Impact of maternal undernutrition around the time of conception on factors regulating hepatic lipid metabolism and microRNAs in singleton and twin fetuses

Abstract

We have demonstrated that periconceptional undernutrition and preimplantation undernutrition each resulted in decreased hepatic fatty acid ␤-oxidation regulators, PGC-1␣ (P Ͻ 0.05), PDK2 (P Ͻ 0.01), and PDK4 (P Ͻ 0.01) mRNA expression in singleton and twin fetuses at 135-138 days gestation. In singletons, there was also lower hepatic PDK4 (P Ͻ 0.01), CPT-1 (P Ͻ 0.01), and PKC (P Ͻ 0.01) protein abundance in the PCUN and PIUN groups and a lower protein abundance of PDPK-1 (P Ͻ 0.05) in the PCUN group. Interestingly, in twins, the hepatic protein abundance of p-AMPK (Ser 485 ) (P Ͻ 0.01), p-PDPK-1 (Ser 41 ) (P Ͻ 0.05), and PKC (P Ͻ 0.05) was higher in the PCUN and PIUN groups, and hepatic PDK4 (P Ͻ 0.001) and CPT-1 (P Ͻ 0.05) protein abundance was also higher in the PIUN twin fetus. We also found that the expression of a number of microRNAs was altered in response to PCUN or PIUN and that there is evidence that these changes may underlie the changes in the protein abundance of key regulators of hepatic fatty acid ␤-oxidation in the PCUN and PIUN groups. Therefore, embryo number and the timing of maternal undernutrition in early pregnancy have a differential impact on hepatic microRNA expression and on the factors that regulate hepatic fatty acid oxidation and lipid synthesis. pregnancy; nutrition; liver; fatty acid; epigenetic THERE IS EVIDENCE that exposure of the oocyte, embryo, or fetus to a range of environmental stressors, including poor maternal nutrition, can result in altered development of metabolic, endocrine, and cardiovascular systems, leading to an increased risk of visceral obesity and insulin resistance in postnatal life (6,8,11,24,39,48,49). In adult life, intrahepatic triglyceride accumulation is associated with insulin resistance and a lack of suppression of hepatic glucose output (22). It has also been shown that mitochondrial dysfunction contributes to hepatic insulin resistance and steatosis, leading to the development of nonalcoholic fatty liver disease (38). The rate of fatty acid ␤-oxidation in hepatic mitochondria is important in maintaining cellular energy production and in limiting the accumulation of excess triglycerides in the hepatocyte. Therefore, programming of a dysregulation of hepatic lipid metabolism in response to poor maternal nutrition in early life may contribute toward poor metabolic outcomes in adult life.Maternal undernutrition during midgestation in sheep resulted in increased feed intake and body weight gain, lower insulin sensitivity, and greater hepatic lipid content (12). There is also evidence that exposure to maternal undernutrition in midpregnancy during the period of hepatogenesis results in an increased hepatic lipid accumulation in obese lambs (19). It is not known, however, whether exposure of the oocyte and/or embryo to maternal undernutrition can result in the programming of changes in lipid metabolism in the developing liver or whether the impact of maternal undernutrition during this early period is different in the presence of a singleton or twin pregnanc...

MicroRNA-27b Depletion Enhances Endotrophic and Intravascular Lipid Accumulation and Induces Adipocyte Hyperplasia in Zebrafish

“…Apart from the classical transcriptional regulators, microRNAs (miRs) have been shown to participate in almost every metabolic homeostasis process, including adipogenesis [ 1 , 2 ], lipogenesis [ 3 ], and glucose-stimulated insulin secretion [ 4 , 5 ], in order to exert influence on metabolic pathways which are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [ 6 ]. Recent research has demonstrated that miRs are able to regulate the expression of key genes involved in lipid homeostasis, including miR-122, miR-33, miR-106, miR-758, miR-26, miR-370, miR-378, let-7, miR-27, miR-143, miR-34a, and miR-335 [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

The role of miR-369-3p in proliferation and differentiation of preadipocytes in Aohan fine-wool sheep

“…Liu et al (2019) found that miR-369-3p regulates the proliferation and migration of EEC (endometrioid adenocarcinoma) cells, suggesting that miR-369-3p can also inhibit adipocyte differentiation by inhibiting the expression of ATG10 in human body. Lie et al (2016) showed that miR-369-3p targeted PDPK-1 (3-phosphoinositide-dependent protein kinase-1) in sheep, and expression levels were negatively correlated. PDPK-1 is the key gene to initiate autophagy (Hu et al, 2021), and the expression of PDPK-1 and PPARγ resulted in a synergistic effect (Yin et al, 2006).…”

“…CDK4 indirectly inhibits oxidative metabolism by controlling E2F1 transcription factors in muscle and brown adipose tissue (BAT) (Blanchet et al, 2011) and also promotes insulin signalling pathways in mature adipocytes (Lagarrigue et al, 2016). In sheep, miR-369-3p targets the key gene PDPK-1 that activates autophagy, and its expression is negatively correlated (Lie et al, 2016;Hu et al, 2021). The miR-369-3p can also regulate and inhibit the autophagy-related gene ATG10 (Liu et al, 2019).…”

Growth hormone reverses dyslipidemia in adult offspring after maternal undernutrition

“…It has been reported that lipid metabolism might be more sensitive to malnutrition during intrauterine development of fetus 24–26 . Here we speculated that hypertriglyceridemia observed in adult SGA rats exposed to maternal undernutrition during pregnancy might be a result of abnormal expression of AMPK-α1/SREBP-1c/ACC-1 pathway.…”

“…Our study observed that the adult SGA rats showed weak ability to handle a lipid load resulting in increased serum TG levels, coincident with Choi’s study 23 . It has been reported that lipid metabolism might be more sensitive to malnutrition during intrauterine development of fetus 24 – 26 . Here we speculated that hypertriglyceridemia observed in adult SGA rats exposed to maternal undernutrition during pregnancy might be a result of abnormal expression of AMPK-α1/SREBP-1c/ACC-1 pathway.…”