Perinatal programming of appetite regulation and metabolic health

According to the concept of perinatal programming environmental factors during fetal development and early postnatal life can influence phenotype in later life by modifying organ and tissue development and the epigenetic information of specific genes which, in turn, induce alteration in gene expression. Global nutrient restriction is a well-established intervention to study fetal programming but choline, a micronutrient essential for tissue growth and development, has not been extensively studied. The aim of this thesis is to investigate long term effects of modifications in maternal macro and micronutrient intake on the offsprings‟ appetite regulation and metabolic health. Twin-pregnant sheep were fed to requirements until 110 days of gestation and then randomised to stay on the same diet (R) or be restricted to 60% of caloric requirements (N) until term (~145 days). Offspring were subsequently subject either to a standard early postnatal growth rate as both twins remained with the mother (S) or to an accelerated growth rate resulting when only one twin remained to be mother fed (A). After weaning, offspring were reared in either a lean (L) or an obesogenic environment (O) until 17 months of age. These interventions gave rise to 4 groups: RAO, NAO, NSO and NSL. There were no differences in body weight, composition or adipocyte size with perinatal nutrient restriction but insulin response to a glucose tolerance test was increased in offspring born to N mothers. Measurement of hypothalamic gene expression in the latter offspring suggested a more orexigenic and cortisol-sensitive regulatory phenotype. During lactation, rats were fed a diet that was either choline-devoid (D), or contained a standard amount of choline either as bitartrate (C) or as phosphatidylcholine (PC). After weaning, female offspring were maintained on a standard choline diet until 11 weeks of age. D mothers had a substantial decrease in food intake and offspring were smaller at weaning but had similar glucose tolerance. Adult offsprings‟ brain phospholipid concentrations were reduced, which may suggest changes in brain development, but food intake and hypothalamic protein expression were unchanged. Intake of different forms of choline, i.e. bitartrate versus PC, during lactation had no long term effects on offspring. Both maternal dietary interventions had long term effects on offspring. Sheep developed the most adverse metabolic phenotype when the offspring were subjected to slow growth in late gestation followed by rapid growth and obesity, with the onset of insulin resistance mediated through changes in peripheral tissues. Maternal choline intake during lactation is essential for the health of the offspring as it alters brain composition. In conclusion, both studies produced results which are consistent with the concept of perinatal programming as adult metabolic health was affected in the sheep study and organ development was affected in a long term manner in the rat study

Perinatal programming of appetite regulation and metabolic health

According to the concept of perinatal programming environmental factors during fetal development and early postnatal life can influence phenotype in later life by modifying organ and tissue development and the epigenetic information of specific genes which, in turn, induce alteration in gene expression. Global nutrient restriction is a well-established intervention to study fetal programming but choline, a micronutrient essential for tissue growth and development, has not been extensively studied. The aim of this thesis is to investigate long term effects of modifications in maternal macro and micronutrient intake on the offsprings‟ appetite regulation and metabolic health. Twin-pregnant sheep were fed to requirements until 110 days of gestation and then randomised to stay on the same diet (R) or be restricted to 60% of caloric requirements (N) until term (~145 days). Offspring were subsequently subject either to a standard early postnatal growth rate as both twins remained with the mother (S) or to an accelerated growth rate resulting when only one twin remained to be mother fed (A). After weaning, offspring were reared in either a lean (L) or an obesogenic environment (O) until 17 months of age. These interventions gave rise to 4 groups: RAO, NAO, NSO and NSL. There were no differences in body weight, composition or adipocyte size with perinatal nutrient restriction but insulin response to a glucose tolerance test was increased in offspring born to N mothers. Measurement of hypothalamic gene expression in the latter offspring suggested a more orexigenic and cortisol-sensitive regulatory phenotype. During lactation, rats were fed a diet that was either choline-devoid (D), or contained a standard amount of choline either as bitartrate (C) or as phosphatidylcholine (PC). After weaning, female offspring were maintained on a standard choline diet until 11 weeks of age. D mothers had a substantial decrease in food intake and offspring were smaller at weaning but had similar glucose tolerance. Adult offsprings‟ brain phospholipid concentrations were reduced, which may suggest changes in brain development, but food intake and hypothalamic protein expression were unchanged. Intake of different forms of choline, i.e. bitartrate versus PC, during lactation had no long term effects on offspring. Both maternal dietary interventions had long term effects on offspring. Sheep developed the most adverse metabolic phenotype when the offspring were subjected to slow growth in late gestation followed by rapid growth and obesity, with the onset of insulin resistance mediated through changes in peripheral tissues. Maternal choline intake during lactation is essential for the health of the offspring as it alters brain composition. In conclusion, both studies produced results which are consistent with the concept of perinatal programming as adult metabolic health was affected in the sheep study and organ development was affected in a long term manner in the rat study

