Publications by authors named "Mark H Vickers"

116 Publications

Untangling the genetic link between type 1 and type 2 diabetes using functional genomics.

Sci Rep 2021 Jul 6;11(1):13871. Epub 2021 Jul 6.

Liggins Institute, The University of Auckland, Auckland, New Zealand.

There is evidence pointing towards shared etiological features between type 1 diabetes (T1D) and type 2 diabetes (T2D) despite both phenotypes being considered genetically distinct. However, the existence of shared genetic features for T1D and T2D remains complex and poorly defined. To better understand the link between T1D and T2D, we employed an integrated functional genomics approach involving extensive chromatin interaction data (Hi-C) and expression quantitative trait loci (eQTL) data to characterize the tissue-specific impacts of single nucleotide polymorphisms associated with T1D and T2D. We identified 195 pleiotropic genes that are modulated by tissue-specific spatial eQTLs associated with both T1D and T2D. The pleiotropic genes are enriched in inflammatory and metabolic pathways that include mitogen-activated protein kinase activity, pertussis toxin signaling, and the Parkinson's disease pathway. We identified 8 regulatory elements within the TCF7L2 locus that modulate transcript levels of genes involved in immune regulation as well as genes important in the etiology of T2D. Despite the observed gene and pathway overlaps, there was no significant genetic correlation between variant effects on T1D and T2D risk using European ancestral summary data. Collectively, our findings support the hypothesis that T1D and T2D specific genetic variants act through genetic regulatory mechanisms to alter the regulation of common genes, and genes that co-locate in biological pathways, to mediate pleiotropic effects on disease development. Crucially, a high risk genetic profile for T1D alters biological pathways that increase the risk of developing both T1D and T2D. The same is not true for genetic profiles that increase the risk of developing T2D. The conversion of information on genetic susceptibility to the protein pathways that are altered provides an important resource for repurposing or designing novel therapies for the management of diabetes.
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http://dx.doi.org/10.1038/s41598-021-93346-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260770PMC
July 2021

Metabolic Hormone Profiles in Breast Milk From Mothers of Moderate-Late Preterm Infants Are Associated With Growth From Birth to 4 Months in a Sex-Specific Manner.

Front Nutr 2021 28;8:641227. Epub 2021 May 28.

The Liggins Institute, University of Auckland, Auckland, New Zealand.

Differing environmental conditions experienced by mother-infant dyads may influence composition of the milk received by the infant. As a consequence, diverse milk compositional profiles may contribute to different postnatal outcomes, especially in infants facing adverse perinatal environments. We investigated whether variability in milk concentrations of key metabolic hormones is associated with different growth outcomes in infants born preterm, a perinatal complication known to impact on infant growth. Human milk samples were collected from 169 mothers of 191 infants enrolled in the DIAMOND trial, a randomized trial of nutrition for moderate-late preterm infants, at 5 and 10 days postpartum and again at 4 months' corrected age and analyzed for leptin, adiponectin and insulin-like growth factor (IGF)-1. Infant weight and body composition were measured at birth, discharge and 4 months' corrected age. Multiple linear regression models were used to examine correlations between milk hormone concentrations, weight z-scores and body composition at discharge and 4 months' corrected age, and weight gain from birth to 4 months' corrected age. Sex-specific interactions were examined. Higher milk IGF-1 concentrations on day 5 after birth were associated with greater infant fat-free mass at 4 months' corrected age. Milk IGF-1 concentrations at 4 months were positively associated with fat mass and fat-free mass at 4 months in boys but not girls. Milk leptin concentrations on day 5 after birth were positively associated with fat mass at discharge from hospital, but negatively associated with fat mass at 4 months' corrected age. No significant association was found for milk adiponectin concentrations. Milk IGF-1 and leptin concentrations in mothers of moderate-late preterm babies are associated with different growth and body composition through to 4 months' corrected age and these associations are often different in boys and girls. The sex-specific effects of nutrient and hormone exposure during early life in preterm infants warrants further investigation to optimize the nutritional care these infants receive, particularly in hospital, where the same nutrition is provided to boys and girls.
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http://dx.doi.org/10.3389/fnut.2021.641227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193224PMC
May 2021

Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review.

Int J Mol Sci 2021 May 10;22(9). Epub 2021 May 10.

Liggins Institute, The University of Auckland, Auckland 1023, New Zealand.

Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications and small RNA-mediated processes, particularly that of microRNAs. Epigenetic changes are reversible and are closely interconnected. They are recognised to play a critical role as mediators of gene regulation, and any alteration in these mechanisms has been identified to mediate various pathophysiological conditions. Moreover, genetic predisposition and environmental factors, including dietary alterations, lifestyle or metabolic status, are identified to interact with the human epigenome, highlighting the importance of epigenetic factors as underlying processes in the aetiology of various diseases such as MetS. This review will reflect on how both the classical and microRNA-regulated epigenetic changes are associated with the pathophysiology of metabolic syndrome. We will then focus on the various aspects of epigenetic-based strategies used to modify MetS outcomes, including epigenetic diet, epigenetic drugs, epigenome editing tools and miRNA-based therapies.
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http://dx.doi.org/10.3390/ijms22095047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126218PMC
May 2021

The association of maternal gestational hyperglycemia with breastfeeding duration and markers of milk production.

Am J Clin Nutr 2021 May 8. Epub 2021 May 8.

Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), Singapore.

Background: Previous studies focusing on the association between gestational diabetes and breastfeeding duration have been inconclusive.

Objectives: We aimed to determine whether maternal gestational hyperglycemia is associated with the duration of breastfeeding and the concentrations of markers linked to breastmilk production.

Methods: Data from the prospective, multiethnic Growing Up in Singapore Towards Healthy Outcomes study were used to assess the association of fasting plasma glucose (FPG) and 2-h postglucose challenge (2hPG) measured at 26-28 wk of gestation with duration of breastfeeding and concentrations of protein, lactose, citrate, sodium, potassium, and zinc in breastmilk 3 wk postpartum.

