Joanne E. Cecil

An obesity-associated FTO gene variant and increased energy intake in children

BACKGROUND Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. METHODS We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. RESULTS In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). CONCLUSIONS The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods.

Comparison of the effects of a high-fat and high-carbohydrate soup delivered orally and intragastrically on gastric emptying, appetite, and eating behaviour.

To investigate the effects of fat and carbohydrate on appetite, food intake and gastric emptying with and without the influence of orosensory factors, a group of nine healthy, fasted male subjects took part in two separate paired experiments involving high-fat and high-carbohydrate radiolabelled soup preloads. In the first experiment subjects received direct intragastric isocaloric infusions of either a high-fat tomato soup or a high-carbohydrate tomato soup (400 kcal in 425 mL) over 15 min, on two occasions. In the second paired experiment subjects ingested the same high-fat and high-carbohydrate soup over 15 min. In both experiments ratings of hunger and fullness were recorded over a period of 135 min and gastric emptying was measured by scintigraphy. Food intake was evaluated from a test meal (yoghurt drink) given 2 h after the end of the soup infusion/ingestion. When soup was administered intragastrically (Experiment 1) both the high-fat and high-carbohydrate soup preloads suppressed appetite ratings from baseline, but there were no differences in ratings of hunger and fullness, food intake from the test meal, or rate of gastric emptying between the two soup preloads. When the same soups were ingested (Experiment 2), the high-fat soup suppressed hunger, induced fullness, and slowed gastric emptying more than the high-carbohydrate soup and also tended to be more effective at reducing energy intake from the test meal. The results of these studies demonstrate that orosensory stimulation plays an important role in appetite regulation, and also indicate that subtle differences in orosensory stimulation produced by particular nutrients may profoundly influence appetite and gastrointestinal responses.

Association between common variation at the FTO locus and changes in body mass index from infancy to late childhood: the complex nature of genetic association through growth and development.

An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10−20) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10−23). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (−0.40% (95% CI: −0.74, −0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (−4.72% (−5.81, −3.63), p = 10−17), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.

Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes

Aims/hypothesisThe Pro12Ala polymorphism of peroxisome proliferator-activated receptor (PPAR)γ has been consistently associated with Type 2 diabetes. The rare Ala12 variant is estimated to reduce the risk of developing Type 2 diabetes by 20 percent. This variant is in linkage disequilibrium with another common variant, T1431. Both have opposing associations with body weight. We therefore examined the association of specific haplotypes marked by these two variants with susceptibility to Type 2 diabetes.MethodsWe determined the PPARG genotype of a large Scottish cohort of Type 2 diabetic patients (n=1997) and compared allele frequencies with a cohort of local children (n=2444) and a middle-aged, population-based cohort from Scotland (n=1061).ResultsFrequency of the Ala12 allele was slightly lower in the Type 2 diabetic cohort than in the children [odds ratio (OR)=0.91, p=0.1]. In contrast, the Ala12 variant was under-represented in the Type 2 diabetic population when compared with similarly aged non-diabetic adults (OR=0.74, p=0.0006). When the Ala12 variant was on a haplotype not bearing the 1431T variant, it conferred greater protection (OR=0.66, p=0.003). However, when it was present in haplotypes containing the 1431T variant (70% of Ala12 carriers), this protection was absent (OR=0.99, p=0.94).Conclusions/interpretationWe replicated the finding that the Ala12 variant of PPARγ affords protection from Type 2 diabetes, and suggest that this protection is modulated by additional common variation at the PPARG locus.

