Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models

Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models

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Journal Pre-proof Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models Amanda N. Sferruzzi-Perri, Jorge Lopez-Tello, Tina Napso, Hannah E.J. Yong PII:

S0143-4004(20)30033-3

DOI:

https://doi.org/10.1016/j.placenta.2020.01.015

Reference:

YPLAC 4095

To appear in:

Placenta

Received Date: 15 October 2019 Revised Date:

20 January 2020

Accepted Date: 29 January 2020

Please cite this article as: Sferruzzi-Perri AN, Lopez-Tello J, Napso T, Yong HEJ, Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models, Placenta (2020), doi: https://doi.org/10.1016/j.placenta.2020.01.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.

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Exploring the causes and consequences of maternal metabolic maladaptations during

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pregnancy: lessons from animal models

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Amanda N. Sferruzzi-Perri1, Jorge Lopez-Tello, Tina Napso and Hannah E.J. Yong

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Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience,

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Downing Street, University of Cambridge, Cambridge, UK CB2 3EG

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Corresponding author:

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Amanda Sferruzzi-Perri

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Centre for Trophoblast Research,

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Department of Physiology, Development and Neuroscience,

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University of Cambridge,

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Cambridge, UK CB2 3EG

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Telephone: +44 (0) 1223333807

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Email: [email protected]

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Keywords: gestational diabetes; metabolism; fetal growth; placenta; hormones; pregnancy;

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nutrient partitioning

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Running title: Maternal metabolic maladaptations during pregnancy

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Abstract:

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Pregnancy is a remarkable physiological state, during which the metabolic system of the mother

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adapts to ensure that nutrients are made available for transfer to the fetus for growth and

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development. Adaptations of maternal metabolism during pregnancy are influenced by the

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metabolic and nutritional status of the mother and the production of endocrine factors by the

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placenta that exert metabolic effects. Insufficient or inappropriate adaptations in maternal

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metabolism during pregnancy may lead to pregnancy complications with important short- and long-

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term effects for both the health of the child and mother. This is very evident in gestational diabetes,

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which is marked by greater glucose intolerance and insulin resistance above that expected of a

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normal pregnancy. Gestational diabetes is associated with increased fetal weight and/or increased

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adiposity, higher instrumented delivery rates and greater risks for both mother and child of

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developing type 2 diabetes in the long-term. However, despite the negative health impacts of such

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metabolic imbalances during pregnancy, the precise mechanisms responsible for orchestrating

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these changes remain largely unknown. The present review describes the dynamic pregnancy-

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specific changes that occur in the metabolic system of the mother during pregnancy. It also 1

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discusses findings using surgical, pharmacological, genetic and dietary methods in experimental

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animals that highlight the role of pathways in maternal tissues that lead to metabolic dysfunction,

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with a particular focus on gestational diabetes. Finally, it summarises the work largely employing

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gene targeting and hormone administration in rodents that have illuminated the involvement of

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placental endocrine function in driving maternal metabolic adaptations. While current animal

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models may not fully replicate what is observed in humans, these have been instrumental in

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showing that there is a dynamic interplay between changes in maternal metabolic physiology and

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the placental production of endocrine factors that govern the availability of nutrients to the growing

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fetus. However, more work is required to specifically identify the placenta-driven changes in

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maternal metabolic physiology that ensure the appropriate level of insulin production and action

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during pregnancy. In doing so, these studies may pave the way to understanding the development

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of pregnancy complications like gestational diabetes, as well as further our understanding of type-2

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diabetes and the control of metabolic physiology more broadly.

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Maternal metabolic adaptation during pregnancy and its importance for life-long health

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Pregnancy is a remarkable physiological state, during which the metabolic system of the mother

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adapts to ensure that nutrients are made available for transfer to the fetus for growth and

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development. Adaptations of maternal metabolism during pregnancy are influenced by the

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metabolic and nutritional status of the mother (from before pregnancy) and the production of

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endocrine factors by the placenta that exert metabolic effects. If maternal health status before

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getting pregnant is unfavourable (e.g. increased body adiposity) and/or adaptations in maternal

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metabolism during pregnancy are insufficient or inappropriate, these could lead to abnormal

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nutrient partitioning to the fetus and pregnancy complications such as gestational diabetes (GDM)

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and abnormal fetal growth. These pregnancy complications can have important short- and long-

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term effects for both the health of the mother and child. In the mother, GDM raises the risk of

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hypertension during pregnancy, an instrumented delivery and the development of type-2 diabetes

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in later motherhood. In the child, alterations in intrauterine growth (indicated by being born either

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small or large for gestational age), significantly increase the risk of neonatal hypoglycaemia and

