Impact of embryo number and periconceptional undernutrition on factors regulating adipogenesis, lipogenesis, and metabolism in adipose tissuein the sheep fetus

Abstract

-Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We hypothesized that maternal undernutrition during the periconceptional (PCUN: Ϫ60 to 7 days) and/or preimplantation (PIUN: 0 -7 days) periods would result in a decrease in UCP1 expression and the abundance of insulin signaling molecules and an increase in the abundance of factors that regulate adipogenesis and lipogenesis in fetal perirenal adipose tissue (PAT) and that these effects would be different in singletons and twins. Maternal PCUN and PIUN resulted in a decrease in UCP1 expression in PAT, and PIUN resulted in higher circulating insulin concentrations, an increased abundance of pPKC and PDK4, and a decreased abundance of Akt1, phosphorylated mTOR, and PPAR␥ in PAT in singleton and twin fetuses. In singletons, there was also a decrease in the abundance of p110␤ in PAT in the PCUN and PIUN groups and an increase in total AMPK␣ in PAT in the PIUN group. In twins, however, there was an increase in the abundance of mTOR in the PCUN group and an increase in PDK2 and decrease in total AMPK␣ in the PIUN group. Thus exposure to periconceptional undernutrition programs changes in the thermogenic capacity and the insulin and fatty acid oxidation signaling pathway in visceral fat, and these effects are different in singletons and twins. These findings are important, as the thermogenic capacity of brown fat and the insulin sensitivity of visceral fat are important determinants of the risk of developing obesity and an insulin resistance phenotype in later life. pregnancy; nutrition; programming; metabolism A RANGE OF EXPERIMENTAL AND CLINICAL STUDIES has shown that poor maternal nutrition experienced around the time of conception or during pregnancy, placental insufficiency, and being of low birth weight are each associated with an increase in visceral fat mass in postnatal life (5,9,11,17,21,27,30,31). Interestingly, exposure to a poor nutrient supply in early pregnancy, such as which occurred in the Dutch Winter Famine of 1944Famine of -1945, in the absence of a change in birth weight resulted in increased adiposity in later life (38, 39). Maternal undernutrition around the time of conception has also been shown to result in glucose intolerance and insulin resistance in the human and in the sheep (36,41,47). However, the impact of maternal undernutrition during the periconceptional period on the factors that regulate adipogenesis, lipogenesis, and insulin sensitivity in visceral fat is not known.In the sheep fetus, fat is deposited at a rate of ϳ0.8 g·kg body wt Ϫ1 ·day Ϫ1 in late gestation, and the proportion of body fat at term is between 0.3 and 2.0%. The perirenal adipose tissue (PAT) is the major fat depot present in the sheep fetus and is comprised predominantly of brown fat cells that express adipogenic and lipogenic factors, including peroxisome proliferator-activated receptor-␥ (PPAR␥), lipoprotein lipase (LPL), and the adipokines leptin and adiponectin (10,28,54). Brown fat i...

Undernutrition and stage of gestation influence fetal adipose tissue gene expression

“…Previous studies of adipose tissue development have largely involved adult ewes undernourished during discrete windows of gestation, with little consensus on the impact on fetal weight or PAT mass (Symonds et al 1998; Bispham et al 2003; Budge et al 2004; Lie et al 2013). None of these studies involving undernutrition quantified adipocyte cell populations, but conversely when fetal nutrient supply in normal late gestation pregnancies was increased by a 10-day intrafetal glucose infusion, the unilocular fat mass was enhanced and the size of the dominant lipid locule was positively correlated with fetal glucose concentrations (Mühlhäusler et al 2005).…”

“…Previous studies investigating the impact of maternal nutrition on prenatal adipose gene expression in precocial animals have not reported fetal sex (Bispham et al 2003; Budge et al 2004; Mühlhäusler et al 2007; Nguyen et al 2010; Lie et al 2013) but it is clearly an important consideration; imbalances in the male:female ratio may have confounded earlier results and may explain the lack of consensus in the sheep literature. Indeed, sexually-dimorphic differences in fetal growth and expression of genes involved in adipogenesis and brown adipose tissue development following in vitro adipocyte differentiation in culture are seen in fetal baboons following modest maternal undernutrition throughout gestation (Tchoukalova et al 2014).…”

“…Maternal undernutrition via its negative impact on fetal nutrient availability may alter relative proportions of white and brown fat in the fetus, with implications for subsequent survival and body composition, but this hypothesis has not been tested. Published studies have examined selected molecular markers of adipose tissue growth, differentiation and function in PAT of late gestation sheep fetuses whose mothers were undernourished during specific windows of gestation, but no clear consensus emerged regarding the impact of nutrition on fetal growth, PAT depot mass or gene expression (Symonds et al 1998; Bispham et al 2003; Budge et al 2004; Lie et al 2013). …”

Periconception Weight Loss: Common Sense for Mothers, but What about for Babies?

“…Preimplantation, but not periconceptional undernutrition, results in higher circulating insulin in the late gestation fetus, marking the first few days of gestation as critical in this system [37]. Exaggerated insulin response in early life is believed to be suggestive of early pancreatic maturation or altered pancreatic beta cell function [36, 38].…”

“…Predisposition for later-life insulin resistance is therefore more likely in animals with these changes [39]. There are also epigenetic modifications to visceral fat depots likely to impair thermogenic capacity and insulin sensitivity of adipose tissue in postnatal life [37]. Thus, altered energy metabolism that may be protective in a nutritionally restricted fetal environment predisposes the postnatal offspring to metabolic disease when faced with an energy-abundant environment.…”