Beyond obesity - thermogenic adipocytes and cardiometabolic health

The global prevalence of obesity and related cardiometabolic disease continues to increase through the 21st century. Whilst multi-factorial, obesity is ultimately caused by chronic caloric excess. However, despite numerous interventions focussing on reducing caloric intake these either fail or only elicit short-term changes in body mass. There is now a focus on increasing energy expenditure instead which has stemmed from the recent ‘re-discovery’ of cold-activated brown adipose tissue (BAT) in adult humans and inducible ‘beige’ adipocytes. Through the unique mitochondrial uncoupling protein (UCP1), these thermogenic adipocytes are capable of combusting large amounts of chemical energy as heat and in animal models can prevent obesity and cardiometabolic disease. At present, human data does not point to a role for thermogenic adipocytes in regulating body weight or fat mass but points to a pivotal role in regulating metabolic health by improving insulin resistance as well as glucose and lipid homeostasis. This review will therefore focus on the metabolic benefits of BAT activation and the mechanisms and signalling pathways by which these could occur including improvements in insulin signalling in peripheral tissues, systemic lipid and cholesterol metabolism and cardiac and vascular function

The haemodynamics of the human placenta in utero

© 2020 Dellschaft et al. We have used magnetic resonance imaging (MRI) to provide important new insights into the function of the human placenta in utero. We have measured slow net flow and high net oxygenation in the placenta in vivo, which are consistent with efficient delivery of oxygen from mother to fetus. Our experimental evidence substantiates previous hypotheses on the effects of spiral artery remodelling in utero and also indicates rapid venous drainage from the placenta, which is important because this outflow has been largely neglected in the past. Furthermore, beyond Braxton Hicks contractions, which involve the entire uterus, we have identified a new physiological phenomenon, the 'utero-placental pump', by which the placenta and underlying uterine wall contract independently of the rest of the uterus, expelling maternal blood from the intervillous space

Housing temperature modulates the impact of diet-induced rise in fat mass on adipose tissue before and during pregnancy in rats

Aim: To investigate whether housing temperature influences rat adiposity, and the extent it is modified by diet and/or pregnancy. Housing temperature impacts on brown adipose tissue, that possess a unique uncoupling protein (UCP) 1, which, when activated by reduced ambient temperature, enables rapid heat generation. Methods: We, therefore, examined whether the effects of dietary induced rise in fat mass on interscapular brown fat in female rats were dependent on housing temperature, and whether pregnancy further modulates the response. Four week old rats were either maintained at thermoneutrality (27°C) or at a “standard” cool temperature (20°C), and fed either a control or obesogenic (high in fat and sugar) diet until 10 weeks old. They were then either tissue sampled or mated with a male maintained under the same conditions. The remaining dams were tissue sampled at either 10 or 19 days gestation. Results: Diet had the greatest effect on fat mass at thermoneutrality although, by 19 days gestation, fat weight was similar between groups. Prior to mating, the abundance of UCP1 was higher at 20°C, but was similar between groups during pregnancy. UCP1 mRNA followed a similar pattern, with expression declining to a greater extent in the animals maintained at 20°C. Conclusion: Housing temperature has a marked influence on the effect of dietary induced rise in fat deposition that was modified through gestation. This maybe mediated by the reduction in UCP1 with housing at thermoneutrality prior to pregnancy and could subsequently impact on growth and development of the offspring

Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes.

BackgroundPeople with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF.MethodsWe conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers.ResultsWe randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events.ConclusionsOur data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators.ClinicalTrials.gov registrationNCT04006873 (02/07/2019

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study

BackgroundPeople with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF.MethodsWe conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers.ResultsWe randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events.ConclusionsOur data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators.ClinicalTrials.gov registrationNCT04006873 (02/07/2019

Housing Temperature Modulates the Impact of Diet-Induced Rise in Fat Mass on Adipose Tissue Before and During Pregnancy in Rats

Aim: To investigate whether housing temperature influences rat adiposity, and the extent it is modified by diet and/or pregnancy. Housing temperature impacts on brown adipose tissue, that possess a unique uncoupling protein (UCP) 1, which, when activated by reduced ambient temperature, enables rapid heat generation.Methods: We, therefore, examined whether the effects of dietary induced rise in fat mass on interscapular brown fat in female rats were dependent on housing temperature, and whether pregnancy further modulates the response. Four week old rats were either maintained at thermoneutrality (27°C) or at a “standard” cool temperature (20°C), and fed either a control or obesogenic (high in fat and sugar) diet until 10 weeks old. They were then either tissue sampled or mated with a male maintained under the same conditions. The remaining dams were tissue sampled at either 10 or 19 days gestation.Results: Diet had the greatest effect on fat mass at thermoneutrality although, by 19 days gestation, fat weight was similar between groups. Prior to mating, the abundance of UCP1 was higher at 20°C, but was similar between groups during pregnancy. UCP1 mRNA followed a similar pattern, with expression declining to a greater extent in the animals maintained at 20°C.Conclusion: Housing temperature has a marked influence on the effect of dietary induced rise in fat deposition that was modified through gestation. This maybe mediated by the reduction in UCP1 with housing at thermoneutrality prior to pregnancy and could subsequently impact on growth and development of the offspring