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perinatal mortality, as well as increase the risk of developing obesity and type-2 diabetes in later

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adult life. Pre-existing maternal obesity predisposes a woman to developing GDM and abnormal

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fetal growth during pregnancy. Many countries are now contending with the burden of obesity and

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type-2 diabetes, which have assumed epidemic proportions. Moreover, pregnancy complications

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impose major financial drains on the health services around the world. With these in mind, it is

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important to understand the mechanisms driving changes in maternal metabolic function during

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pregnancy as these will likely be useful in devising strategies to prevent pregnancy complications

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and the associated lifelong impacts in women and their child. Therefore, this review aims to 1)

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describe the dynamic pregnancy-specific changes that occur in the metabolic system of the mother

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during pregnancy, 2) discuss the findings from experimental animals that highlight the role of

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pathways in maternal tissues that lead to metabolic dysfunction, with a particular focus on GDM,

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and 3) summarise the work largely undertaken in rodents, which illuminate the involvement of

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placental endocrine function in driving maternal metabolic adaptations.

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Maternal metabolic alterations during normal and complicated pregnancies

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Maternal metabolism changes dynamically during gestation, in line with the metabolic demands of

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the growing fetus (Figure 1). There are changes in insulin sensitivity, which affects the availability

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and fate of nutrients in both mother and conceptus. In particular, early pregnancy is characterised

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by a period of maternal tissue growth (eg liver, kidneys, pancreas and adipose tissue), energy

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accumulation (eg lipid storage) and sometimes, increased insulin sensitivity [1-5]. In contrast, later

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pregnancy is characterised by energy reserve (lipid) mobilization and decreased insulin sensitivity

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of maternal tissues, including the skeletal muscle and white adipose tissue, which increases fatty

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acid and glucose availability for fetal growth [4, 6-8]. The increased availability of lipids in the

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mother can also contribute to the decreased insulin sensitivity observed in late pregnancy [9]. To 3

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balance the normal state of insulin resistance in the mother, pancreatic β-cell mass and glucose-

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stimulated insulin release increases in the second half of the pregnancy [10-12]. In pregnant

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women with GDM, there is evidence for impaired pancreatic insulin secretion, dyslipidemia and

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defects in the insulin signalling pathway in the skeletal muscle and adipose tissue that relate to the

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altered glucose-insulin handling and higher prevalence of increased fetal adiposity and large for

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gestational age babies seen [1, 13-15]. However, less is known about the metabolic physiology of

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women who deliver babies that are small for gestational age, and particularly, whether an inability

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of the mother to metabolically adapt, such as acquire insulin resistance and glucose intolerance in

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mid-late gestation may be associated with poor fetal outcomes. Thus, further work is required to

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understand the mechanisms driving changes in maternal metabolism and insulin resistance during

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the course of gestation in both normal and complicated pregnancies.

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Maternal manipulations to study metabolic alterations during pregnancy

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Multiple animal models have been used to study maternal metabolic alterations during pregnancy

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and, in particular, with regard to the pathophysiology of GDM (Table 1). All these models are based

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on inducing diabetes during pregnancy by surgical, chemical, genetic or dietary methods, but many

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of these are not dependent on the pregnancy. For example, surgical removal of the pancreas in

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rats [16] or administration of drugs like streptozotocin or alloxan, which induce death of pancreatic

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β cells in mice, rats, rabbits, pigs and sheep [17-23] can lead to the development of a GDM

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phenotype (hyperglycemia or glucose intolerance) in association with failed β cell mass expansion

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and insulin insufficiency. Maternal global genetic manipulation of genes including the leptin

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receptor, adiponectin, vascular-derived connective tissue growth factor, free fatty acid receptor-2

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and serotonin receptor 5-hydroxytryptamine receptor-2b [24-33] or conditional alterations in the

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insulin-producing β cells of the pancreas by manipulating genes such as aryl-hydrocarbon receptor

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nuclear translocator, menin, Mafb, c-Met, adenosine receptor A2a, forehead box transcription

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factors and islet amyloid polypeptide in mice [34-39] also compromise β cell mass expansion and

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lead to hyperglycemia and glucose intolerance. However, in the case of some genetic

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manipulations, investigators have failed to fully recapitulate maternal metabolic alterations; for

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instance deletion of the leptin receptor in mice is not always associated with glucose intolerance in

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the mother during pregnancy [40-42]. Moreover, only a few of the aforementioned animal models

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reported increased fetal/birth weight [17, 24, 26, 43] and the majority of the surgical and

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pharmacological animal models were linked to fetal hyperglycemia, perinatal loss and

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developmental defects [16, 18-22], which are typically observed in women with type 1 and type 2

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diabetes. Notwithstanding, the findings overall highlight the importance of β cell mass expansion

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and insulin production in balancing the pregnancy-induced decline in insulin sensitivity of the

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mother.

