Abstract

BackgroundNutritional status in early life is critically involved in the metabolic phenotype of offspring. However the changes triggered by maternal consumption of high-fat diet (HFD) in pre- or postnatal period should be better understood. Here we evaluated whether maternal HFD consumption during gestation and lactation could differently affect liver miR-122 and miR-370 expression leading to metabolic damages observed in offspring. Moreover, we investigate whether early overnutrition program offspring to more harmful response to HFD in later life.MethodsFemale mice were fed either a standard chow (SC) diet or a HFD three weeks before and during mating, gestation and/or lactation. Offspring were evaluated on the delivery day (d0), in a cross-fostering model at day 28 (d28) and in adult life, after a re-challenge with a HFD (d82).ResultsIn vitro analysis using liver cell line showed that palmitate could induced decrease in miR-122 and increase in miR-370 expression. Newborn pups (d0) from obese dams showed a decrease in lipid oxidation markers (Cpt1a and Acadvl), an increase in triacylglycerol synthesis markers (Agpat and Gpam), as well as lower miR-122 and higher miR-370 hepatic content that was inversely correlated to maternal serum NEFA and TAG. Pups fostered to SC dams presented an increase in body weight and Agpat/Gpam expression at d28 compared to pups fostered to HFD dams and an inverse correlation was observed between miR-122 hepatic expression and offspring serum TAG. In adult life (d82), the reintroduction of HFD resulted in higher body weight gain and hepatic lipid content. These effects were accompanied by impairment in lipid and glucose metabolism, demonstrated by reduced Cpt1a/Acadvl and increased Agpat/Gpam expression, lower glucose tolerance and insulin sensitivity.ConclusionOur data suggest that both gestational and lactation overnutrition results in metabolic changes that can permanently alter lipid homeostasis in offspring. The presence of fatty acids in maternal blood and milk seem to be responsible for modulating the expression of miR-122 and miR-370, which are involved in liver metabolism. These alterations significantly increase susceptibility to obesity and ectopic lipid accumulation and lead to a more harmful response to HFD in offspring.

Highlights

  • Nutritional status in early life is critically involved in the metabolic phenotype of offspring

  • Offspring exposed to a high-fat diet (HFD) in utero and through lactation presents impaired hepatic mitochondrial function and up-regulation of lipogenesis, factors that may contribute to the development of Non-alcoholic fatty liver disease (NAFLD) and to the progression to a more aggressive liver disease, the non-alcoholic steatohepatitis (NASH) [12]

  • We observed that H presented higher fasting glucose levels (9% more than C) immediately after birth, but the same insulin levels compared to C (Fig. 3d and e, respectively)

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Summary

Introduction

Nutritional status in early life is critically involved in the metabolic phenotype of offspring. Nutritional status in early or pre-natal life is critically involved in susceptibility to cardiovascular and metabolic diseases development, such as hypertension, dyslipidemia, hyperglycemia and obesity [1, 2], events which characterize the metabolic syndrome. Recent studies demonstrated that increased adiposity, hepatic insulin resistance and ectopic fat accumulation have been associated with maternal body weight gain and exposure to a high-fat diet (HFD) along critical phases of development, such as gestation and lactation [8,9,10,11]. Offspring exposed to a HFD in utero and through lactation presents impaired hepatic mitochondrial function and up-regulation of lipogenesis, factors that may contribute to the development of NAFLD and to the progression to a more aggressive liver disease, the non-alcoholic steatohepatitis (NASH) [12]. Saturated fatty acids (SFA), induce hypothalamic inflammation, endoplasmatic reticulum stress, deleterious effects on blood lipid and lipoprotein profile and, in the liver, can bind to nuclear receptors of transcriptional factors involved in lipid homeostasis and induce lipid droplet accumulation [15, 16]

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