Obesity and diabetes gene discovery approaches

New treatments are currently required for the common metabolic diseases obesity and type 2 diabetes. The identification of physiological and  biochemical factors that underlie the metabolic disturbances observed in obesity and type 2 diabetes is a key step in developing better therapeutic outcomes. The discovery of new genes and pathways involved in the  pathogenesis of these diseases is critical to this process, however  identification of genes that contribute to the risk of developing these diseases represents a significant challenge as obesity and type 2 diabetes are complex diseases with many genetic and environmental causes. A number of diverse approaches have been used to discover and validate potential new targets for obesity and diabetes. To date, DNA-based approaches using candidate gene and genome-wide linkage analysis have had limited success in identifying genomic regions or genes involved in the development of these diseases. Recent advances in the ability to evaluate linkage analysis data from large family pedigrees using variance components based linkage analysis show great promise in robustly identifying genomic regions associated with the development of obesity and diabetes. RNA-based technologies such as cDNA microarrays have identified many genes differentially expressed in tissues of healthy and diseased subjects. Using a combined approach, we are endeavouring to focus attention on differentially expressed genes located in chromosomal regions previously linked with obesity and / or diabetes. Using this strategy, we have identified Beacon as a potential new target for obesity and diabetes.

The taq IA and Ser311Cys polymorphisms in the dopamine D2 receptor gene and obesity

Dopamine D2 receptors (DRD2) in the central nervous system are involved in the regulation of feeding. It remains to be elucidated if mutations in the DRD2 gene contribute to the development of obesity. The aim of the present study was to investigate whether the Taq IA and Ser311Cys polymorphisms in the DRD2 gene are associated with obesity in Nauruan and Australian subjects. Subjects were selected based on extremes of the body mass index (BMI) distribution. Two groups of Australian women were selected. The leanest group had a mean BMI of 22.5 kg/m2 (range: 20.3-24.3) and the heaviest group had a mean of 36.1 kg/m2 (32.5-44.1). Four groups of Nauruan subjects were selected. Leanest men had a mean BMI of 33.0 kg/m2 (28.4-36.9), heaviest men had a mean of 52.8 kg/m2 (46.5-69.2), leanest women had a mean of 34.8 kg/m2 (28.2-41.8) and heaviest women had a mean of 55.1 kg/m2 (49.3-73.8). Subjects were genotyped for the Taq IA and Ser311Cys polymorphisms using polymerase chain reaction (PCR) restriction fragment length polymorphism analysis and allelic discrimination TaqmanTM PCR respectively. Leanest and heaviest groups were examined for differences in genotype frequency. Taq IA and Ser311Cys genotype frequencies did not differ significantly between leanest and heaviest Nauruan groups, or between leanest and heaviest Australians. Haplotype frequencies of these polymorphisms did not differ between leanest and heaviest groups. The Taq IA and Ser311Cys polymorphisms in the DRD2 gene are unlikely to be common causes of obesity in these populations.

Dusting off the epidemiological triad: could it work with obesity

The search for effective ways of dealing with obesity has centred on biological research and clinical management. However, obesity needs to be conceptualized more broadly if the modern pandemic is to be arrested. The epidemiological triad (hosts, agent/vectors and environments) has served us well in dealing with epidemics in the past, and may be worth re-evaluating to this end. Education, behaviour change and clinical practices deal predominantly with the host, although multidisciplinary practices such as shared-care might also be expected to impact on other corners of the triad. Technology deals best with the agent of obesity (energy imbalance) and it's vectors (excessive energy intake and/or inadequate energy expenditure), and policy and social change are needed to cope with the environment. The value of a broad model like this, rather than specific isolated approaches, is that the key players such as legislators, health professionals, governments and industry can see their roles in attenuating and eventually reversing the epidemic. It also highlights the need to intervene at all levels in obesity control and reduces the relevance of arguments about nature vs. nurture.


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Social factors and obesity: an investigation of the role of health behaviours

OBJECTIVES: This study evaluated a behavioural model of the relation between social factors and obesity, in which differences in body mass index (BMI) across sociodemographic groups were hypothesized to be attributable to social group differences in health behaviours affecting energy expenditure (physical activity, diet and alcohol consumption and weight control).

METHODS: A total of 8667 adults who participated in the 1995 Australian National Health and Nutrition Surveys provided data on a range of health factors including objectively measured height and weight, health behaviours, and social factors including family status, employment status, housing situation and migration status.

RESULTS: Social factors remained significant predictors of BMI after controlling for all health behaviours. Neither social factors alone, nor health behaviours alone, adequately explained the variance in BMI. Gender-specific interactions were found between social factors and individual health behaviours.

CONCLUSIONS: These results suggest that social factors moderate the relation between BMI and weight-related behaviours, and that the mechanisms underlying sociodemographic group differences in obesity may vary among men and women. Additional factors are likely to act in conjunction with current health behaviours to explain variation in obesity prevalence across sociodemographic groups.