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In mice, selectively altering the expression of insulin-responsive genes (insulin receptor,

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phosphoinositol 3-kinase isoforms, hexokinase) in the mother or specifically in her liver also leads

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to a GDM phenotype (hyperglycemia, hyperinsulinemia and/or glucose intolerance during

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pregnancy) although this is related to increased insulin resistance in the dam and unchanged or

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reduced fetal/birth weight [44-46]. Metabolic studies in mouse dams with deletion of SOCS3 from

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leptin-receptor expressing cells have also highlighted a role for increased leptin resistance in the

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development of a GDM phenotype [47].

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Consumption of diets containing high amounts of fat and sugar lead to insulin and leptin resistance

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[48]. In developed societies, such diets are now the norm and contribute to the increasing rates of

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women who are overweight or obese during pregnancy, which is a risk factor for GDM, as well as

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abnormal birthweight. In rodents and dogs, a maternal diet high in fat and/or sugar induces a

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GDM-like phenotype (hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance)

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(Table 1). This is accompanied with disrupted expression of glucose and lipid metabolic proteins

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and insulin signaling components (including insulin receptor and phosphoinositol 3-kinase

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isoforms) in the liver, skeletal muscle and white adipose of the mother in late gestation [49-57].

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There may also be insufficient β-cell mass expansion in diet-induced GDM-like mice [50, 58],

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although work is required to assess the expression of genes involved in β-cell proliferation and

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glucose-stimulated insulin release (as shown in Table 1; global and β-cell specific gene

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manipulation). The specific composition of the diet, when the diet is fed (from prior to or just during

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pregnancy) and level of adiposity in the mother appears to dictate the specific changes observed in

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maternal metabolism and whether these are accompanied with reduced, increased or unchanged

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fetal weight [59]. However, regardless, several of these models of diet-induced maternal metabolic

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maladaptation are associated with programmed changes in the metabolic function of the adult

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rodent offspring [51, 59-61]. Interestingly, a period of maternal exercise prevents the development

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of insulin resistance in the mouse dams fed a high fat or high sugar and high fat diet during

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pregnancy, as well as in their offspring postnatally [51, 53]. Most notably, improved insulin handling

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in the mother is linked to a restoration of insulin signaling primarily in the white adipose tissue,

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although there are also some changes in the maternal skeletal muscle and liver [53, 62].

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Fascinatingly, in rats, exposure to mild maternal diabetes during development was linked to

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alterations in the metabolism of female offspring that emerged when they were pregnant

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(resembling GDM; hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia)

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[63]. These findings are interesting given that a family history of diabetes is a risk factor for

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developing GDM during pregnancy. Female rat offspring that experienced reduced supply of

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nutrients and oxygen in utero, also developed alterations in glucose and insulin handling when they

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were pregnant [64]. Together, these findings highlight the importance of a family history of

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diabetes/genetic factors, as well as exposure to a suboptimal environment during intrauterine /

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early postnatal life in determining the subsequent development of GDM during pregnancy.

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Thus, studies in experimental animals collectively signify the role of genetics, signalling pathways,

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obesogenic diets and even the process of developmental programming in the pathogenesis of

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metabolic problems in the mother during pregnancy, like GDM (Figure 2). They also demonstrate

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the importance of adequate insulin production and insulin sensitivity of maternal tissues, like the

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skeletal muscle and white adipose fat depot in the appropriate control of glucose-insulin handling in

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the mother during pregnancy. Indeed, exacerbated insulin resistance or insufficient insulin

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production can result in abnormal metabolic responses resembling GDM. However, the majority of

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the animal models that have been employed thus far, also show metabolic derangements, such as

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abnormal pancreatic development, hyperglycemia, glucose intolerance, hyperphagia and/or

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adiposity in the female prior to pregnancy, which limits their utility as an accurate model to study

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pregnancy-induced changes in maternal metabolism. Moreover, whilst fetal growth/birthweight is

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not reported to be altered in most of the animal models, human pregnancy metabolic disorders, like

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GDM also do not always lead to altered birthweight. Rather, metabolic disorders, like GDM are

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associated with increased fetal adiposity – an index challenging to measure in small experimental

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animals for which the majority of data are available (Table 1). Thus, additional work is required to

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precisely study the molecular and cellular mechanisms underlying maternal metabolic imbalances

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and alterations in fetal growth and body composition during gestation, as well as the increased risk

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of the mother and child to developing conditions like type 2 diabetes after delivery.

