Biology subjects

Ozanne, S. E.

Publications and source records attributed to Ozanne, S. E..

8 recordsLinked to original sources

bioRxiv2026

Maternal cardiometabolic dysfunction and fetal sex-specific alterations to uterine vascular reactivity in an ovine model of diet-induced obesity during pregnancy

Obesity during pregnancy is at pandemic proportions and predisposes women to pre- and postnatal cardiovascular dysfunction. The mechanisms underlying this maternal cardiovascular vulnerability remain unclear, partly due to a lack of translatable models capable of longitudinal in vivo cardiovascular monitoring. Here, we characterise a novel ovine model of maternal diet-induced obesity during pregnancy. Ewes were fed a control (CON) or obesogenic (OB; ad libitum concentrates) diet for 60 days pre-pregnancy and throughout gestation. Pregnant ewes were surgically instrumented with vascular catheters and Transonic flow probes using the wireless CamDAS system, which measured maternal cardiovascular function near term in free-moving ewes. Uterine artery vasoreactivity was assessed ex vivo by in vitro wire myography. OB ewes entered pregnancy 30% heavier than controls (P<0.003) and were hyperglycaemic, hyperinsulinemic, and hyperlipidaemic during pregnancy, relative to CON ewes (all P<0.05). OB ewes had elevated haematocrit and haemoglobin across pregnancy, and were hypertensive near term, with an increase in basal femoral artery blood flow, and elevated peripheral oxygen and glucose delivery (all P<0.05). OB mothers carrying a female fetus showed increased uterine artery vascular resistance in vivo (P<0.005) and reduced smooth muscle-dependent vasorelaxation ex vivo (P<0.05) relative to CON. Conversely, OB mothers carrying a male fetus showed greater NO-independent mechanisms mediating the uterine vasodilator response to methacholine ex vivo (P<0.001). Collectively, this study characterises a robust model of maternal obesity during pregnancy that offers clinical translational potential and highlights fetal sex-specific changes to uterine artery function. Key points summaryO_LIObesity during pregnancy is increasingly common and predisposes women to cardiovascular dysfunction during pregnancy and long after birth, but the specific mechanisms underlying this remain unclear. C_LIO_LIWe developed a novel ovine model of diet-induced obesity during pregnancy that displays maternal hypertension, elevated haemoglobin, metabolic dysfunction and alterations in uterine and peripheral blood flow and nutrient delivery near term. C_LIO_LIMothers with obesity carrying a female fetus had elevated uterine vascular resistance in vivo and reduced uterine artery smooth muscle-dependent vasodilator reactivity ex vivo. C_LIO_LIMothers with obesity carrying a male fetus showed no effect on uterine vascular resistance in vivo, but greater NO-independent mechanisms mediating the uterine vasodilator response to methacholine ex vivo. C_LIO_LIThese findings highlight that fetal sex may influence maternal cardiovascular function during obese pregnancy. C_LI

developmental biology↗

bioRxiv2025

Developmentally cascading structures do not lose evolutionary potential, but compound developmental instability in rat molars

Increasing variability down serially segmented structures, such as mammalian molar teeth and vertebrate limb segments, is a much-replicated pattern. The same phenotypic pattern has conflicting interpretations at different evolutionary scales. Macroevolutionary patterns are thought to reflect greater evolutionary potential in later-forming segments, but microevolutionary patterns are thought to reflect less evolutionary potential and greater phenotypic plasticity. We address this conflict by recalculating evolutionary potential (evolvability) from a systematic review of published mammalian molar sizes, then directly measure phenotypic plasticity from a controlled feeding experiment. Effects on lengths and widths are discordant in a way that suggests general growth pathways have a role in phenotypically plastic dental responses to nutrition. Effects on successive trait means do not necessarily increase downstream, contrary to long-standing hypotheses. We confirm prior findings of increasing non-inherited variance downstream, showing decoupling between effects on trait mean and variance. These patterns can be explained by a cascading model of tooth development compounding the effect of developmental instability as an influence separate from general environmental effects on the developing embryo. When evaluated in terms of evolvability, later-developing molars are equally or more evolvable than earlier-developing molars, aligning their microevolutionary potential with macroevolutionary patterns in other serially segmented structures.

evolutionary biology↗

bioRxiv2022

The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.

developmental biology↗

bioRxiv2022

Maternal obesity programs hypothalamic miR-505-5p expression in mouse offspring and impacts hypothalamic fatty acid sensing

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and over-expression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased high-fat diet intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced high-fat diet intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.

