Shalini Ojha

Adult Epicardial Fat Exhibits Beige Features

CONTEXT Human epicardial fat has been designated previously as brown-like fat. The supraclavicular fat depot in man has been defined as beige coexistent with classical brown based on its gene expression profile. OBJECTIVE The aim of the study was to establish the gene expression profile and morphology of human epicardial and visceral paracardial fat compared with sc fat. SETTING The study was conducted at a tertiary care hospital cardiac center. PATIENTS Epicardial, visceral paracardial, and sc fat samples had been taken from middle-aged patients with severe coronary atherosclerosis or valvular heart disease. INTERVENTIONS Gene expression was determined by reverse transcription-quantitative PCR and relative abundance of the mitochondrial uncoupling protein-1 (UCP-1) by Western blotting. Epicardial tissue sections from patients were examined by light microscopy, UCP-1 immunohistochemistry, and cell morphometry. MAIN OUTCOME MEASURES We hypothesized that epicardial fat has a mixed phenotype with a gene expression profile similar to that described for beige cell lineage. RESULTS Immunoreactive UCP-1 was clearly measurable in each epicardial sample analyzed but was undetectable in each of the 4 other visceral and sc depots. Epicardial fat exhibited high expression of genes for UCP-1, PRDM16, PGC-1α, PPARγ, and the beige adipocyte-specific marker CD137, which were also expressed in visceral paracardial fat but only weakly in sternal, upper abdominal, and lower extremity sc fat. Histology of epicardial fat showed small unilocular adipocytes without UCP-1 immunostaining. CONCLUSION UCP-1 is relatively abundant in epicardial fat, and this depot possesses molecular features characteristic of those found in vitro in beige lineage adipocytes.

Use of heated humidified high-flow nasal cannula oxygen in neonates: a UK wide survey.

Heated humidified high‐flow nasal cannula (HHHFNC) oxygen is a relatively new form of respiratory support and is increasing in popularity despite lack of supportive evidence and amid safety concerns. We investigated the prevalence of its use in tertiary neonatal units in the UK.

Excess nutrient supply in early life and its later metabolic consequences.

Suboptimal nutrition in early life, both in utero and during infancy, is linked to increased risk of adult obesity and its associated adverse metabolic health problems. Excess nutrient supply during early life can lead to metabolic programming in the offspring. Such overnutrition can occur in the offspring of obese mothers, the offspring of mothers who gain excess weight during gestation, infants of diabetic mothers and infants who undergo rapid growth, particularly weight gain, during early infancy. Postnatal overnutrition is particularly detrimental for infants who are born small for gestational age, who are overfed to attain ‘catch‐up growth’. Potential mechanisms underlying metabolic programming that results from excess nutrition during early life include resetting of hypothalamic energy sensing and appetite regulation, altered adipose tissue insulin sensitivity and impaired brown adipose tissue function. More detailed understanding of the mechanisms involved in metabolic programming could enable the development of therapeutic strategies for ameliorating its ill effects. Research in this field could potentially identify optimal and appropriate preventative interventions for a burgeoning population at risk of increased mortality and morbidity from obesity and its concomitant metabolic conditions.

Body Mass Index as a Determinant of Brown Adipose Tissue Function in Healthy Children

OBJECTIVE To determine whether body mass index (BMI) percentile and ethnicity influence skin temperature overlying brown adipose tissue (BAT) depots in the supraclavicular region in healthy children. STUDY DESIGN Infrared thermography measured supraclavicular region temperature (T(SCR)) at baseline and after exposure to a mild cool stimulus (single hand immersion in water at 20.1 °C) for 5 minutes in children aged 6-11 years (n = 55). The studies were undertaken in a normal school environment. RESULTS BMI percentile and ethnicity were significant predictors of baseline T(SCR), with an inverse relationship between BMI percentile persisting after adjustment for ethnicity. Twenty-four children demonstrated a significant rise in T(SCR) after exposure to the cool stimulus. BMI percentile was a significant predictor of T(SCR) response, although there was no effect of ethnicity on T(SCR) change after exposure to the cool stimulus. CONCLUSION We have demonstrated a negative relationship between BMI percentile and both baseline T(SCR), colocating with the primary region of BAT, and the change in T(SCR) in response to the cool stimulus. Future studies aimed at determining the primary factors regulating BAT function in healthy children should be targeted at the goal of maintaining a healthy BMI trajectory during childhood.

Brown adipose tissue genes in pericardial adipose tissue of newborn sheep are downregulated by maternal nutrient restriction in late gestation

Background:Brown adipose tissue (BAT) thermogenesis is essential for newborn survival. Pericardial adipose tissue is a visceral depot that promotes metabolic and cardiovascular adaptations. We determined whether BAT is present in pericardial adipose tissue in newborns and whether maternal nutrition during late gestation compromises BAT in the postnatal period.Methods:We measured uncoupling protein 1 (UCP1) and other BAT-specific genes (e.g., β3-adrenergic receptor (β3ADR) and deiodinase type 2 (DIO2)), together with markers of white adipose tissue (WAT) in sheep on either the first or 30th day after birth. These were twin offspring born to mothers fed with either 100% or nutrient restricted (NR) to 60% of their total metabolizable requirements from 110 d gestation to term.Results:Gene expression of UCP1 and other BAT-related genes decreased significantly with age. In newborns, maternal nutrient restriction downregulated gene expression of DIO2 and the β3-adrenergic receptor with reduced UCP1 but had no effect on genes predominantly expressed in WAT.Conclusion:BAT is present around the heart in newborns. Exposure to a suboptimal maternal diet in late gestation specifically compromises BAT development and has the potential to place these offspring at increased risk of hypothermia after birth without effects on the subsequent appearance of WAT.