Oral, gastric and intestinal influences on human feeding

Direct infusion of specific nutrients or foods into different areas of the gastrointestinal tract, and techniques to distend the stomach, are useful tools enabling eating behaviour to be studied without the influence of orosensory factors. Using these techniques, the role of nutrients on gastrointestinal mechanisms of satiation as well as the interactions between the various systems in the control of feeding can be examined. Recent research in humans investigating the relative contribution of signals arising from different areas of the gastrointestinal tract has demonstrated that optimal control of appetite occurs only when orosensory signals are coupled with signals arising from the stomach and intestine. Interactions between gastric and intestinal signals do however combine to produce a more potent suppression of appetite and food intake than when either of these sites is stimulated alone. Gastric distension probably exerts a predominate influence on appetite suppression compared with intestinal stimulation, whereas nutrient stimulation of the intestine may function to modulate the sensations arising from gastric distension to elicit a meal-like sensation of satiety. In addition, these studies have highlighted that previous hypotheses concerning differential fat and carbohydrate satiation may require an orosensory component and probably do not reflect an inherent difference in the physiological effects of these macronutrients at the level of the GI tract. The interaction of orosensory influences, such as palatability, with negative feedback signals arising from the GI tract can be further studied using a combination of these techniques with measurement of microstructure of feeding in humans.

Susceptibility to weight gain. Eating behaviour traits and physical activity as predictors of weight gain during the first year of university.

The transition to University has been identified as a possible period for weight gain but few studies have addressed the extent of this experience in UK Universities. The present study was conducted in four Universities in England and Scotland to directly measure changes in body weight, waist circumference and body composition in students during their first year. Two hundred and fifty first-year students completed psychometric eating behaviour questionnaires and a validated physical activity survey before attending one of the laboratories for standardised assessments of height, body weight, waist circumference and body composition at 0, 3, and 12-months. Significant but small and transitory increases in all weight outcomes (e.g. body weight=0.83±2.1 kg) were observed except for fat-free mass. Weight-related measures at baseline predicted changes in weight over 12-months but not 3-months. Disinhibition, power of food and binge eating were associated with change in fat mass while physical activity, cognitive restraint and sensitivity to reward were associated with change in fat-free mass. Weight gain occurs in the first year of University in the UK, but appears to be small and transitory. Changes in fat mass were related to opportunistic eating and the tendency to overconsume, while change in fat-free mass related to physical activity and low dietary restraint in conjunction with drive to experience reward. Psychological markers underlying changes in body composition can inform strategies to promote self-regulation in young adults during a critical life period for weight gain.

Energy balance and food intake: The role of PPARγ gene polymorphisms

Mechanisms regulating energy balance involve complex interactions between genetic, environmental and behavioural (learnt and intrinsic) factors. Genotype may drive the partitioning of energy metabolism and predispose to site-specific adiposity, culminating in a state of energy imbalance. One candidate gene with a direct link to adiposity is the peroxisome proliferator-activated receptor γ (PPARG) gene. PPARG is a cell nuclear receptor expressed almost exclusively in adipose tissue that regulates adipocyte differentiation, lipid metabolism and insulin sensitivity. PPARγ appears to be a key regulator of energy balance, with polymorphisms on the PPARG gene linked to obesity and effects on body composition. Our research has confirmed an association between the pro12ala allele and reduced incidence of obesity in pre-pubertal children and there are strong associations between genetic variation at the PPARG locus and percentage body fat. Moreover, our evidence suggests that PPARG C-681G and pro12ala polymorphisms display opposing effects in terms of growth phenotype, with pro12Ala associated with deficient energy utilisation, leading to reduced growth and the G-681 variant associated with accelerated growth compared with wildtypes. Common differences in this gene have also been associated with variations in body weight in response to dietary macronutrients. Preliminary evidence suggests that PPARG variants may even be involved in the control of short term energy compensation. Taken together these data suggest that the role of PPARG is varied and complex, influencing fat deposition and growth velocity early in life, with potential impact in the control of energy intake and appetite regulation, and could provide a key target for future research and anti-obesity agents.

Effects of intragastric infusions of fat and carbohydrate on appetite ratings and food intake from a test meal.