Results: Of the 1035 participants, 5.2% and 9.5% had elevated FPG and 2hPG, respectively, consistent with a diagnosis of gestational diabetes mellitus based on International Association of Diabetes and Pregnancy Study Groups criteria. FPG ≥5.1 mmol/L was associated with a crude reduction in median breastfeeding duration of 2.3 mo. In a model adjusted for maternal prepregnancy BMI and intention to breastfeed, FPG ≥5.1 mmol/L predicted earlier termination of any breastfeeding (adjusted HR: 1.47; 95% CI: 1.04, 2.08) but not full breastfeeding (adjusted HR: 1.08; 0.76, 1.55). 2hPG ≥8.5 mmol/L was not significantly associated with the durations of any (adjusted HR: 0.86; 95% CI: 0.62, 1.19) or full (adjusted HR: 0.85; 95% CI: 0.62, 1.18) breastfeeding. Maternal FPG was significantly and positively associated with breastmilk sodium (adjusted coefficient: 1.28; 95% CI: 1.08, 1.51) and sodium-to-potassium ratio (adjusted coefficient: 1.29; 95% CI: 1.08, 1.54) but not with other measured breastmilk components.

Conclusions: Women with FPG ≥5.1 mmol/L during pregnancy breastfeed for a shorter duration. Future work involving measurement of milk production is needed to determine whether low milk production predicts breastfeeding duration among women with elevated FPG. This trial was registered at www.clinicaltrials.gov as NCT01174875.
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http://dx.doi.org/10.1093/ajcn/nqab142DOI Listing
May 2021

Maternal undernutrition during pregnancy and lactation increases transcription factors, ETV5 and GDNF, and alters regulation of apoptosis and heat shock proteins in the testis of adult offspring in the rat.

Reprod Fertil Dev 2021 May;33(7):484-496

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, L8S 4L8, Canada; and Department of Pediatrics, McMaster University, Hamilton, L8S 4L8, Canada, and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, L8S 4L8, Canada.

We tested whether changes in Sertoli cell transcription factors and germ cell heat shock proteins (HSPs) are linked to the effects of maternal undernutrition on male offspring fertility. Rats were fed ad libitum with a standard diet (CONTROL) throughout pregnancy and lactation or with 50% of CONTROL intake throughout pregnancy (UNP) or lactation (UNL) or both periods (UNPL). After postnatal Day 21, 10 male pups per group were fed a standard diet ad libitum until postnatal Day 160 when testes were processed for histological, mRNA and immunohistochemical analyses. Compared with CONTROL: caspase-3 was increased in UNP and UNPL (P=0.001); Bax was increased in UNL (P=0.002); Bcl-2 (P<0.0001) was increased in all underfed groups; glial cell line-derived neurotrophic factor (P=0.002) was increased in UNP and UNL; E twenty-six transformation variant gene 5 and HSP70 were increased, and HSP90 was diminished in all underfed groups (P<0.0001). It appears that maternal undernutrition during pregnancy and lactation disrupts the balance between proliferation and apoptosis in germ cells, increasing germ cell production and perhaps exceeding the support capacity of the Sertoli cells. Moreover, fertility could be further compromised by changes in meiosis and spermiogenesis mediated by germ cell HSP90 and HSP70.
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http://dx.doi.org/10.1071/RD20260DOI Listing
May 2021

Maternal and Infant Factors Influencing Human Milk Oligosaccharide Composition: Beyond Maternal Genetics.

J Nutr 2021 Jun;151(6):1383-1393

Liggins Institute, The University of Auckland, Auckland, New Zealand.

Maternal genetics is a key determinant of human milk oligosaccharide (HMO) composition in human milk. Beyond genetic status, other factors influencing the HMO profile are poorly defined. Thus, we aimed to review the existing evidence on the associations between nongenetic maternal and infant factors and HMO composition. A systematic search was performed on PubMed and Web of Science (without a time restriction) to identify any relevant studies published. In total, 1056 results were obtained, of which 29 articles were selected to be included in this review. The range of factors investigated include lactation stage, maternal pre-pregnancy BMI (ppBMI), maternal age, parity, maternal diet, mode of delivery, infant gestational age, and infant sex. The data suggest that, beyond maternal genetics, HMO composition seems to be influenced by all these factors, but the underlining mechanisms remain speculative. The published evidence is discussed in this review, along with potential implications for infant growth and development. For example, 2'-fucosyllactose, which was reportedly increased in mothers with higher ppBMIs, was also associated with increased infant weight and height. In addition, greater levels of sialylated HMOs after preterm birth may support brain development in these infants.
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http://dx.doi.org/10.1093/jn/nxab028DOI Listing
June 2021

First 1000 days: New Zealand Mothers' perceptions of early life nutrition resources.

J Dev Orig Health Dis 2021 Feb 5:1-7. Epub 2021 Feb 5.

Liggins Institute, University of Auckland, Private Bag 92019, Victoria Street West, Auckland1142, New Zealand.

Research into associations between early life nutritional exposures and vulnerability to adult non-communicable disease (NCD) highlights the importance of maternal diet. A booklet outlining evidence-based dietary guidelines for the first 1000 days of life was first published in 2016 by early life nutrition experts for distribution to pregnant women in Australia and New Zealand. First-time New Zealand mothers' (n=9) perceptions of the booklet and its relevance for the future health of their child were explored via semi-structured focus groups and interviews. Recruitment took place via social media channels and antenatal classes around Auckland. Three major themes were identified using thematic analysis: 1. A difference in the ways mothers related to the booklet depending on their apparent level of health literacy and communication preferences; 2. A tendency for women to outsource decision-making to nutrition 'rules', rather than interpreting information to suit personal circumstances; 3. Intense pressure to comply, resulting in feelings of shame or guilt when the 'rules' were not followed. In this study, first-time mums expressed feeling under pressure to 'get it right' and identified a desire for more support from healthcare providers and society. Nutrition education is essential; however, a booklet should provide a starting point for conversation rather than a stand-alone list of recommendations. Further exploration is needed to develop a resource that can be used by health professionals working alongside women and their partners to support healthy child development.
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http://dx.doi.org/10.1017/S2040174420001336DOI Listing
February 2021

Maternal exercise alters rat fetoplacental stress response: Minimal effects of maternal growth restriction and high-fat feeding.

Placenta 2021 01 18;104:57-70. Epub 2020 Nov 18.

