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      Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring

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          Abstract

          Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed.

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          Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates.

          Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.
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            The pathogenesis of diabetic nephropathy.

            Between 20% and 40% of patients with diabetes ultimately develop diabetic nephropathy, which in the US is the most common cause of end-stage renal disease requiring dialysis. Diabetic nephropathy has several distinct phases of development and multiple mechanisms contribute to the development of the disease and its outcomes. This Review provides a summary of the latest published data dealing with these mechanisms; it focuses not only on candidate genes associated with susceptibility to diabetic nephropathy but also on alterations in various cytokines and their interaction with products of advanced glycation and oxidant stress. Additionally, the interactions between fibrotic and hemodynamic cytokines, such as transforming growth factor beta1 and angiotensin II, respectively, are discussed in the context of new information concerning nephropathy development. We touch on the expanding clinical data regarding markers of nephropathy, such as microalbuminuria, and put them into context; microalbuminuria reflects cardiovascular and not renal risk. If albuminuria levels continue to increase over time then nephropathy is present. Lastly, we look at advances being made to enable identification of genetically predisposed individuals.
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              Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood.

              We sought to examine the association of gestational weight gain (GWG) and prepregnancy weight with offspring adiposity and cardiovascular risk factors. Data from 5154 (for adiposity and blood pressure) and 3457 (for blood assays) mother-offspring pairs from a UK prospective pregnancy cohort were used. Random-effects multilevel models were used to assess incremental GWG (median and range of repeat weight measures per woman: 10 [1, 17]). Women who exceeded the 2009 Institute of Medicine-recommended GWG were more likely to have offspring with greater body mass index, waist, fat mass, leptin, systolic blood pressure, C-reactive protein, and interleukin-6 levels and lower high-density lipoprotein cholesterol and apolipoprotein A1 levels. Children of women who gained less than the recommended amounts had lower levels of adiposity, but other cardiovascular risk factors tended to be similar in this group to those of offspring of women gaining recommended amounts. When examined in more detail, greater prepregnancy weight was associated with greater offspring adiposity and more adverse cardiovascular risk factors at age 9 years. GWG in early pregnancy (0 to 14 weeks) was positively associated with offspring adiposity across the entire distribution but strengthened in women gaining >500 g/wk. By contrast, between 14 and 36 weeks, GWG was only associated with offspring adiposity in women gaining >500 g/wk. GWG between 14 and 36 weeks was positively and linearly associated with adverse lipid and inflammatory profiles, with these associations largely mediated by the associations with offspring adiposity. Greater maternal prepregnancy weight and GWG up to 36 weeks of gestation are associated with greater offspring adiposity and adverse cardiovascular risk factors. Before any GWG recommendations are implemented, the balance of risks and benefits of attempts to control GWG for short- and long-term outcomes in mother and child should be ascertained.
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                Author and article information

                Journal
                Biosci Rep
                Biosci. Rep
                ppbioscirep
                BSR
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                26 February 2018
                27 April 2018
                29 March 2018
                : 38
                : 2
                : BSR20180050
                Affiliations
                [1 ]Department of Medicine, Kolling Institute, University of Sydney, Sydney, Australia
                [2 ]Department of Diabetes, Endocrinology and Metabolism, Royal North Shore Hospital, St Leonards, NSW 2065, Australia
                [3 ]School of Life Sciences, Faculty of Science, University of Technology Sydney, Australia
                Author notes
                Correspondence: Sarah J. Glastras ( sarah.glastras@ 123456sydney.edu.au )
                Article
                10.1042/BSR20180050
                5874265
                29483369
                68d6d570-3027-4384-a45d-a1e1c1c81405
                © 2018 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 07 December 2017
                : 17 February 2018
                : 26 February 2018
                Page count
                Pages: 15
                Categories
                Review Articles
                Review Article
                46
                40
                41

                Life sciences
                chronic kidney disease,developmental programming,epigenetics,fetal programming,maternal obesity,metabolic

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