Research ArticleRole of microRNA-122 in hepatic lipid metabolism of the weanling female rat offspring exposed to prenatal and postnatal caloric restriction☆
Introduction
Unbalanced nutrition is a major cause for metabolic associated maladies. Occurrence of overweight among the children of developed countries and its association with type II diabetes mellitus and other metabolic syndromes implies a combination of factors, majority of which bear connections with nutritional intake during different phases of the life cycle [1]. The relevance of nutrition during pregnancy and early infancy in defining long-term effects on health and survival has been described earlier [2]. The Developmental Origins of Health and Disease (DOHaD) paradigm also provides a framework to assess the effect of early nutrition and growth on long-term health. This body of literature shows that early nutrition has significant consequences on later health and well-being [3], [4], [5], [6], [7].
Consistent with DOHaD, altered glucose and lipid metabolism with various metabolic maladies occur in animal models of prenatal caloric restriction. These dysregulations include fatty liver, increased hepatic cholesterol concentrations, upregulation of lipogenic genes [8] and downregulation of transcription factors like PPARα and PPARγ [9]. Increased lipogenesis may contribute to the increased adiposity in adult IUGR animal models, but also in children and human adults. In contrast, postnatal calorie and protein restriction or delayed “catch up growth” reversed development of obesity in IUGR animal models [10]. Reduction of fat mass and body weight was observed in maternal calorie restricted offspring exposed to postnatal calorie restriction in mice [11] and rats [12], [13]. Differential changes in glucose and fatty acid synthesizing regulatory genes such as hepatic fatty acid synthase (FAS), Sterol Regulatory Element Binding Protein 1c (SREBP-1c) and Phosphoenolpyruvate Carboxykinase (PEPCK) were noted at the adult stage [14]. However, the underlying mechanisms that alter transcription factors or genes that regulate triglycerides (TG), cholesterol and fatty acid homeostasis in the offspring, exposed to either prenatal or postnatal calorie restriction, have not been investigated at an early stage in life. Such changes if present early in life would provide credence to the concept of persistent changes in the adult offspring in response to early life events.
Lipid metabolism is closely controlled at the cellular level by classical transcriptional regulatory components of cholesterol metabolism, SREBP and Liver X Receptor (LXR) along with members of noncoding RNAs consisting of microRNAs (miRNAs) as one class of them [14], [15]. miRNAs are RNAs of 20–25 nucleotides size and are recognized as negative post-transcriptional regulators of genes. By binding to the complementary 3′- untranslated region (UTR) of messenger RNAs, microRNAs degrade target mRNAs or block translation. Several miRNAs are functionally involved in regulating the lipid metabolism, such as miR-33, miR-122, miR-27a/b, miR-378, miR-34a and miR-21. Of these miRs, miR-122 is expressed with high prominence in developing and adult livers and has been reported to be a key regulator of hepatic fatty acid and cholesterol metabolism [15]. In addition, miR-122 has various other regulatory roles related to cellular senescence and stress response, circadian regulation of hepatic genes, iron metabolism, and propagation of specific hepatitis producing viruses. While miR-122 promotes hepatic fatty acid synthesis in adult livers, in the IUGR offspring, when exposed to postnatal caloric restriction or of the female sex, there is a protection against developing adult onset obesity with the metabolic syndrome phenotype. Whether hepatic miR-122 expression and its role in lipid biosynthesis are modified in response to IUGR with or without postnatal calorie restriction, or by the female sex, remains unexplored. Our previous investigations in the female IUGR offspring revealed perturbed milk and food intake patterns [16] suggestive of hypothalamic involvement [16]. Further, while we have previously observed that the metabolic phenotype of the male IUGR offspring with postnatal calorie restriction displays circadian dysregulation [17], the perturbed expression of hypothalamic genes including miR-122[18], associated with such hepatic dysregulation requires investigation. Therefore, in the present study, we hypothesized that hepatic fatty acid and cholesterol metabolism are adversely affected by reduced miR-122 expression. This is in association with perturbed hypothalamic circadian genes and miR-122, responsive to postnatal calorie and thereby growth restriction (GR) by itself, or when superimposed on prenatal calorie restriction with IUGR, particularly in the female offspring at an early stage of development. In order to test this hypothesis, we separated the effects of prenatal (IUGR) vs. postnatal (PNGR) and superimposed postnatal on prenatal calorie and thereby growth restriction (IPGR) in weanling female rats.
Section snippets
Maternal Nutrition Restriction Model
Pregnant Sprague–Dawley rats received ~50% of their daily food intake beginning from gestation day 11 through day 21, causing caloric restriction during mid- to late pregnancy (~11 g/day), compared to their control counterparts who received ad libitum rat chow (~22 g/d) (Diet 7013 from Envigo, Madison, WI, USA: Energy 3.1 kcal/kg, [calories from protein 23%, from fat 18%, and from carbohydrate 59%] crude protein 18%, fat [ether extract] 6.2%, carbohydrate 45%, crude fiber 4%, neutral detergent
Impact of early life caloric restriction on body weight, organ weight and lipid profile
Although the birth weight of female IUGR pups was 88% of CON (P<.05), total TG in IUGR was 1.2-fold higher compared to CON (P<.05). However, no significant difference was observed in plasma cholesterol (both total and UC), HDL, free fatty acids (FFA) and glucose (Table 2A) concentrations. IUGR pups caught up, thus at 21d of age, body weight was similar to that of CON (P>.05). In contrast to IUGR, the body weight of the other two groups remained low, i.e. IPGR was 27% and PNGR was 37% of CON (P
Discussion
We have for the first time, demonstrated changes in postnatal hepatic and plasma miR-122 expression in the context of genes mediating fatty acid synthesis and oxidation, thereby regulating lipid metabolism. Our four experimental groups allowed distinction between IUGR exposed to adequate postnatal nutrition with catch-up growth from the poorly postnatal nourished PNGR and IPGR groups. The latter two groups demonstrated reduced body, liver, skeletal muscle, pancreas and brown adipose tissue
Acknowledgments
This work was supported by grants from the National Institutes of HealthHD-41230 and HD-81206 (to SUD).
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The authors have no conflicts of interest.
This work was supported by grants from the National Institutes of Health HD-41230 and HD-81206 (to SUD).