Department of Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia. Electronic address:

Introduction: Fetal growth restriction complicates 10% of pregnancies and increases offspring (F1) risk of metabolic disorders, including obesity and gestational diabetes mellitus (GDM). This disease predisposition can be passed onto the next generation (F2). Importantly, the risk of pregnancy complications in obese women can be exacerbated by a stressful pregnancy. Exercise can reduce adiposity and improve health outcomes in obese women and those with GDM. This study investigated the impacts of maternal growth restriction, obesity, exercise, and stress on fetal and placental endocrine function.

Methods: Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in F0 Wistar-Kyoto rats. F1 offspring were fed a Chow or High-fat (HFD) diet from weaning and, at 16 weeks, were randomly allocated an exercise protocol; Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised only during pregnancy (PregEx). Females were mated and further randomly allocated to either undergo (Stress), or not undergo (Unstressed), physiological measurements during pregnancy. On E20, F2 fetal plasma (steroid hormones), tissues (brain, liver), and placentae (morphology, stress genes) were collected.

Results: Maternal growth restriction and high-fat feeding had minimal impact on fetoplacental endocrine function. PregEx and Exercise increased cross-sectional labyrinth and junctional zone areas. PregEx, but not Exercise, increased fetal deoxycorticosterone concentrations and reduced placental Hsd11b2 and Nr3c2 gene abundance. Maternal stress increased fetal corticosterone concentrations in Sedentary HFD dams and increased placental cross-sectional areas in PregEx mothers.

Discussion: PregEx and Stress independently dysregulates the endocrine status of the developing fetus, which may program future disease.
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http://dx.doi.org/10.1016/j.placenta.2020.11.006DOI Listing
January 2021

GWAS SNPs Impact Shared Regulatory Pathways Amongst Multimorbid Psychiatric Disorders and Cognitive Functioning.

Front Psychiatry 2020 23;11:560751. Epub 2020 Oct 23.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Epidemiological research has reported that attention-deficit hyperactivity disorder (ADHD), anxiety, bipolar disorder (BD), schizophrenia (SCZ), and unipolar depression (UD) are multimorbid conditions that are typically accompanied by cognitive advantages or deficits, suggesting that common biological mechanisms may underlie these phenotypes. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with psychiatric disorders and cognitive functioning. However, the mechanisms by which these SNPs contribute to multimorbidities amongst psychiatric and cognitive phenotypes remains largely unknown. To identify shared regulatory mechanisms amongst multimorbid psychiatric disorders and cognitive functioning. We integrated data on 3D genome organization, expression quantitative trait loci (eQTLs), and pathway analyses to identify shared and specific regulatory impacts of 2,893 GWAS SNPs ( < 1 × 10) associated with ADHD, anxiety, BD, SCZ, UD, and cognitive functioning on genes and biological pathways. Drug-gene interaction analysis was performed to identify potential pharmacological impacts on these genes and pathways. The analysis revealed 33 genes and 62 pathways that were commonly affected by tissue-specific gene regulatory interactions associated with all six phenotypes despite there being no common SNPs in our original dataset. The analysis of brain-specific regulatory connections revealed similar patterns at eQTL and eGene levels, but no pathways shared by all six phenotypes. Instead, pairwise overlaps and individualized pathways were identified for psychiatric and cognitive phenotypes in brain tissues. This study offers insight into the shared genes and biological pathways that are affected by tissue-specific regulatory impacts resulting from psychiatric- and cognition-associated genetic variants. These results provide limited support for the "p-factor" hypothesis for psychiatric disorders and potential mechanisms that explain drug side-effects. Our results highlight key biological pathways for development of therapies that target single or multiple psychiatric and cognitive phenotypes.
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http://dx.doi.org/10.3389/fpsyt.2020.560751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649776PMC
October 2020

The 20-kDa Placental GH Variant: A New and Improved Growth Hormone?

Endocrinology 2020 10;161(10)

Liggins Institute, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1210/endocr/bqaa147DOI Listing
October 2020

Preterm human milk: associations between perinatal factors and hormone concentrations throughout lactation.

Pediatr Res 2021 May 29;89(6):1461-1469. Epub 2020 Jul 29.

The Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Infants born moderate to late preterm constitute the majority of preterm births, yet guidelines for their nutritional care are unclear. Maternal milk is the most appropriate nutrition for these infants; however, its composition can be influenced by environmental factors. The present study therefore investigated perinatal predictors of human milk composition in a preterm cohort.

Methods: Milk was collected during the DIAMOND trial (DIfferent Approaches to Moderate and late preterm Nutrition: Determinants of feed tolerance, body composition and development) from 169 mothers of 191 infants at three time-points (5 and 10 days post partum and 4 months' corrected age). Leptin, adiponectin and insulin-like growth factor-1 (IGF-1) were analysed by enzyme-linked immunosorbent assay. Generalised mixed models were used to evaluate associations between milk composition and maternal/infant/perinatal factors.

Results: Most findings were independent of collection time-point. Gestational diabetes was associated with lower adiponectin. Higher adiponectin and lower leptin were associated with higher socioeconomic status, higher maternal education and ability to fully breastfeed at discharge from hospital. Higher leptin was associated with high perceived stress during hospital admission. Milk IGF-1 displayed sex-specific patterns in association with maternal social deprivation.

Conclusion: Maternal, infant and environmental factors during the perinatal period were associated with milk compositional profiles throughout lactation. Further clinical trials should investigate the impact of such changes in terms of long-term infant outcomes.

Impact: Human milk is the best nutrition for the infant. However, its composition may be susceptible to alterations determined by pathological conditions mother and infant may face throughout pregnancy and in the perinatal period. This study found that perinatal factors are associated with human milk composition from early to late lactation. If human milk composition throughout lactation is "programmed" during pregnancy or early lactation, infants who were exposed in utero to environmental insults may still be exposed to them during lactation. The impact of human milk compositional alteration on infant growth following perinatal pathological events requires further investigation.
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http://dx.doi.org/10.1038/s41390-020-1069-1DOI Listing
May 2021

Interleukin 1 Receptor 1 Knockout and Maternal High Fat Diet Exposure Induces Sex-Specific Effects on Adipose Tissue Adipogenic and Inflammatory Gene Expression in Adult Mouse Offspring.

Front Physiol 2020 23;11:601. Epub 2020 Jun 23.

Developmental Programming Research Group, The Liggins Institute, The University of Auckland, Auckland, New Zealand.