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The endocrine placenta and maternal metabolic alterations

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Adaptations in maternal metabolism are signalled, at least partly, by changes in placental hormone

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production during gestation. The placenta secretes hormones, cytokines, neuropeptides and other

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endocrine factors into the mother to modulate her glycemic control, as well as lipid metabolism,

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which is likely to happen mainly by influencing insulin secretion and action [59, 65, 66]. The

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function of placental hormones during pregnancy has been assessed experimentally by either

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exogenous administration or genetically manipulating the expression of specific hormones and

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hormone receptors in rodents in vivo (Table 2). Placental-derived hormones such as prolactin

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(PRL), placental lactogen (PL), growth hormone (GH) variant, insulin-like growth factor-2 (IGF2),

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parathyroid hormone-related protein, placental growth factor and progesterone increase in the

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maternal circulation from early pregnancy and change pancreatic β cell proliferation and insulin

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secretion [43, 67-84]. Changes in proliferation and insulin secretion with PRL and PL are mediated

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through downregulating Menin gene expression and inducing serotonin synthesis and signalling in

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the pancreatic β cells during pregnancy [28, 35, 85]. They can also increase maternal adiposity

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and reduce whole body insulin sensitivity and glucose utilisation, particularly by disrupting insulin 6

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signaling pathway components like phosphoinositol 3-kinase isoforms in skeletal muscle and white

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adipose tissue [13, 77, 86-88]. However, other placentally-derived hormones, like estrogen, which

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peak in the maternal circulation in late pregnancy, have been shown to both decrease and

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increase whole body insulin sensitivity, depending on the hormonal milieu of the mother [83, 89-

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96]. Placental-derived hormones that rise in the circulation towards term and are able to increase

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insulin sensitivity likely play a role in re-partitioning glucose and lipid use to the mother in

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anticipation of delivery and lactation [4]. Placental hormones thus, appear to interact to help drive

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changes in maternal metabolic physiology at different stages of pregnancy.

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Although much of the data on the roles of placental hormones in vivo are from non-pregnant

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animals or genetically-altered mice that have pre-pregnant metabolic alterations [43, 66, 68, 74,

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75, 88, 92, 97], several studies have examined consequences of hormonal changes specifically

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induced during pregnancy. In mice fed a high sugar and high fat diet just from the start of

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pregnancy, expression PRL/PL genes by the placenta is perturbed and associated with maternal

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hyperglycaemia, glucose intolerance and insulin resistance [50, 98]. Placental PRL/PL expression

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is also altered in genetically-modified mice and aged rats that display insulin resistance during

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gestation [46, 99]. However, in turn, the sensitivity of tissues in the mother to the effects of

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placental hormones during pregnancy will be modified by maternal health state (such as nutrition

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and obesity prior to and during pregnancy) [100]. The importance of placental hormones in the

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development of metabolic conditions during pregnancy has been additionally inferred from

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association studies in humans. Studies have reported alterations in the circulating abundance of

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placental hormones in women with GDM [101-105]. Moreover, polymorphisms in the receptor for

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PRL are associated with the development of GDM in women [106]. Further support for the notion

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that placental endocrine dysfunction may underlie maternal metabolic imbalances during gestation

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has been provided by observations in wildtype mice with genetically-altered mutant fetuses and

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placentas. In particular, in mice, manipulating the expression of the Igf2, H19 and Dlk1 genes in

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the conceptus, which results in overgrowth or undergrowth of the placenta (and hence changes in

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placental endocrine output), is associated with alterations in maternal body composition and

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glucose, lipid and insulin handling of wildtype dams during pregnancy [107-109]. Thus, the

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placenta signals fetal needs to the mother, via its secretion of hormones which affect maternal

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metabolic physiology and thus, the supply of nutrients for fetal growth [110] (Figure 2). However, a

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placental-specific approach is required to definitively determine whether altered placental hormone

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production has a causative role in the development of metabolic conditions, like GDM in the mother

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during pregnancy and its long-term effects. Moreover, the application of unbiased gene and protein

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sequencing approaches is needed to identify the complete repertoire of hormones and endocrine

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factors released by the placenta that drive metabolic changes in the mother during pregnancy.

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Summary and conclusions 7

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Taken together, there is a dynamic interplay between changes in maternal metabolic physiology

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and the placental production of endocrine factors that govern the availability of glucose and other

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nutrients to the growing fetus (Figure 2). However, more work is required to specifically identify the

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placenta-driven changes in maternal metabolic physiology that ensure appropriate level of insulin

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production and action during pregnancy. In doing so, these studies may hold the key to

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understanding the development of pregnancy complications like abnormal fetal growth and GDM,

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as well as further our understanding of type-2 diabetes and the control of metabolic physiology

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more broadly. Ultimately, the findings of such work would aid in the development of diagnostic,

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preventive and therapeutic strategies to combat pregnancy complications and metabolic

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derangements like GDM and type-2 diabetes, the latter of which are rapidly increasing in many

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parts of the world.

