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      Maternal High-Fat Diet Impairs Placental Fatty Acid β-Oxidation and Metabolic Homeostasis in the Offspring

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          Abstract

          Maternal overnutrition can affect fetal growth and development, thus increasing susceptibility to obesity and diabetes in later life of the offspring. Placenta is the central organ connecting the developing fetus with the maternal environment. It is indicated placental fatty acid metabolism plays an essential role in affecting the outcome of the pregnancy and fetus. However, the role of placental fatty acid β-oxidation (FAO) in maternal overnutrition affecting glucose metabolism in the offspring remains unclear. In this study, C57BL/6J female mice were fed with normal chow or high-fat diet before and during pregnancy and lactation. The placenta and fetal liver were collected at gestation day 18.5, and the offspring's liver was collected at weaning. FAO-related genes and AMP-activated protein kinase (AMPK) signaling pathway were examined both in the placenta and in the human JEG-3 trophoblast cells. FAO-related genes were further examined in the liver of the fetuses and in the offspring at weaning. We found that dams fed with high-fat diet showed higher fasting blood glucose, impaired glucose tolerance at gestation day 14.5 and higher serum total cholesterol (T-CHO) at gestation day 18.5. The placental weight and lipid deposition were significantly increased in maternal high-fat diet group. At weaning, the offspring mice of high-fat diet group exhibited higher body weight, impaired glucose tolerance, insulin resistance and increased serum T-CHO, compared with control group. We further found that maternal high-fat diet downregulated mRNA and protein expressions of carnitine palmitoyltransferase 2 (CPT2), a key enzyme in FAO, by suppressing the AMPK/Sirt1/PGC1α signaling pathway in the placenta. In JEG-3 cells, protein expressions of CPT2 and CPT1b were both downregulated by suppressing the AMPK/Sirt1/PGC1α signaling pathway under glucolipotoxic condition, but were later restored by the AMPK agonist 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). However, there was no difference in CPT2 and CPT1 gene expression in the liver of fetuses and offspring at weaning age. In conclusion, maternal high-fat diet can impair gene expression involved in FAO in the placenta by downregulating the AMPK signaling pathway, and can cause glucose and lipid dysfunction of offspring at weaning, indicating that placental FAO may play a crucial role in regulating maternal overnutrition and metabolic health in the offspring.

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          AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.

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          The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells.
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            The Epidemiology of Obesity: A Big Picture.

            The epidemic of overweight and obesity presents a major challenge to chronic disease prevention and health across the life course around the world. Fueled by economic growth, industrialization, mechanized transport, urbanization, an increasingly sedentary lifestyle, and a nutritional transition to processed foods and high-calorie diets over the last 30 years, many countries have witnessed the prevalence of obesity in its citizens double and even quadruple. A rising prevalence of childhood obesity, in particular, forebodes a staggering burden of disease in individuals and healthcare systems in the decades to come. A complex, multifactorial disease, with genetic, behavioral, socioeconomic, and environmental origins, obesity raises the risk of debilitating morbidity and mortality. Relying primarily on epidemiologic evidence published within the last decade, this non-exhaustive review discusses the extent of the obesity epidemic, its risk factors-known and novel-, sequelae, and economic impact across the globe.
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              AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.

              AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
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                Author and article information

                Contributors
                Journal
                Front Nutr
                Front Nutr
                Front. Nutr.
                Frontiers in Nutrition
                Frontiers Media S.A.
                2296-861X
                14 April 2022
                2022
                : 9
                : 849684
                Affiliations
                Department of Endocrinology, Peking University First Hospital , Beijing, China
                Author notes

                Edited by: Demin Cai, Yangzhou University, China

                Reviewed by: Kate J. Claycombe, United States Department of Agriculture (USDA), United States; Amanda Brandon, The University of Sydney, Australia

                *Correspondence: Jia Zheng zhengjia@ 123456bjmu.edu.cn

                This article was submitted to Nutrition and Metabolism, a section of the journal Frontiers in Nutrition

                Article
                10.3389/fnut.2022.849684
                9050107
                35495939
                e403ba57-30d0-43d5-a894-6b03eacb7bda
                Copyright © 2022 Zhang, Wang, Wu, Gao, Zheng and Zhang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 January 2022
                : 22 March 2022
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 63, Pages: 13, Words: 8265
                Funding
                Funded by: National Natural Science Foundation of China, doi 10.13039/501100001809;
                Award ID: 81800703
                Award ID: 81970701
                Funded by: Beijing Municipal Natural Science Foundation, doi 10.13039/501100005089;
                Award ID: 7184252
                Funded by: Beijing Nova Program, doi 10.13039/501100005090;
                Award ID: Z201100006820117
                Categories
                Nutrition
                Original Research

                maternal high-fat diet,placenta,fatty acid β-oxidation,ampk,offspring

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