The global incidence of obesity continues to rise, increasing the prevalence of metabolic diseases such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus. Low-grade chronic inflammation, associated with the obese state, also contributes to the development of these metabolic comorbidities. Interleukin-1-receptor-1 (IL-1R1), a pro-inflammatory mediator, bridges the metabolic and inflammatory systems. In young male mice, deficiency of IL-1R1 (IL-1R1) paired with a high-fat diet (HFD) offered beneficial metabolic effects, however in female mice, the same pairing led to metabolic dysfunction. Therefore, we examined the contribution of maternal HFD in combination with IL1R1 to metabolic health in adult offspring. Female C57BL/6 and IL-1R1 mice were randomly assigned to a control diet (10% kcal from fat) or HFD (45% kcal from fat) 10 days prior to mating and throughout gestation and lactation. Male and female offspring were housed in same-sex pairs post-weaning and maintained on control diets until 16 weeks old. At 15 weeks, an oral glucose tolerance test (OGTT) was performed to assess glucose tolerance. Histological analysis was carried out to assess adipocyte size and gene expression of adipogenic and inflammatory markers were examined. IL-1R1 contributed to increased body weight in male and female adult offspring, irrespective of maternal diet. IL-1R1 and maternal HFD increased adipocyte size in the gonadal fat depot of female, but not male offspring. In female offspring, there was reduced expression of genes involved in adipogenesis and lipid metabolism in response to IL1R1 and maternal HFD. While there was an increase in inflammatory gene expression in response to maternal HFD, this appeared to be reversed in IL1R1 female offspring. In male offspring, there was no significant impact on adipogenic or lipid metabolism pathways. There was an increase in inflammatory gene expression in IL1R1 male offspring from HFD-fed mothers. This study suggests that IL-1R1 plays a complex and important role in the metabolic health of offspring, impacting adipogenesis, lipogenesis, and inflammation in a sex-specific manner.
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http://dx.doi.org/10.3389/fphys.2020.00601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324782PMC
June 2020

Supporting Cook Island communities to access DOHaD evidence.

J Dev Orig Health Dis 2020 12 7;11(6):564-572. Epub 2020 Jul 7.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Developmental origins of health and disease research have cemented relationships between the early-life environment and later risk of non-communicable diseases (NCDs). However, there is limited translation of this knowledge in developing-economy nations, such as the Cook Islands, that carry exceptionally high NCD burdens. Considering the evidence, Cook Islands leaders identified a need for increased community awareness of the importance of early-life nutrition. Using a community-based participatory research approach, this study aimed to engage Cook Islands community representatives in the co-construction of a contextually relevant early-life nutrition resource. A booklet distributed to mothers in Australia and New Zealand was used as a starting point. Ten semi-structured focus groups (n = 60) explored views regarding the existing resource and options for contextual adaptation. Three core themes were identified: knowledge of the importance of early-life nutrition, recognition of the need for an early-life nutrition resource and the importance of resources being context specific. A draft booklet was created based on these discussions. Participants were invited to give feedback via a second round of focus groups. This confirmed that the voice of the community was represented in the draft booklet. Suggestions for additional material not included in the original resource were also identified. We report on the process and outcomes of the co-construction with community representatives of a resource that has the potential to be used to stimulate community-level discussion about the importance of early-life nutrition. It is crucial that communities have an active voice in research and in making decisions about interventions for their population.
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http://dx.doi.org/10.1017/S2040174420000252DOI Listing
December 2020

Differences in Compositions of Gut Bacterial Populations and Bacteriophages in 5-11 Year-Olds Born Preterm Compared to Full Term.

Front Cell Infect Microbiol 2020 16;10:276. Epub 2020 Jun 16.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Preterm infants are exposed to major perinatal, post-natal, and early infancy events that could impact on the gut microbiome. These events include infection, steroid and antibiotic exposure, parenteral nutrition, necrotizing enterocolitis, and stress. Studies have shown that there are differences in the gut microbiome during the early months of life in preterm infants. We hypothesized that differences in the gut microbial composition and metabolites in children born very preterm persist into mid-childhood. Participants were healthy prepubertal children aged 5-11 years who were born very preterm (≤32 weeks of gestation; = 51) or at term (37-41 weeks; = 50). We recorded the gestational age, birth weight, mode of feeding, mode of birth, age, sex, and the current height and weight of our cohort. We performed a multi'omics [i.e., 16S rRNA amplicon and shotgun metagenomic sequencing, SPME-GCMS (solid-phase microextraction followed by gas chromatography-mass spectrometry)] analysis to investigate the structure and function of the fecal microbiome (as a proxy of the gut microbiota) in our cross-sectional cohort. Children born very preterm were younger (7.8 vs. 8.3 years; = 0.034), shorter [height-standard deviation score (SDS) 0.31 vs. 0.92; = 0.0006) and leaner [BMI (body mass index) SDS -0.20 vs. 0.29; < 0.0001] than the term group. Children born very preterm had higher fecal calprotectin levels, decreased fecal phage richness, lower plasma arginine, lower fecal branched-chain amino acids and higher fecal volatile (i.e., 3-methyl-butanoic acid, butyrolactone, butanoic acid and pentanoic acid) profiles. The bacterial microbiomes did not differ between preterm and term groups. We speculate that the observed very preterm-specific changes were established in early infancy and may impact on the capacity of the very preterm children to respond to environmental changes.
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http://dx.doi.org/10.3389/fcimb.2020.00276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309444PMC
June 2021

Maternal undernutrition during pregnancy and lactation affects testicular morphology, the stages of spermatogenic cycle, and the testicular IGF-I system in adult offspring.

J Dev Orig Health Dis 2020 10 28;11(5):473-483. Epub 2020 Apr 28.

Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada.