Suboptimal maternal nutrition affects offspring health in adult life

Suboptimal maternal nutrition during pregnancy is prevalent and compromises fetal development. Physiological and metabolic adaptations made by the fetus to an inadequate, or excess, maternal nutritional environment, may promote immediate survival but are lasting, conferring significantly increased risks of ill health in childhood and adulthood. In addition, such fetal adaptations are particularly detrimental when nutrient supply is no longer constrained in contemporary nutrient rich environments. Given the prevalence of suboptimal maternal nutritional environments during fetal development, effective prevention, early detection and therapeutic interventions to reduce the increased risks on population health must be a health priority. Therefore, the mechanisms of these lasting in utero adaptations are highly relevant to establishing how exposure to a suboptimal nutritional environment impacts on the health of current generations living in an environment challenged by excess nutrition.

Suboptimal maternal nutrition during early-to-mid gestation in the sheep enhances pericardial adiposity in the near-term fetus

Manipulation of the maternal diet at defined stages of gestation influences long-term health by inducing changes in fetal adipose tissue development, characterised as possessing brown and white adipocytes. We determined whether suboptimal maternal nutrition in early-to-mid gestation, followed by ad libitum feeding until term, increases adiposity in the pericardial depot of the sheep fetus. Pericardial adipose tissue was sampled from near-term (140 days) fetuses delivered to mothers fed either 100% (C) or 60% (i.e. nutrient restricted (NR)) of their total metabolisable requirements from 28 to 80 days gestation and then fed ad libitum. Adipose tissue mass, uncoupling protein (UCP) 1 and gene expression of brown and white adipogenic genes was measured. Total visceral and pericardial adiposity was increased in offspring born to NR mothers. The abundance of UCP1 was increased, together with those genes involved in brown (e.g. BMP7 and C/EBPβ) and white (e.g. BMP4 and C/EBPα) adipogenesis, whereas insulin receptor gene expression was downregulated. In conclusion, suboptimal maternal nutrition between early-to-mid gestation followed by ad libitum feeding enhances pericardial adiposity near to term. A combination of raised UCP1 and adipose tissue mass could improve survival following cold exposure at birth. In the longer term, this enhanced adipogenic potential could predispose to greater pericardial adiposity.

Gene pathway development in human epicardial adipose tissue during early life

Studies in rodents and newborn humans demonstrate the influence of brown adipose tissue (BAT) in temperature control and energy balance and a critical role in the regulation of body weight. Here, we obtained samples of epicardial adipose tissue (EAT) from neonates, infants, and children in order to evaluate changes in their transcriptional landscape by applying a systems biology approach. Surprisingly, these analyses revealed that the transition to infancy is a critical stage for changes in the morphology of EAT and is reflected in unique gene expression patterns of a substantial proportion of thermogenic gene transcripts (~10%). Our results also indicated that the pattern of gene expression represents a distinct developmental stage, even after the rebound in abundance of thermogenic genes in later childhood. Using weighted gene coexpression network analyses, we found precise anthropometric-specific correlations with changes in gene expression and the decline of thermogenic capacity within EAT. In addition, these results indicate a sequential order of transcriptional events affecting cellular pathways, which could potentially explain the variation in the amount, or activity, of BAT in adulthood. Together, these results provide a resource to elucidate gene regulatory mechanisms underlying the progressive development of BAT during early life.

The Placenta, Maternal Diet and Adipose Tissue Development in the Newborn

Background: A majority of adipose tissue present in the newborn possess the unique mitochondrial protein, uncoupling protein (UCP1). It is thus highly metabolically active and capable of producing 300 times more heat per unit mass than any other organ in the body. The extent to which maternal obesity and/or an obesogenic diet impacts on placental function thereby resetting the relative distribution of different types of fat in the fetus is unknown. Summary: Developmentally the majority (if not all) fat in the fetus can be considered as classical brown fat, in which UCP1 is highly abundant. In contrast, beige (or recruitable) fat which possess 90% less UCP1 may only appear after birth, as a majority of fat depots undergo a pronounced transformation that is usually accompanied by the loss of UCP1. The extent to which this process can be modulated in a depot-specific manner and/or changes in the maternal metabolic environment remain unknown. Key Messages: An increased understanding of the mechanism by which offspring born to mothers possess excessive adipose tissue could enable sustainable interventions designed to promote the abundance of UCP1 possessing adipocytes. Ultimately, this would increase their energy expenditure and improve glucose homeostasis in these individuals.

Protocol for a prospective observational study of adverse drug reactions of anti-epileptic drugs in children in the UK

Background Epilepsy is a common chronic disease of children that can be treated with anti-epileptic drugs (AEDs). AEDs, however, have significant side effects. Newer AEDs are thought to have fewer side effects. There have, however, been few comparative studies of AED toxicity. The aim is to compare the safety profile of the most frequently used AEDs by performing a multicentre prospective cohort study. This protocol describes the planned study. Design A multicentre prospective cohort study of children on AED treatment in hospitals across the UK. Ethical approval will be obtained. Sample size Three thousand children on treatment for epilepsy will be recruited from paediatric clinics. It is expected that this sample size will have the potential to compare toxicity between the most frequently used AEDs. Duration of study 24 months. Outcome measure Adverse drug reactions (ADRs) to AEDs. These will be identified by the use of a validated questionnaire, the Paediatric Epilepsy Side Effect Questionnaire. They will be evaluated using the Naranjo algorithm. Preventability will be assessed using the Schumock and Thornton scale. Discussion Toxicity of individual AEDs when given as monotherapy and polytherapy will be determined. Additionally, discontinuation rates due to ADRs will be determined. The data will assist clinicians in choosing AEDs with the least toxicity.