acid production (58), which are the main products of rumination.…”