Maternal undernutrition decreases sperm production in male offspring, possibly through insulin-like growth factor (IGF-I). To test this hypothesis, we fed pregnant Wistar rats ad libitum with a standard diet (CONTROL) or fed 50% of CONTROL intake, either throughout pregnancy (UNP), lactation (UNL, or both (UNPL). After weaning, male offspring (n = 10 per treatment) were fed a standard diet until postnatal day 160, when testes process for histological and molecular analyses. IGF-I immunostaining area and intensity in the testis were greater (P = 0.003) in the UNPL group compared to CONTROL, but lower in the UNP group (P < 0.0001). Levels of IGF-I receptor transcript were lower in the UNPL and UNL groups, compared to CONTROL. There were more Ki-67-positive germ and Sertoli cells, in all underfed groups than in CONTROL. Compared to CONTROL, frequency of spermatogenic cycle stage VII was lower in all underfed groups, and seminiferous tubule diameter was smaller in UNP and UNPL. Plasma FSH concentrations were greater in UNP male offspring compared to all groups (P = 0.05), whereas inhibin B concentrations were greater in UNP (P = 0.01) and UNL (P = 0.003) than in CONTROL or UNPL. Thus, prenatal undernutrition leads to a decrease in testicular IGF-I levels, whereas of pre- and postnatal undernutrition increased testicular IGF-I levels and decreased amounts of IGF-I receptor mRNA in adult offspring. We conclude that maternal undernutrition during pregnancy and lactation leads to long-lasting effects on adult male offspring testicular morphology, spermatogenesis, and IGF-I testicular system.
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http://dx.doi.org/10.1017/S2040174420000306DOI Listing
October 2020

Consumption of the Artificial Sweetener Acesulfame Potassium throughout Pregnancy Induces Glucose Intolerance and Adipose Tissue Dysfunction in Mice.

J Nutr 2020 07;150(7):1773-1781

The Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Sugar-sweetened beverage consumption is associated with metabolic dysfunction. Artificially sweetened beverages (ASBs) are often promoted as an alternative. However, evidence for the safety of ASB consumption during pregnancy is lacking.

Objectives: The effects of sugar-sweetened beverage and ASB consumption during pregnancy in mice were examined, and we hypothesized that both sugar-sweetened beverages and ASBs would impair maternal metabolic function.

Methods: Pregnant female C57BL/6J mice received control drinking water (CD), high-fructose corn syrup (Fr; 20% kcal intake; 335 mM), or the artificial sweetener acesulfame potassium (AS; 12.5 mM) in their drinking water, from gestational day (GD) 0.5 (n = 8/group). Body weights and food and water intakes were assessed every second day, an oral-glucose-tolerance test (OGTT) was performed at GD 16.5, and mice were culled at GD 18.5. RT-PCR was carried out on adipose tissue, liver, and gut. Adipose tissue morphology was assessed using histological methods. In a separate cohort of animals, pregnancy length was assessed. Repeated-measures ANOVA was performed for the OGTT and weight gain data. All other data were analyzed by 1-way ANOVA.

Results: Fr and AS significantly impaired glucose tolerance, as demonstrated by OGTT (21% and 24% increase in AUC, respectively; P = 0.0006). Fr and AS reduced expression of insulin receptor (39.5% and 33% reduction, respectively; P = 0.02) and peroxisome proliferator-activated receptor γ (45.2% and 47%, respectively; P = 0.039), whereas Fr alone reduced expression of protein kinase B (36.9% reduction; P = 0.048) and resulted in an increase in adipocyte size and leptin concentrations (40% increase; P = 0.03). AS, but not Fr, reduced male fetal weight (16.5% reduction; P = 0.04) and female fetal fasting blood glucose concentration at cull (20% reduction; P = 0.02) compared with CD. AS significantly reduced the length of pregnancy compared with the CD and Fr groups (1.25 d shorter; P = 0.02).

Conclusions: Fr and AS consumption were associated with maternal metabolic dysfunction in mice. AS was also associated with reduced fetal growth and fetal hypoglycemia. Therefore, ASBs may not be a beneficial alternative to sugar-sweetened beverages during pregnancy.
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http://dx.doi.org/10.1093/jn/nxaa106DOI Listing
July 2020

DOHaD in low- and middle-income countries: a systematic review exploring gaps in DOHaD population studies.

J Dev Orig Health Dis 2020 12 21;11(6):557-563. Epub 2020 Apr 21.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Low- and middle-income countries (LMICs) are disproportionately affected by non-communicable diseases (NCDs), accounting for more than 80% of NCD-related deaths globally. Research into early-life influences on these diseases via the developmental origins of health and disease (DOHaD) paradigm has informed health promotion interventions and policies focused on optimising early-life health. However, little is known about where this research occurs and whether it reaches and reflects the countries most affected by NCDs. This review searched for DOHaD studies that investigated relationships between factors during pregnancy and at birth, with later-life NCD incidence, risk and related mortality. The aim of this review was to identify where DOHaD research has been conducted and whether this focus is appropriate and relevant, given the differential burden of NCDs. Embase, MEDLINE and Scopus were searched, and eligibility screening processes identified 136 final articles. This review found that 49.7% of DOHaD research was conducted on populations within Western Europe, 15.9% in East Asia, 12.7% in North America, 8.3% in Latin America and the Caribbean, and fewer in Australasia, South Asia, the Middle East, the Africas, and Central Asia. When categorised by income, this review found that 76.4% of studies were based in high-income countries, 19.1% in upper-middle-income and 4.5% in lower-middle-income countries. No studies were based in low-income countries. There is therefore a marked disconnect between where DOHaD research is undertaken and where the greatest NCD disease burden exists. Increasing DOHaD research capacity in LMICs is crucial to informing local strategies that can contribute to reducing the incidence of NCDs.
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http://dx.doi.org/10.1017/S2040174420000276DOI Listing
December 2020

3D interactions with the growth hormone locus in cellular signalling and cancer-related pathways.

J Mol Endocrinol 2020 05;64(4):209-222

Liggins Institute, University of Auckland, Auckland, New Zealand.