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Acknowledgments

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A.N.S.-P is supported by a Royal Society Dorothy Hodgkin Research Fellowship (RG74249), J.L.-T

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is supported by a Royal Society Newton International Fellowship (NF170988), T.N. is supported by

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salary paid from a Lister Institute Prize and Academy of Medical Science Grant to A.N.S.-P, and

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H.E.J.Y is supported by an A*Star Fellowship. Presented at the PAA Placental Satellite

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Symposium 2018, which was supported by NIH Conference Grant HD084096.

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Conflict of interest

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There are no conflicts of interest to declare.

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Figure 1. Maternal metabolism changes dynamically during gestation, in line with the metabolic

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demands of the growing fetus.

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Figure 2. During pregnancy, there is a dynamic interplay between the placental production of

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hormones

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environmental/nutritional factors and health) that govern the availability of nutrients to the growing

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fetus. Alterations in placental hormone production and maladaptations of maternal metabolism may

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result in pregnancy complications like gestational diabetes and abnormal fetal growth.

and

changes

in

maternal

metabolic

physiology

(influenced

by

genetics,

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102. McIntyre, H. D., Serek, R., Crane, D. I., Veveris-Lowe, T., Parry, A., Johnson, S., Leung, K. C., Ho, K. K., Bougoussa, M., Hennen, G., Igout, A., Chan, F. Y., Cowley, D., Cotterill, A. & Barnard, R. (2000) Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth, The Journal of clinical endocrinology and metabolism. 85, 1143-50. 103. Newbern, D. & Freemark, M. (2011) Placental hormones and the control of maternal metabolism and fetal growth, Curr Opin Endocrinol Diabetes Obes. 18, 409-16. 104. Ngala, R. A., Fondjo, L. A., Gmagna, P., Ghartey, F. N. & Awe, M. A. (2017) Placental peptides metabolism and maternal factors as predictors of risk of gestational diabetes in pregnant women. A casecontrol study, PLoS One. 12, e0181613. 105. Liao, S., Vickers, M. H., Taylor, R. S., Fraser, M., McCowan, L. M. E., Baker, P. N. & Perry, J. K. (2017) Maternal serum placental growth hormone, insulin-like growth factors and their binding proteins at 20 weeks' gestation in pregnancies complicated by gestational diabetes mellitus, Hormones (Athens). 16, 282290. 106. Le, T. N., Elsea, S. H., Romero, R., Chaiworapongsa, T. & Francis, G. L. (2013) Prolactin receptor gene polymorphisms are associated with gestational diabetes, Genetic testing and molecular biomarkers. 17, 567-71. 107. Sferruzzi-Perri, A. N., Vaughan, O. R., Coan, P. M., Suciu, M. C., Darbyshire, R., Constancia, M., Burton, G. J. & Fowden, A. L. (2011) Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice, Endocrinology. 152, 3202-12. 108. Petry, C. J., Evans, M. L., Wingate, D. L., Ong, K. K., Reik, W., Constancia, M. & Dunger, D. B. (2010) Raised late pregnancy glucose concentrations in mice carrying pups with targeted disruption of H19Delta13., Diabetes. 59, 282-286. 109. Cleaton, M. A., Dent, C. L., Howard, M., Corish, J. A., Gutteridge, I., Sovio, U., Gaccioli, F., Takahashi, N., Bauer, S. R., Charnock-Jones, D. S., Powell, T. L., Smith, G. C., Ferguson-Smith, A. C. & Charalambous, M. (2016) Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction, Nat Genet. 48, 1473-1480. 110. Lopez-Tello, J., Khaira, J., Kusinski, L. C., Cooper, W., Andreani, A., Grant, I., Fernandez de Liger, E., Sandovici, I., Constancia, M. & Sferruzzi-Perri, A. N. (2019) Fetal and placental phosphoinositol 3-kinase (PI3K) p110α have distinct contributions in regulating resource allocation to the growing fetus, eLIFE. 8.

