The Obesity Epidemic: From the Environment to Epigenetics – Not Simply a Response to Dietary Manipulation in a Thermoneutral Environment

The prevalence of obesity continues to increase particularly in developed countries. To establish the primary mechanisms involved, relevant animal models which track the developmental pathway to obesity are required. This need is emphasized by the substantial rise in the number of overweight and obese children, of which a majority will remain obese through adulthood. The past half century has been accompanied with unprecedented transitions in our lifestyle. Each of these changes substantially contributes to enhancing our capacity to store energy into adipose tissues. The complex etiology of adiposity is critical as a majority of models investigating obesity utilize a simplistic high-fat/low-carbohydrate diet, fed over a short time period to comparatively young inbred animals maintained in fixed environment. The natural history of obesity is much more complex involving many other mechanisms and this type of challenge may not be the optimal experimental intervention. Such processes include changes in adipose tissue composition with time and the transition from brown to white adipose tissue. Brown adipose tissue, due its unique ability to rapidly produce large amounts of heat could have a pivotal role in energy balance and is under epigenetic regulation mediated by the histone H3k9-specific demethylase Jhdma2a. Furthermore, day length has a potential role in determining endocrine and metabolic responses in brown fat. The potential to utilize novel models and interventions across a range of animal species in adipose tissue development may finally start to yield sustainable strategies by which excess fat mass can, at last, be avoided in humans

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

Brown adipose tissue activation as measured by infrared thermography by mild anticipatory psychological stress in lean healthy females

Brown adipose tissue (BAT) has been implicated in the pathogenesis of obesity, type 2 diabetes and the metabolic syndrome and is a potential therapeutic target. Brown adipose tissue can have a significant impact on energy balance and glucose homeostasis through the action of uncoupling protein 1, dissipating chemical energy as heat following neuroendocrine stimulation. We hypothesized that psychological stress, which is known to promote cortisol secretion, would simultaneously activate BAT at thermoneutrality. Brown adipose tissue activity was measured using infrared thermography to determine changes in the temperature of the skin overlying supraclavicular BAT (TSCR). A mild psychological stress was induced in five healthy, lean, female, Caucasian volunteers using a short mental arithmetic (MA) test. The TSCR was compared with a repeated assessment, in which the MA test was replaced with a period of relaxation. Although MA did not elicit an acute stress response, anticipation of MA testing led to an increase in salivary cortisol, indicative of an anticipatory stress response, that was associated with a trend towards higher absolute and relative TSCR. A positive correlation between TSCR and cortisol was found during the anticipatory phase, a relationship that was enhanced by increased cortisol linked to MA. Our findings suggest that subtle changes in the level of psychological stress can stimulate BAT, findings that may account for the high variability and inconsistency in reported BAT prevalence and activity measured by other modalities. Consistent assessment of this uniquely metabolic tissue is fundamental to the discovery of potential therapeutic strategies against metabolic disease

Brown adipose tissue and glucose homeostasis – the link between climate change and the global rise in obesity and diabetes

There is increasing evidence that the global rise in temperature is contributing to the onset of diabetes, which could be mediated by a concomitant reduction in brown fat activity. Brown (and beige) fat are characterised as possessing a unique mitochondrial protein uncoupling protein (UCP)1 that when activated can rapidly generate large amounts of heat. Primary environmental stimuli of UCP1 include cold-exposure and diet, leading to increased activity of the sympathetic nervous system and large amounts of lipid and glucose being oxidised by brown fat. The exact contribution remains controversial, although recent studies indicate that the amount of brown and beige fat in adult humans has been greatly underestimated. We therefore review the potential mechanisms by which glucose could be utilised within brown and beige fat in adult humans and the extent to which these are sensitive to temperature and diet. This includes the potential contribution from the peridroplet and cytoplasmic mitochondrial sub-fractions recently identified in brown fat, and whether a proportion of glucose oxidation could be UCP1-independent. It is thus predicted that as new methods are developed to assess glucose metabolism by brown fat, a more accurate determination of the thermogenic and non-thermogenic functions could be feasible in humans

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

A survey of nurses prescribing in diabetes care: practices, barriers and facilitators in New Zealand and the United Kingdom