Growth hormone (GH) is a peptide hormone predominantly produced by the anterior pituitary and is essential for normal growth and metabolism. The GH locus contains five evolutionarily related genes under the control of an upstream locus control region that coordinates tissue-specific expression of these genes. Compromised GH signalling and genetic variation in these genes has been implicated in various disorders including cancer. We hypothesised that regulatory regions within the GH locus coordinate expression of a gene network that extends the impact of the GH locus control region. We used the CoDeS3D algorithm to analyse 529 common single nucleotide polymorphisms (SNPs) across the GH locus. This algorithm identifies colocalised Hi-C and eQTL associations to determine which SNPs are associated with a change in gene expression at loci that physically interact within the nucleus. One hundred and eighty-one common SNPs were identified that interacted with 292 eGenes across 48 different tissues. One hundred and forty-five eGenes were regulated in trans. eGenes were found to be enriched in GH/GHR-related cellular signalling pathways including MAPK, PI3K-AKT-mTOR, ERBB and insulin signalling, suggesting that these pathways may be co-regulated with GH signalling. Enrichment was also observed in the Wnt and Hippo signalling pathways and in pathways associated with hepatocellular, colorectal, breast and non-small cell lung carcinoma. Thirty-three eQTL SNPs identified in our study were found to be of regulatory importance in a genome-wide Survey of Regulatory Elements reporter screen. Our data suggest that the GH locus functions as a complex regulatory region that coordinates expression of numerous genes in cis and trans, many of which may be involved in modulating GH function in normal and disease states.
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http://dx.doi.org/10.1530/JME-20-0010DOI Listing
May 2020

Sexually Dimorphic Associations between Maternal Factors and Human Milk Hormonal Concentrations.

Nutrients 2020 Jan 6;12(1). Epub 2020 Jan 6.

The Liggins Institute, University of Auckland, Auckland 1023, New Zealand.

While human milk composition is characterised by marked dynamicity, we are far from having a clear picture of what factors drive this variation. Hormones in human milk are known to vary according to specific maternal phenotypes, but limited evidence shows the infant also has a role in determining milk composition. The present study aimed to investigate the interplay between maternal and infant characteristics in relation to human milk hormonal profile. In total, 501 human milk samples from mothers recruited in the Finnish STEPS cohort study (Steps to the healthy development) were analysed. Pre-pregnancy and pregnancy maternal data, socioeconomic status and infant characteristics at birth were collated. Leptin, adiponectin, insulin-like growth factor-1 and cyclic Glycine-Proline in milk were measured. Multivariate analysis of variance (MANOVA) and linear regression were utilised for statistical analysis. Sex-specific interactions with maternal factors were observed, as the infant sex mediated associations between gestational diabetes and milk adiponectin ( = 0.031), birth-mode and total protein ( = 0.003), maternal education and insulin-like growth factor-1: cyclic Glycine-Proline ratio ( = 0.035). Our results suggest that changes in human milk composition are associated with interactions between maternal and infant characteristics and pathophysiological factors. Future work should expand on these findings and further explore the link between hormonal profiles in human milk and infant outcomes.
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http://dx.doi.org/10.3390/nu12010152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019968PMC
January 2020

Cyclic glycine-proline normalizes systolic blood pressure in high-fat diet-induced obese male rats.

Nutr Metab Cardiovasc Dis 2020 02 25;30(2):339-346. Epub 2019 Sep 25.

The Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1142, New Zealand; Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Grafton, Auckland, 1142, New Zealand; Brain Research New Zealand, A Centre of Research Excellence, New Zealand. Electronic address:

Background And Aims: Insulin-like growth factor (IGF)-1 deficiency is associated with a range of metabolic disorders. Cyclic glycine-proline (cGP) is a natural nutrient and regulates the amount of active IGF-1 in plasma. Plasma cGP decreases in hypertensive women whereas increases in obese women, suggesting its involvement in cardio-metabolic function. We therefore examined the effects of cGP on metabolic profiles and blood pressure in high-fat diet (HFD)-induced obese male rats.

Methods: Male rats were fed either a HFD or a standard chow diet (STD) ad-libitum from 3 to 15 weeks of age. Rats were administered either saline or cGP from 11 to 15 weeks of age. At 14 weeks of age, systolic-blood pressure (SBP) was measured by tail-cuff plethysmography and body composition quantified by DEXA. Blood and retroperitoneal fat tissues were collected. Plasma concentrations of insulin, IGF-1, IGF binding protein (IGFBP)-3 and cGP were evaluated using ELISA and HPLC-MS respectively.

Results: Compared to STD, HFD feeding increased SBP, total fat mass and fat/lean ratio, retroperitoneal fat weight, fasting plasma insulin and cGP concentrations whereas decreased plasma IGF-1 and IGFBP-3 concentrations. Administration of cGP reduced SBP and retroperitoneal fat weight, but had no effect on body composition and plasma insulin concentrations.

Conclusion: HFD-associated decreases in IGFBP-3 and increases in cGP represent an autocrine response to normalize IGF-1 function through improving the amount of bioavailable IGF-1 in the circulation of obese male rats. The beneficial effects of cGP on SBP and retroperitoneal fat mass may suggest a therapeutic potential for cGP in HFD-associated cardio-metabolic complications.
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http://dx.doi.org/10.1016/j.numecd.2019.09.016DOI Listing
February 2020

Interleukin-1 Receptor-1 Deficiency Impairs Metabolic Function in Pregnant and Non-Pregnant Female Mice.

Mol Nutr Food Res 2021 01 15;65(1):e1900770. Epub 2019 Dec 15.

The Liggins Institute, University of Auckland, 85 Park Road, Grafton, 1023, Auckland, New Zealand.

Scope: Glucose intolerance during pregnancy is associated with short- and long-term maternal and offspring health consequences. In young male mice, knockout of the major pro-inflammatory mediator interleukin-1-receptor-1 (IL1R1) protects against high-fat diet (HFD)-induced glucose intolerance and metabolic dysfunction. This phenotype has not been examined during pregnancy. The hypothesis that IL1R1 depletion will protect females against HFD-induced glucose intolerance and metabolic dysfunction before, during, and post pregnancy is tested.

Methods And Results: C57BL/6J control and IL1R1 knockout (IL1R1 ) mice are randomized to either a control diet (10% kcal from fat) or HFD (45% kcal from fat), and three distinct cohorts are established: nulliparous, pregnant, and postpartum females. Contrary to the authors' hypothesis, it is found that IL1R1 does not protect against glucose intolerance in nulliparous or pregnant females, and while control HFD animals see a resolution of glucose tolerance postpartum, IL-1R1 mice remain impaired. These effects are accompanied by adipocyte hypertrophy, hyperleptinemia, and increased adipose tissue inflammatory gene expression. Maternal genotype differentially affects fetal growth in male and female fetuses, demonstrating sexual dimorphism in this genotype prior to birth.

Conclusions: These findings suggest that IL1R1 signaling is important for normal metabolic functioning in females, during and outside of pregnancy.
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http://dx.doi.org/10.1002/mnfr.201900770DOI Listing
January 2021

Supplementation with Bovine Milk or Soy Beverages Recovers Bone Mineralization in Young Growing Rats Fed an Insufficient Diet, in Contrast to an Almond Beverage.