576 577

14

578 579

Table 1 Maternal manipulations to study metabolic alterations during pregnancy Manipulation

Maternal metabolic phenotype

Fetal phenotype

Reference

Glucose intolerance, hyperglycaemia due to insulin deficiency

Compromised fetal

[16]

Surgical removal of beta cells Removal of pancreas in rats

development (increased resorptions) Pharmacological ablation of beta cells Alloxan during pregnancy in pigs

Hyperglycaemia due to insulin deficiency

Increased fetal glucose, no

[20]

change fetal weight Alloxan during pregnancy in

Hyperglycaemia due to insulin deficiency

rabbits Streptozotocin prior to pregnancy

Increased fetal glucose and

[19]

increased fetal mortality Hyperglycaemia due to insulin deficiency

in rats

Increased fetal malformations

[18]

and reduced fetal development (decreased crown-rump length)

Streptozotocin during pregnancy in

Hyperglycaemia due to insulin deficiency

mice

No change birth weight but

[23]

offspring programmed for insulin resistance

Maternal genetic manipulation in mice to study metabolic changes during pregnancy Global gene manipulation Adiponectin deficiency (Adipoq-/-)

Glucose intolerant in late pregnancy due to defective pancreas

in female mated to wildtype male.

beta cell mass expansion and insulin deficiency. Reduced

Compared to reverse cross to

glycogen content and increased glucose production in the liver

Increased fetal weight

[24]

15

control litter genotype

and hyperlipidemia (increased triglycerides and fatty acids)

Leptin receptor heterozygous null

Glucose intolerant only during pregnancy with reduced peripheral

Increased fetal weight

females mated with males of same

tissue insulin sensitivity and GSIS. Increased food intake, hepatic

regardless of fetal genotype

genotype or wildtype males

glucose production, adiposity and hyperleptinemia

[26, 29-32]

Normal glucose tolerance despite hyperleptinemia and increased

Increased fetal length but no

adiposity during pregnancy, expect if fed a high fat diet

change in fetal weight

Increased glucose tolerance despite hyperleptinemia and

ND

[42]

No change in pup number

[25]

ND

[27]

[28]

[40][41]

increased weight during pregnancy Ffar2-/- mice

Fasting hyperglycemia and impaired glucose tolerance, beta cell mass expansion and insulin secretion during, but not before, pregnancy. No change in insulin tolerance before and during pregnancy. Estradiol induces Ffar2 expression in islets

Vascular-derived connective tissue

Impairment in maternal beta cell proliferation during pregnancy

growth factor (Ctgf)

but not apparent in non-pregnant state. Normal glucose tolerance

haploinsufficiency (Ctgf(LacZ/+))

and GSIS in non-pregnant and pregnant state

Serotonin receptor 5-

Impairment in beta cell proliferation during pregnancy and glucose ND

hydroxytryptamine receptor-2b

intolerance in pregnant but not in not-pregnant mice. Related to

(Htr2b)

prolactin and placental lactogen which induce serotonin synthesis and signalling in the beta cells

Serotonin receptor knockout Htr3a

Glucose intolerance and diminished GSIS (via increased resting

-/-

beta cell membrane potential) in pregnant but not in not-pregnant

No change in litter size

[85]

mice. No change in beta cell mass prior to or during pregnancy. Prolactin and placental lactogen induce serotonin synthesis and 16

signalling in the beta cells Serotonin transporter null

Failed brown adipose tissue expansion, increased white adipose

ND

[33]

No change in fetal weight

[46]

ND

[37]

ND

[36]

[35]

tissue, reduced plasma insulin and improved glucose tolerance during pregnancy Phosphoinositol 3-kinase p110α

Reduced liver weight, hyperleptinemia, reduced triglycerides,

(Pik3ca) +/- female mated to

hyperinsulinemia and no change in glucose (insulin resistance)

wildtype male. Compared to

during pregnancy

reverse cross to control litter genotype Beta cell specific gene manipulation Transgenic mice expressing

Beta cell deficit and hyperglycemia in prior to and during

human IAPP in the beta cells in

pregnancy, but these worsen in the second pregnancy

not-pregnant and pregnant state following mating to wildtype males Beta cell loss of HGF-cMet in

Failed beta cell mass expansion, reduced GSIS and glucose

females mated to wildtype males

intolerance during pregnancy (but not in non-pregnant state). Related to reduced PRLR expression by beta cells. Estradiol increases cMet expression

Beta cell Menin overexpression in

Failed beta cell mass expansion, insulin deficiency,

No change in birthweight or

female pregnant mice

hyperglycaemia and glucose intolerance

litter size

Beta cell Foxm1 deletion in female

Failed beta cell mass expansion and glucose intolerance during

ND

[39]

mice

pregnancy but beta cell defect present in non-pregnant state.