neuroscience↗

bioRxiv2021

Small-RNA sequencing reveals altered skeletal muscle microRNAs and snoRNAs signatures in weanling male offspring from mouse dams fed a low protein diet during lactation

Nutrition plays a key role in pre- and postnatal growth of the musculoskeletal system. Maternal diet during gestation and lactation affects the development of skeletal muscles in the offspring and determines muscle health in later life, however, the molecular mechanisms that govern these effects are largely unknown. In this study, we aim to describe the association between maternal low protein diet-induced changes in offspring skeletal muscle and the differential expression (DE) of small non-coding RNAs (sncRNAs). We used a mouse model of maternal protein restriction to characterise the impact of early-life undernutrition on skeletal muscle morphology in male offspring at weaning. Mouse dams were fed either a normal (N, 20%) or a low protein (L, 8%) diet during gestation and newborn pups were cross-fostered to N or L lactating dams, resulting in the generation of NN, NL and LN offspring groups. Total body and tibialis anterior (TA) weights were decreased in NL males but not different in the LN group, as compared to NN, although neonates from low protein fed dams were smaller at birth than those born to dams fed a normal protein. However, histological evaluation of TA muscle revealed reduced muscle fibre size in both groups at the end of lactation. Small RNA-seq analysis demonstrated DE of multiple classes of sncRNAs, including miRs, snoRNAs and snRNAs. Bioinformatic analyses of miRs-15a, -34a, -122 and -199a, in combination with known myomiRs, confirmed their implication in key muscle-specific biological processes and cellular functions and suggest a promising set of miRs in muscle physiology studies. To our knowledge, this is the first comprehensive report for the DE of sncRNAs in nutrition-associated programming of skeletal muscle development, highlighting the need for further research.

molecular biology↗

bioRxiv2020

Low protein intake compromises the recovery of lactation-induced bone loss in female mouse dams without affecting skeletal muscles.

ABSTRACTLactation-induced bone loss occurs due to high calcium requirements for fetal growth but skeletal recovery is normally achieved promptly post-weaning. Dietary protein is vital for fetus and mother but the effects of protein undernutrition on the maternal skeleton and skeletal muscles is largely unknown. We used mouse dams fed with normal (N, 20%) or low (L, 8%) protein diet during gestation and lactation and maintained on the same diets (NN, LL) or switched from low to normal (LN) during a 28d skeletal restoration period post lactation. Skeletal muscle morphology and neuromuscular junction integrity was not different between any of the groups. However, dams fed the low protein diet showed extensive bone loss by the end of lactation, followed by full skeletal recovery in NN dams, partial recovery in LN and poor bone recovery in LL dams. Primary osteoblasts from low protein diet fed mice showed decreased in vitro bone formation and decreased osteogenic marker gene expression; promoter methylation analysis by pyrosequencing showed no differences in Bmpr1a, Ptch1, Sirt1, Osx and Igf1r osteoregulators, while miR-26a, -34a and -125b expression was found altered in low protein fed mice. Therefore, normal protein diet is indispensable for maternal musculoskeletal health during the reproductive period.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2019

Mesenchymal Igf2 is a major paracrine regulator of pancreatic growth and function

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Here we demonstrate that many imprinted genes are highly expressed in the pancreatic mesenchyme, and explore the role of Igf2 in-vivo. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy. Surprisingly, mesenchymal mass is unaffected, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Furthermore, increased IGF2 activity specifically in the mesenchyme, through Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Ex-vivo exposure of primary acinar cells to exogenous IGF2 increases cell proliferation and amylase production through AKT signalling. We propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.

developmental biology↗

bioRxiv2019

Exposure to maternal obesity per se programs sex-differences in pancreatic islets of the offspring

Maternal obesity increases type 2 diabetes (T2D) risk in the offspring. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Using a well-established mouse model of diet-induced obesity, we examined offspring islets before the onset of metabolic dysfunction. This allowed us to determine inherent changes, in males and females, which are distinct from the response of islets to an existing obesogenic, insulin resistant milieu hence identifying islet dysregulation reflecting very early manifestation of the disease before the onset of disrupted glucose homeostasis. Female offspring of obese dams displayed higher glucose-stimulated insulin secretion and mitochondrial respiration, increased expression of estrogen receptor and decreased cleaved-caspase 3 and Bax:Bcl-2 reflecting reduced susceptibility to apoptosis. In contrast, male offspring of obese dams displayed compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration and increased \"uncoupled\" respiration and reduced docked insulin granules in {beta}-cells. Thus, maternal obesity \"programs\" sex-differences in offspring islet function. Islets of female but not male offspring appear primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future T2D risk.

physiology↗