Curr Dev Nutr 2019 Nov 12;3(11):nzz115. Epub 2019 Oct 12.

Dairy Foods, AgResearch, Hamilton, New Zealand.

Background: Nondairy beverages, produced from soy, rice, oat, almond, or coconut, are increasingly being used as alternatives to dairy milk, with the perception that they are healthier and/or more sustainable products than dairy products.

Objective: The aim of this study was to compare the effects of supplementing either bovine milk, soy, or almond-based beverages to young, growing rats fed an intact-protein diet or a diet that had protein substituted with amino acids (AA-diet).

Methods: Three-week-old male Sprague-Dawley rats were randomly assigned to 5 groups ( = 10/group) and fed ad libitum for 4 wk. Two control groups were fed either standard AIN-93G food [20% casein (CN) protein] or AIN-93G with amino acids (AAs) equivalent to CN protein, and water to drink. Three treatment groups were fed AIN-93G AA and supplemented with either bovine ultra-heat treatment (UHT) milk or soy or almond UHT beverages. Rat weight gain and food intakes were recorded. During week 4, body composition was assessed using DEXA to determine lean soft tissue, fat, and bone mass. At trial end, bone biomechanical properties and blood plasma mineral concentrations were measured.

Results: At the end of the trial, animals supplemented with almond beverage were lightest ( > 0.05), with higher plasma calcium concentrations ( > 0.05) and lower bone mineral content (BMC) and bone density ( > 0.05) than animals supplemented with milk or soy beverage. Soy-supplemented animals had similar BMC and bone density compared with milk-supplemented animals, although the soy group gained most weight ( > 0.05) and had the highest fat:lean ratio ( > 0.05) compared with other groups.

Conclusions: In the model tested, supplementing rats with bovine UHT milk and soy UHT beverage provided favorable bone health outcomes. Conversely, almond UHT beverage was not an effective supplement and could be detrimental to bone mineralization and strength outcomes.
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http://dx.doi.org/10.1093/cdn/nzz115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829496PMC
November 2019

Feasibility of Standardized Human Milk Collection in Neonatal Care Units.

Sci Rep 2019 10 4;9(1):14343. Epub 2019 Oct 4.

The Liggins Institute, The University of Auckland, Auckland, New Zealand.

Research in human lactation is a growing field. However, difficulties in studying human milk originate from the dynamicity of its composition. Using standardized collection protocols is mandatory to minimize variation and warrant comparability of findings across different studies. Yet, information on the feasibility of collecting human milk with standardized procedures, especially in neonatal units, are lacking. The present study aims to report on the feasibility and difficulties to collect human milk according to a standardized protocol, during early lactation from women who gave birth to preterm infants. Human milk was collected from 129 mothers of moderate- to late-preterm infants according to two variations of a standard protocol which differed for number of collection time-points. Collection rates and adherence to the sampling protocol were evaluated together with reason for missed collection. Collection of ≥1 sample was successful for 80% of the mothers. However adherence to the standard protocol was overall low (36% and 27%). Collection rates were different between the two protocol variations (73% against 92%, p ≤ 0.001). Amongst the reason for missed collection, low milk supply was the most recurrent (40%). Our findings show that while collecting human milk in neonatal units is achievable, obtaining standard and comparable samples results challenging.
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http://dx.doi.org/10.1038/s41598-019-50560-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778269PMC
October 2019

Nutritional Supplementation for the Prevention and/or Treatment of Gestational Diabetes Mellitus.

Curr Diab Rep 2019 08 1;19(9):73. Epub 2019 Aug 1.

Liggins Institute, University of Auckland, 85 Park Rd, Grafton, 1021, Auckland, New Zealand.

Purpose Of Review: Gestational diabetes mellitus (GDM) is a common pregnancy complication that has short- and long-term health implications for both the mother and child. While lifestyle modifications, insulin therapy, and oral agents such as metformin are effective, they can be difficult to adhere to, and there remain concerns over long-term effects of oral agents on the infant. Further, GDM has no proven preventive strategies, which could be more effective than treatment postdiagnosis. Nutritional supplements are an appealing, potentially safer, and better tolerated alternative to pharmaceuticals to treat and/or prevent GDM. Here, we review the existing evidence for nutritional supplementation for treatment and prevention of GDM.

Recent Findings: There is limited evidence that myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics might be beneficial for the prevention or treatment of GDM. There are very few studies for each nutrient, and the existing studies tend to have few participants. Where multiple studies of a nutrient exist, often those studies were conducted within the same country, limiting the generalizability of the findings, or alternatively there was no consensus across findings. There is limited evidence that nutritional supplementation of myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics could improve glycemic control or prevent GDM. Our understanding is constrained by the small number of studies, small sample sizes in most studies, and by lack of consistency across findings. Further large, high-quality, randomized controlled trials are required to determine the efficacy of nutritional supplements to treat or prevent GDM.
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http://dx.doi.org/10.1007/s11892-019-1199-1DOI Listing
August 2019

TNF-α Differentially Regulates Cell Cycle Genes in Promyelocytic and Granulocytic HL-60/S4 Cells.

G3 (Bethesda) 2019 08 8;9(8):2775-2786. Epub 2019 Aug 8.

Liggins Institute, University of Auckland, Auckland, New Zealand

Tumor necrosis factor alpha (TNF-α) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF-α are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF-α treatment has been investigated as part of a combined therapy for acute myeloid leukemia due to its modifying effects on all-trans retinoic acid (ATRA) mediated differentiation into granulocytes. To investigate the interaction between cellular differentiation and TNF-α, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-α. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF-α treatment compared to the undifferentiated promyelocytes. The observed TNF-α responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF-α treated promyelocytes, and downregulated in TNF-α treated granulocytes. This is consistent with TNF-α induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, we found evidence that TNF-α treatment of granulocytes shifts the transcriptome toward that of a macrophage. We conclude that TNF-α treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF-α promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF-α stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.
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http://dx.doi.org/10.1534/g3.119.400361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686940PMC
August 2019

Cyclic glycine-proline administration normalizes high-fat diet-induced synaptophysin expression in obese rats.