Mildly increased fetal weight

[34]

Impacts on beta cells during pregnancy related to the effect of placental lactogen. Glucose handling restores postpartum Beta cell specific Arnt null mated to Mutants have impaired glucose tolerance secondary to defective

17

wildtype male. Compared to

insulin secretion in non-pregnant state, which worsens with

reverse parental cross

pregnancy

Liver specific gene manipulation Hepatic insulin receptor deficiency

Hyperinsulinemic with normal blood glucose levels before

Reduced birthweight followed

mated to wildtype males

pregnancy but became glucose intolerant and more insulin

by rapid postnatal catch up

resistant compared during pregnancy

growth and increased glucose,

[44]

insulin, glucagon, leptin and GLP1 Hepatic overexpression of

Lower insulin and GSIS but improved glucose tolerance in

hexokinase

association with increased hepatic, white adipose and skeletal

ND

[45]

ND

[45]

No effect on fetal outcome

[47]

ND

[55]

muscle insulin signalling. Impacts observed only during pregnancy Hepatic deletion of hexokinase

Similar insulin but reduced glucose tolerance only during pregnancy

Cell specific gene manipulation-other SOCS3 deletion from leptin

Inability to undergo pregnancy-induced hyperphagia, body fat

receptor cells

accumulation, as well as inability to acquire leptin and insulin resistance. Protected females against long-term postpartum fat retention and streptozotocin-induced hyperglycaemia and glucose intolerance during pregnancy during to improved peripheral insulin sensitivity

Maternal obesogenic diet High fructose and high fat diet from Glucose intolerance, reduced hepatic and skeletal muscle insulin mid-pregnancy in dogs

sensitivity without a change in beta cell mass density or plasma insulin 18

High fructose diet just during

Increased adiposity, hyperinsulinemia and glucose intolerance

Increased fetal weight

[57]

pregnancy in rats

related to peripheral insulin resistance

High sugar and high fat just in

Increased adiposity, reduced glucose tolerance and reduced

Reduced fetal weight followed

[49, 50]

pregnancy in mice

peripheral insulin sensitivity but increased hepatic sensitivity and

by accelerated fetal growth

reduced glucose production. Changes in maternal metabolic

just prior to term

phenotype related to alterations in the expression of insulin signalling and glucose and lipid handling proteins in the liver, skeletal muscle and WAT, as well as reduced prolactin/placental lactogen genes in the placenta High sucrose and high fat for 1

Increased adiposity, reduced glucose tolerance related to reduced No change in fetal weight or

week prior to and during

beta cell mass, insulin deficiency, decreased GSIS and elevated

pregnancy in mice

leptin during pregnancy which is not apparent prior to pregnancy.

[58]

litter size

Glucose intolerance resolves after pregnancy, but dams have a propensity to develop glucose intolerance and hypertriglyceridemia on a high fat diet postpartum High fat diet for 3 weeks prior to

Increased adiposity, reduced glucose tolerance and

and during pregnancy in mice

hyperglycaemia prior to and during pregnancy. Exercise

ND

[53]

[54]

ameliorated diet-induced maternal glucose intolerance and hyperglycaemia in association with changes in insulin signalling proteins primarily in WAT during pregnancy High sugar and high fat diet for 4

Increased adiposity, glucose intolerance and hyperinsulinemia

No change in fetal weight but

weeks prior to and during

which are aggravated by pregnancy

increased litter size

Diet fed 6 weeks prior to and

Increased adiposity, glucose intolerance, hyperinsulinemia,

Increased fetal weight and

during pregnancy in mice

hyperleptinemia and reduced adiponectin. Adiponectin

glucose

pregnancy in rats [52, 56]

19

ameliorated diet-induced maternal hyperinsulinemia, hyperleptinemia Diet fed 9 weeks prior to and

Increased adiposity, glucose intolerance, insulin resistance,

during pregnancy in mice

hyperinsulinemia and hyperleptinemia related to alterations in the

Reduced fetal weight

[51, 62]

expression of insulin signalling and glucose and lipid handling proteins in the liver, skeletal muscle and WAT. Exercise ameliorated diet-induced maternal glucose intolerance, insulin resistance and hyperinsulinemia in association with changes in insulin signalling proteins primarily in the WAT 580

GSIS: glucose-stimulated insulin secretion, ND: not determined, WAT: white adipose tissue.

581

20

582

Table 2 The function of placental hormones in driving metabolic changes assessed experimentally in rodents in vivo Hormone/manipulation

Maternal metabolic phenotype

Fetal phenotype

References

Exogenous administration of growth

Non-pregnant: Hyperinsulinemia and reduced insulin sensitivity

NA

[75-78]

hormone or overexpression of human

associated with impaired stimulation of IRS1-PI3K signalling

placental growth hormone in mice

(increased PI3K-p85α) and GLUT4 in skeletal muscle and WAT.