Previous studies using meal preloads have indicated that carbohydrate has a greater satiating power than fat. To investigate the effects of macronutrients on ingestion and satiety, without the influence of meal design and orosensory factors, two groups of ten healthy, fasted male volunteers took part in two separate experiments involving rapid direct intragastric infusions of macronutrients. In the first experiment volunteers received isocaloric infusions of either Intralipid, or 1:1 Intralipid and glucose mixture or saline over 15 min on three separate occasions. In a second experiment volunteers received isocaloric infusions of either Intralipid or glucose. For both studies, appetite ratings were recorded for the first two hours of the study and energy and macronutrient intakes were evaluated from a test meal given 1.5 h after the infusion. Food diaries were used to monitor food intake for the remainder of the study day. In the first experiment, both Intralipid and the Intralipid/glucose mixture suppressed appetite ratings and reduced energy intake at lunch compared with saline but had no effect on energy intake during the remainder of the study day. No differences were found between nutrient conditions in suppressing appetite ratings or energy intake. In the second experiment there were no differences between the effects of Intralipid and glucose on hunger, fullness or on energy intake from the test meal or intake over the remainder of the day. Taken together, these results suggest that intragastric infusions of either Intralipid, glucose or a mixture of the two, reduced hunger and increased fullness, but they failed to confirm the hypothesis that different macronutrients have different satiating capacities.

Childhood obesity and socioeconomic status: a novel role for height growth limitation.

OBJECTIVE:To assess prevalence and socioeconomic context of overweight and obesity in a cohort of Scottish children.DESIGN:Cross-sectional study.SETTING:Primary schools in Dundee, Angus, and Fife, Eastern Scotland, UK.PARTICIPANTS:A total of 1240 boys and 1214 girls aged between 4–10 y.MAIN OUTCOME MEASURE:Weight, height and body mass index (weight/height2).RESULTS:Overall overweight or obesity prevalence was 24.6%, while prevalence of obesity alone was 6.1%. Individuals from schools with a high level of low-income families were 65% more likely to be overweight as judged by BMI. However, these children weighed the same as more affluent children of the same age, but were 1.26 cm shorter.CONCLUSION:These data confirm the continued increase in childhood obesity in the UK and reveal a role for height-growth limitation in the absence of overall growth restriction, among children from low-income groups. This observation raises important questions regarding socioeconomic environmental factors in promoting the currently increasing levels of obesity.

Behaviour and burnout in medical students

Background Burnout is prevalent in doctors and can impact on job dissatisfaction and patient care. In medical students, burnout is associated with poorer self-rated health; however, it is unclear what factors influence its development. This study investigated whether health behaviours predict burnout in medical students. Methods Medical students (n=356) at the Universities of St Andrews and Manchester completed an online questionnaire assessing: emotional exhaustion (EE), depersonalisation (DP), personal accomplishment (PA), alcohol use, physical activity, diet, and smoking. Results Approximately 55% (54.8%) of students reported high levels of EE, 34% reported high levels of DP, and 46.6% reported low levels of PA. Linear regression analysis revealed that year of study, physical activity, and smoking status significantly predicted EE whilst gender, year of study, and institution significantly predicted DP. PA was significantly predicted by alcohol binge score, year of study, gender, and physical activity. Conclusions Burnout is present in undergraduate medical students in the United Kingdom, and health behaviours, particularly physical activity, predict components of burnout. Gender, year of study, and institution also appear to influence the prevalence of burnout. Encouraging medical students to make healthier lifestyle choices early in their medical training may reduce the likelihood of the development of burnout.Background Burnout is prevalent in doctors and can impact on job dissatisfaction and patient care. In medical students, burnout is associated with poorer self-rated health; however, it is unclear what factors influence its development. This study investigated whether health behaviours predict burnout in medical students. Methods Medical students (n=356) at the Universities of St Andrews and Manchester completed an online questionnaire assessing: emotional exhaustion (EE), depersonalisation (DP), personal accomplishment (PA), alcohol use, physical activity, diet, and smoking. Results Approximately 55% (54.8%) of students reported high levels of EE, 34% reported high levels of DP, and 46.6% reported low levels of PA. Linear regression analysis revealed that year of study, physical activity, and smoking status significantly predicted EE whilst gender, year of study, and institution significantly predicted DP. PA was significantly predicted by alcohol binge score, year of study, gender, and physical activity. Conclusions Burnout is present in undergraduate medical students in the United Kingdom, and health behaviours, particularly physical activity, predict components of burnout. Gender, year of study, and institution also appear to influence the prevalence of burnout. Encouraging medical students to make healthier lifestyle choices early in their medical training may reduce the likelihood of the development of burnout.