Neuropeptides 2019 Aug 22;76:101935. Epub 2019 May 22.

The Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1142, New Zealand; Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1124, New Zealand; Brain Research New Zealand, A Centre of Research Excellence, New Zealand. Electronic address:

Childhood metabolic disorders are associated with insulin-like growth factor (IGF)-1 deficiency, which can adversely affect brain development and function. As a neuropeptide, cyclic glycine-proline (cGP) improves IGF-1 function in brain and regulates IGF-1 bioavailability in plasma. Whether such a regulatory process mediates the neurotrophic effects of cGP remains unknown. This study examined the effects cGP treatment on synaptic expression and their association with IGF-1, IGF binding protein (IGFBP)-2 and cGP concentrations in the brain of rats with high fat diet (HFD)-induced obesity. Male rats received either a HFD or a standard chow diet (STD) from weaning and were then treated with either saline or cGP from 11 to 15 weeks of age. The concentrations of cGP, IGF-1 and IGFBP-2 were measured in the brain tissues using ELISA and HPLC-MS. The expressions of synaptic markers were evaluated in the hippocampus, hypothalamus and striatum using immunohistochemical staining. Compared to the STD group, IGF-1 and IGFBP-2, but not cGP concentrations, were lower in the HFD groups. The expression of hippocampal synaptophysin, glutamate receptor-1, GFAP and striatal tyrosine-hydroxylase were also reduced in the HFD groups. While treatment did not alter tissue IGF-1, cGP administration that increased the concentration of cGP in brain tissues, normalized the expression of synaptophysin, GFAP and tyrosine-hydroxylase, but not glutamate receptor-1. IGF-1 concentration in brain tissues correlated with the expression of all synaptic markers. HFD feeding reduced synaptic expression and tissue IGF-1 in brains which were closely associated, thus suggesting IGF-1 in the brain is largely bioavailable. Without increasing IGF-1 in the brain, administration of cGP normalized synaptic expression, possibly be mediated through increasing bioavailable IGF-1, but further studies are required to confirm this.
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http://dx.doi.org/10.1016/j.npep.2019.05.006DOI Listing
August 2019

Hi-C detects novel structural variants in HL-60 and HL-60/S4 cell lines.

Genomics 2020 01 13;112(1):151-162. Epub 2019 May 13.

Liggins Institute, University of Auckland, Auckland, New Zealand. Electronic address:

Cancer cell lines often have large structural variants (SVs) that evolve over time. There are many reported differences in large scale SVs between HL-60 and HL-60/S4, two cell lines derived from the same acute myeloid leukemia sample. However, the stability and variability of inter- and intra-chromosomal structural variants between different sources of the same cell line is unknown. Here, we used Hi-C and RNA-seq to identify and compare large SVs in HL-60 and HL-60/S4 cell lines. Comparisons with previously published karyotypes identified novel SVs in both cell lines. Hi-C was used to characterize the known expansion centered on the MYC locus. The MYC expansion was integrated into known locations in HL-60/S4, and a novel location (chr4) in HL-60. The HL-60 cell line has more within-line structural variation than the HL-60/S4 derivative cell line. Collectively we demonstrate the usefulness of Hi-C and with RNA-seq data for the identification and characterization of SVs.
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http://dx.doi.org/10.1016/j.ygeno.2019.05.009DOI Listing
January 2020

Preclinical Models of Altered Early Life Nutrition and Development of Reproductive Disorders in Female Offspring.

Adv Exp Med Biol 2019 ;1134:59-87

The Liggins Institute, University of Auckland, Auckland, New Zealand.

Early epidemiology studies in humans have and continue to offer valuable insight into the Developmental Origins of Health and Disease (DOHaD) hypothesis, which emphasises the importance of early-life nutritional and environmental changes on the increased risk of metabolic and reproductive disease in later life. Human studies are limited and constrained by a range of factors which do not apply to preclinical research. Animal models therefore offer a unique opportunity to fully investigate the mechanisms associated with developmental programming, helping to elucidate the developmental processes which influence reproductive diseases, and highlight potential biomarkers which can be translated back to the human condition. This review covers the use and limitations of a number of animal models frequently utilised in developmental programming investigations, with an emphasis on dietary manipulations which can lead to reproductive dysfunction in offspring.
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http://dx.doi.org/10.1007/978-3-030-12668-1_4DOI Listing
August 2019

Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks.

Front Genet 2018 21;9:535. Epub 2018 Nov 21.

The Liggins Institute, The University of Auckland, Auckland, New Zealand.

Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including , , , , , , , , , , , and , which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D.
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http://dx.doi.org/10.3389/fgene.2018.00535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258722PMC
November 2018

Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells.

BMC Biol 2018 11 26;16(1):142. Epub 2018 Nov 26.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: Mammalian cells are flexible and can rapidly change shape when they contract, adhere, or migrate. The nucleus must be stiff enough to withstand cytoskeletal forces, but flexible enough to remodel as the cell changes shape. This is particularly important for cells migrating through confined spaces, where the nuclear shape must change in order to fit through a constriction. This occurs many times in the life cycle of a neutrophil, which must protect its chromatin from damage and disruption associated with migration. Here we characterized the effects of constricted migration in neutrophil-like cells.

Results: Total RNA sequencing identified that migration of neutrophil-like cells through 5- or 14-μm pores was associated with changes in the transcript levels of inflammation and chemotaxis-related genes when compared to unmigrated cells. Differentially expressed transcripts specific to migration with constriction were enriched for groups of genes associated with cytoskeletal remodeling. Hi-C was used to capture the genome organization in control and migrated cells. Limited switching was observed between the active (A) and inactive (B) compartments after migration. However, global depletion of short-range contacts was observed following migration with constriction compared to migration without constriction. Regions with disrupted contacts, TADs, and compartments were enriched for inactive chromatin.

Conclusion: Short-range genome organization is preferentially altered in inactive chromatin, possibly protecting transcriptionally active contacts from the disruptive effects of migration with constriction. This is consistent with current hypotheses implicating heterochromatin as the mechanoresponsive form of chromatin. Further investigation concerning the contribution of heterochromatin to stiffness, flexibility, and protection of nuclear function will be important for understanding cell migration in relation to human health and disease.
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http://dx.doi.org/10.1186/s12915-018-0608-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257957PMC
November 2018