Pregnant: Hyperinsulinemia and reduced insulin sensitivity associated

No change in litter

[87]

with reduced hepatic GLUT4 without a change in fasting glucose levels

size or fetal weight

and body weight.

but reduced fetal

Growth hormone

Increased body weight and IGF1 and reduced adiposity, adiponectin and free fatty acids.

crown-rump length. Deficiency of growth hormone in mice

Non-pregnant: Elevated adiponectin and increased adipocyte size with

NA

[78]

[73]

higher insulin sensitivity related to reduced PI3K-p85α expression in WAT. Placental growth factor Pharmacological administration

Pregnant: increased β-cell proliferation during pregnancy in mice with

Fetal weight not

placental growth factor in mice

defects in β-cell mass expansion due to L-name treatment

assessed.

Deficiency of prolactin receptor in

Non-pregnant: Reduced islet density, β-cell mass and insulin

NA

mice

content/islet and GSIS. Reduced body weight, adipose mass and

treated with L-NAME Prolactin [68, 79, 80]

plasma leptin. No change in glucose tolerance. 21

Deficiency of prolactin in mice

Pregnant: Glucose intolerant in association with failed β-cell

No change in litter

proliferation expansion and reduced GSIS.

size, fetal weight.

Pregnant: glycaemia is normal.

No change in litter

[68, 80]

[80]

size, fetal weight. Transgenic mice with deficiency of

Non-pregnant: Similar levels of glucose, insulin, glucose and insulin

NA

[70]

the prolactin receptor in β-cells

tolerance, pancreatic weight and β-cell mass. Pregnant: Hyperglycaemic and glucose intolerant due to reduced β-cell

Increased fetal

[43]

proliferation and expansion of β-cell mass.

weight.

Transgenic mice with overexpression

Non-pregnant: Hypoglycaemia due to increased β-cell size, mass and

NA

[84]

of placental lactogen 1 in β-cells

GSIS.

NA

[74]

NA

[72]

Placental lactogen

Parathyroid hormone-related protein Transgenic mice with overexpression

Non-pregnant: Reduced in size and have hypoglycaemia and

of parathyroid hormone-related

hyperinsulinemia due to expansion of β-cell mass.

protein in β-cells Insulin like growth factors Transgenic mice with loss of IGF2 in

Non-pregnant: Young mice have similar glucose tolerance, insulin

β-cells

sensitivity and GSIS. However, aged females display lower levels of insulin, which is compensated by increased insulin sensitivity to maintain normal glucose tolerance. β-cell mass expansion in response high fat diet or pharmacological induction of insulin resistance is reduced.

22

Pregnant mice: have reduced β-cell proliferation.

ND

[72]

Wildtype mice carrying litters with

Pregnant: Increased body weight, increased insulin and corticosterone

Reduced fetal and

[107]

placental loss of the Igf2 P0 isoform

and reduced α-amino nitrogen concentrations. Higher plasma glucose,

placental weights.

corticosterone and leptin in undernourished dams during pregnancy. Wildtype mice carrying litters with

Pregnant: Elevated circulating glucose and glucose intolerant.

placental overexpression of the Igf2

Increased fetal and

[108]

placental weights.

(H19 deletion) Estrogens Deficiency of estrogen receptor-α in

Non-pregnant: Hyperglycemia, hyperleptinemia, hyperinsulinemia,

mice

reduced insulin sensitivity, hepatic insulin resistance, glucose

NA

[92, 93]

NA

[92]

NA

[83, 90, 94-

intolerance and increased body weight. Deficiency of estrogen receptor-β in

Non-pregnant: Normal body size, glycaemia, insulinemia and glucose

mice

tolerance.

Exogenous administration of

Non-pregnant: Increased insulin sensitivity and reduced plasma

estrogens to mice and rats

glucose levels due to increased insulin-stimulated PI3K signalling,

96]

GLUT4 translocation and glucose uptake by the skeletal muscle. Increased plasma leptin and reduced food intake.

Pregnant: Increased insulin sensitivity and reduced plasma glucose in

ND

[83]

NA

[81]

NA

[82, 83]

association with increased GSIS and β-cell size Progesterone Deficiency of progesterone

Non-pregnant: Reduced glucose levels and improved glucose

receptor in mice

tolerance due to increased β-cell proliferation and insulin secretion/production.

Exogenous administration of

Non-pregnant: Increased in food intake, body weight, adiposity and

23

estrogens to mice and rats 583

insulin secretion.

GSIS: glucose-stimulated insulin secretion, NA: not applicable, ND: not determined, PI3K: phosphoinositol 3-kinase, WAT: white adipose tissue.

584 585 586

24