Abstract
ObjectiveThis study investigated the effect of maternal obesity on aged-male offspring liver phenotype and hepatic expression of a programmed miRNA.MethodsA mouse model (C57BL/6 J) of maternal diet-induced obesity was used to investigate fasting-serum metabolites, hepatic lipid content, steatosis, and relative mRNA levels (RT-PCR) and protein expression (Western blotting) of key components involved in hepatic and mitochondrial metabolism in 12-month-old offspring. We also measured hepatic lipid peroxidation, mitochondrial content, fibrosis stage, and apoptosis in the offspring. To investigate potential mechanisms leading to the observed phenotype, we also measured the expression of miR-582 (a miRNA previously implicated in liver cirrhosis) in 8-week-old and 12-month-old offspring.ResultsBody weight and composition was similar between 8-week-old offspring, however, 12-month-old offspring from obese mothers had increased body weight and fat mass (19.5 ± 0.8 g versus 10.4 ± 0.9 g, p < 0.001), as well as elevated serum levels of LDL and leptin and hepatic lipid content (21.4 ± 2.1 g versus 12.9 ± 1.8 g, p < 0.01). This was accompanied by steatosis, increased Bax/Bcl-2 ratio, and overexpression of p-SAPK/JNK, Tgfβ1, Map3k14, and Col1a1 in the liver. Decreased levels of Bcl-2, p-AMPKα, total AMPKα and mitochondrial complexes were also observed. Maternal obesity was associated with increased hepatic miR-582-3p (p < 0.001) and miR-582-5p (p < 0.05). Age was also associated with an increase in both miR-582-3p and miR-582-5p, however, this was more pronounced in the offspring of obese dams, such that differences were greater in 12-month-old animals (−3p: 7.34 ± 1.35 versus 1.39 ± 0.50, p < 0.0001 and −5p: 4.66 ± 1.16 versus 1.63 ± 0.65, p < 0.05).ConclusionOur findings demonstrate that maternal diet-induced obesity has detrimental effects on offspring body composition as well as hepatic phenotype that may be indicative of accelerated-ageing phenotype. These whole-body and cellular phenotypes were associated with age-dependent changes in expression of miRNA-582 that might contribute mechanistically to the development of metabolic disorders in the older progeny.
Highlights
Global incidence of obesity has increased dramatically in all age groups, including women of reproductive age [1, 2]
Body weight and composition In both groups, body weight and body-fat content increased with age, the effect was greater in the offspring of obese dams (Fig. 1a)
There were no significant differences between offspring groups for total cholesterol, HDL, FFA, insulin, fasting glucose, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), or glucose tolerance (Table 2)
Summary
Global incidence of obesity has increased dramatically in all age groups, including women of reproductive age [1, 2]. Maternal obesity during pregnancy has been shown to have long-term “programmed” effects on the offspring [4, 5] This involves changes in gene expression and permanent structural and functional changes in tissues that make the offspring susceptible to obesity and related diseases [6,7,8]. These effects of maternal obesity could be mediated by the maternal nutritional status and/or dietary composition [5, 9,10,11]. The major epigenetic determinants are DNA methylation, histone modification and noncoding RNAs, such as microRNAs (miRNAs) [5]. It is predicted that at least 30% of all human genes are regulated by miRNAs and disturbances in Received: 13 April 2021 Revised: 22 September 2021 Accepted: 1 October 2021
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