Public perceptions of the causes and prevention of obesity among primary school children

OBJECTIVE: To investigate lay perceptions of the causes and prevention of obesity among primary school children.

DESIGN: A cross-sectional survey of randomly selected sample of adults in a shopping centre.

SUBJECTS: 315 adults in Melbourne, Australia.

MEASUREMENTS: Subjects completed a self-completion questionnaire, in which they rated the importance of 25 possible causes of obesity and the importance of 13 preventive measures on four-point scales: not important; quite important; very important; extremely important. Demographic information about the respondents' age, sex, marital status, education level and parental status was also collected.

RESULTS: The most important reported causes of childhood obesity were related to overconsumption of unhealthy food, parental responsibility, modern technology and the mass media. The most popular prevention activities were associated with specific actions aimed at children. Principal components analysis of the causes data revealed eight factors, provisionally named: parental responsibility, modern technology and media, overconsumption of unhealthy food, children's lack of knowledge and motivation, physical activity environment, lack of healthy food, lack of physical activity and genes. Two prevention factors were also derived, named government action and children's health promotion. Parents saw modern technology and media, and government activities as more important causes, and government policy as a more important means of prevention than nonparents and men. Women's responses tended to be similar to those of parents. There were few educational differences, although nontertiary educated respondents reported that modern technology and media were more important causes of obesity than did the tertiary educated.

CONCLUSION: The findings suggest that the public appears to hold quite sophisticated views of the causes and prevention of children's obesity. They suggest that a number of prevention strategies would be widely supported by the public, especially by parents.

Snowballing obesity: Australians will get run over if they just sit there.

* Overweight and obesity are very common in Australian adults (56%) and children (27%). * Rates of overweight and obesity are snowballing and will place greater burdens on health services for the treatment and care of chronic diseases. * Prevention is urgently required from health, social and economic perspectives, but the response to date has been inadequate.
* A long-term, sustained action plan starting with a focus on young people is needed. This should particularly address the “obesogenic” environments causing the epidemic. * Although whole-of-government action is required, support from and involvement by parents, carers, community leaders, healthcare professionals, teachers, childcare workers, urban planners, recreation managers, food manufacturers, employers, advertisers, and communicators is essential. *  The health sector should take the lead, but success will only come from concerted and integrated action across the whole of society. * There are now signs of political commitment to addressing overweight and obesity. Doctors should get behind this and help mobilise community support.

Identification of hypothalamic genes implicated in the development of obesity in Psammomys obesus using differential display PCR

The hypothalamus is a key central controller of energy homeostasis and is the source and/or site of action of many neuropeptides involved in this process. The aim of this study was to isolate hypothalamic genes differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity and type 2 diabetes. Differential display PCR was used to compare hypothalamic gene expression profiles of lean and healthy, obese and hyperinsulinemic, and obese, diabetic P. obesus in both the fed and fasted states. We conducted differential display with 180 separate primer combinations to amplify approximately 9000 expressed transcripts. Sixty differentially expressed bands were excised. Taqman PCR was performed on 36 of these transcripts to confirm differential gene expression in a larger sample population. Of these 36 transcripts, 9 showed homology to known genes, and 27 were considered to be novel sequences. Gene expression profiles for two of these genes are presented here. In conclusion, differential display PCR was successfully used to isolate several transcripts that may be involved in the central regulation of energy balance. We are currently conducting numerous studies to further investigate the role of these genes in the development of obesity in P. obesus.

Diet, nutrition and the prevention of excess weight gain and obesity

Objective: To review the evidence on the diet and nutrition causes of obesity and to recommend strategies to reduce obesity prevalence.
Design: The evidence for potential aetiological factors and strategies to reduce obesity prevalence was reviewed, and recommendations for public health action, population nutrition goals and further research were made.
Results: Protective factors against obesity were considered to be: regular physical activity (convincing); a high intake of dietary non-starch polysaccharides (NSP)/fibre (convincing); supportive home and school environments for children (probable); and breastfeeding (probable). Risk factors for obesity were considered to be sedentary lifestyles (convincing); a high intake of energy-dense, micronutrient-poor foods (convincing); heavy marketing of energy-dense foods and fast food outlets (probable); sugar-sweetened soft drinks and fruit juices (probable); adverse social and economic conditions—developed countries, especially in women (probable).
A broad range of strategies were recommended to reduce obesity prevalence including: influencing the food supply to make healthy choices easier; reducing the marketing of energy dense foods and beverages to children; influencing urban environments and transport systems to promote physical activity; developing community-wide programmes in multiple settings; increased communications about healthy eating and physical activity; and improved health services to promote breastfeeding and manage currently overweight or obese people.
Conclusions: The increasing prevalence of obesity is a major health threat in both low- and high income countries. Comprehensive programmes will be needed to turn the epidemic around.