Aims and objectives To compare diabetes-related prescribing practices, barriers and facilitators amongst nurse prescribers in New Zealand and the United Kingdom. Background Nurses have been prescribing in the United Kingdom for many years but nurse prescribing in New Zealand is relatively recent. It is unknown whether similar system factors act to facilitate or limit prescribing. Design A survey of 250 nurses prescribing in diabetes care in New Zealand (n = 111) and the United Kingdom (n = 139). Methods A SurveyMonkey questionnaire was used to survey nurses about the extent of their prescribing practices, and barriers and facilitators experienced. Quantitative data were explored descriptively, and qualitative responses were grouped according to content, with quotes provided to exemplify thematic content. This study is reported following STROBE guidelines. Results Insulin, metformin and sulphonylureas are the drugs most frequently prescribed in both countries. Considerably more New Zealand than United Kingdom nurses reported prescribing for cardiovascular and renal disease. In both countries, direct prescribing to the patient was most common, followed by remote prescribing in New Zealand and via recommendation to other prescribers in the United Kingdom. Most common barriers were lack of time and inadequate mentoring. Most common facilitators were as follows: good supervision; collegial relationships with specialists, pharmacists and peers; and ongoing education. Conclusions These New Zealand and United Kingdom nurses are prescribing a broad range of diabetes-related medications. Similar barriers and facilitators were identified in both countries. Adequate supervision, support from multidisciplinary team colleagues and prescribing education and guidelines are paramount. Relevance to clinical practice Important insights on barriers and facilitators to implementation of nurse prescribing in two countries are highlighted and, despite a considerable difference in the longevity of prescribing practice, similar issues were identified

Association between opioid use during mechanical ventilation in preterm infants and evidence of brain injury: a propensity score-matched cohort study

SummaryBackgroundPreterm infants often require mechanical ventilation (MV), which can be a painful experience. Opioids (such as morphine) are used to provide analgesia, despite conflicting evidence about their impact on the developing brain. We aimed to quantify the use of opioids during MV in infants born at 2 consecutive days, the odds of any preterm brain injury (adjusted odds ratio 1.22, 95% CI 1.10–1.35) were higher in those who received opioids compared with those who did not (received opioids, 990/3608 (27.4%) vs. did not receive opioids, 855/3608 (23.7%). The adjusted odds of these adverse outcomes increased with increasing number of days of opioid exposure.InterpretationUse of opioids during mechanical ventilation of preterm infants increased during the study period (2012–2020). Although causation cannot be determined, among those ventilated for >2 consecutive days, these data suggest that opioid use is associated with an increased risk of preterm brain injury and the risk increases with longer durations of exposure

Newborn infants with bilious vomiting: a national audit of neonatal transport services

Objective: The precautionary approach to urgently investigate infants with bilious vomiting has increased the numbers referred to transport teams and tertiary surgical centres. The aim of this national UK audit was to quantify referrals, determine the frequency of surgical diagnoses, with the purpose to inform the consequent inclusion of these referals in the national 'time critical' dataset. Method: A prospective, multi-centre UK-wide audit was conducted (01 August 2015 to 31 October 2015). Term infants, ≤ 7 days of age, referred for transfer due to bilious vomiting were included. Data at the time of transport and outcomes at seven days after transfer were collected by the local teams and tranferred anonymously for analysis. Results: Sixteen teams contributed data on 165 cases. Teams that consider such transfers as “time-critical” responded significantly faster than those that do not classify bilious vomiting as time-critical. There was a surgical diagnosis in 22% cases and 7% had a condition where delayed treatment may have caused bowel loss. Most surgical problems could be predicted by clinical and/or X-ray findings but two infants with normal X-ray features were found to have a surgical problem. Conclusion: The results of this study support the need for infants with bilious vomiting to be investigated for potential surgical pathologies, but the data do not provide evidence for the default designation of such referrals as “time critical.” Decisions should be made by clinical collaboration between the teams and, where appropriate, swift transfer provided

Recent advances in our understanding of brown and beige adipose tissue: the good fat that keeps you healthy [version 1; referees: 2 approved]

Brown adipose tissue (BAT) possesses a unique uncoupling protein (UCP1) which, when activated, enables the rapid generation of heat and the oxidation of lipids or glucose or both. It is present in small amounts (~15–350 mL) in adult humans. UCP1 is rapidly activated at birth and is essential in preventing hypothermia in newborns, who rapidly generate large amounts of heat through non-shivering thermogenesis. Since the “re-discovery” of BAT in adult humans about 10 years ago, there has been an exceptional amount of research interest. This has been accompanied by the establishment of beige fat, characterised as discrete areas of UCP1-containing cells dispersed within white adipocytes. Typically, the amount of UCP1 in these depots is around 10% of the amount found in classic BAT. The abundance of brown/beige fat is reduced with obesity, and the challenge is to prevent its loss with ageing or to reactivate existing depots or both. This is difficult, as the current gold standard for assessing BAT function in humans measures radio-labelled glucose uptake in the fasted state and is usually dependent on cold exposure and the same subject can be found to exhibit both positive and negative scans with repeated scanning. Rodent studies have identified multiple pathways that may modulate brown/beige fat function, but their direct relevance to humans is constrained, as these studies typically are undertaken in cool-adapted animals. BAT remains a challenging organ to study in humans and is able to swiftly adapt to changes in the thermal environment and thus enable rapid changes in heat production and glucose oxidation