An investigation into the incidence of obesity and underweight among adults with an intellectual disability in an Australian sample

Reports suggest that 7% to 18% of Australian adults are obese and a further 16% to 55% are overweight. Studies from other countries have indicated that obesity among people with an intellectual disability may be at least, or even more, prevalent. Prevalence rates range from 28% to 59%. The aim of the current study was to investigate the weight distribution of an Australian sample of people with an intellectual disability using Body Mass Index (BMI) to classify males and females, and Kelly and Rimmer's (1987) Percentage of Body Fat (PBF) formula to also classify males. Forty-one females and 52 males with a mild to severe intellectual disability were assessed. The correlation between BMI and PBF for males was r=.89. BMI classifications revealed a higher percentage of females as overweight (41.4%) and obese (36.6%) compared to overweight males (30.8%) and obese males (30.8%). There were more underweight males (7.6%) than females (4.9%). There was no relationship between living environment and weight classifications on the BMI. The PBF formula indicated that 73% of the males were classified as obese. The possibility of misclassification using the BMI and the need for weight interventions are discussed.

Perceptions of local neighbourhood environments and their relationship to childhood overweight and obesity

OBJECTIVES: To examine associations between parent and child perceptions of the local neighbourhood and overweight/obesity among children aged 5–6 and 10–12 y. DESIGN: Cross-sectional survey. SUBJECTS: In total, 291 families of 5–6-y-old and 919 families of 10–12-y-old children. MEASURES: Parent's perceptions of local neighbourhood and perceived child access to eight local destinations within walking distance of home; 10–12-y-old children's perception of local neighbourhood; socio-demographic characteristics (survey). Children's height and weight (measured). RESULTS: No perceptions of the local neighbourhood were associated with weight status among 5–6-y-old children. Among 10–12-y-old children, those whose parents agreed that there was heavy traffic in their local streets were more likely to be overweight or obese (OR=1.4, 95% CI=1.0–1.8), and those whose parents agreed that road safety was a concern were more likely to be obese (OR=3.9, 95% CI=1.0–15.2), compared to those whose parents disagreed with these statements. CONCLUSIONS: This study suggests that parental perceptions of heavy traffic on local streets and concern about road safety may be indirect influences on overweight and obesity among 10–12-y-old children. Future work should also consider perceptions of the neighbourhood related to food choice.

Obesity prevention: a proposed framework for translating evidence into action

Obesity as a major public health and economic problem has risen to the top of policy and programme agendas in many countries, with prevention of childhood obesity providing a particularly compelling mandate for action. There is widespread agreement that action is needed urgently, that it should be comprehensive and sustained, and that it should be evidence-based. While policy and programme funding decisions are inevitably subject to a variety of historical, social, and political influences, a framework for defining their evidence base is needed. This paper describes the development of an evidence-based, decision-making framework that is particularly relevant to obesity prevention. Building upon existing work within the fields of public health and health promotion, the Prevention Group of the International Obesity Task Force (IOTF) developed a set of key issues and evidence requirements for obesity prevention. These were presented and discussed at an IOTF workshop in April 2004 and were then further developed into a practical framework. The framework is defined by five key policy and
programme issues that form the basis of the framework. These are: (i) building a case for action on obesity; (ii) identifying contributing factors and points of intervention; (iii) defining the opportunities for action; (iv)evaluating potential interventions; and (v) selecting a portfolio of specific policies, programmes, and actions. Each issue has a different set of evidence requirements and analytical outputs to support policy and programme decision-making. Issue 4 was identified as currently the most problematic because of the relative lack of efficacy and effectiveness studies. Compared with clinical decision-making where the evidence base is dominated by randomized controlled trials with high internal validity, the evidence base for obesity prevention needs many different types of evidence and often needs the informed opinions of stakeholders to ensure external validity and contextual relevance.

Obesity and the right to sue: would you like fries with that?

There is little chance that obese customers in Australia would fare any better in a claim against fast food companies than their counterparts in the US.

Parental concerns about childhood obesity and the strategies employed to prevent unhealthy weight gain in children.

Objectives: To describe parental concerns about their child’s weight, to determine the proportion of parents taking preventive action to avoid obesity in their children and the predictors of taking preventive action, and to describe the strategies adopted by parents.
Design: A cross-sectional survey was conducted. Children’s heights and weights were measured, and parents completed a questionnaire that included measures of their own weight status, perceptions of their child’s weight, concerns about their child’s current weight and future weight as an adolescent and adult, and the strategies used to prevent obesity.
Setting: The study was conducted in Melbourne, Australia.
Subjects: A total of 291 families of children aged 5–6 years and 919 families of children aged 10–12 years participated.
Results: Eighty-nine per cent of parents of overweight 5–6-year-olds and 63% of parents of overweight 10–12-year-olds were unaware their child was overweight. Seventy-one per cent of parents of overweight 5–6-year-olds and 43% of parents of overweight 10–12-year-olds were not concerned about their child’s current weight. Although 31% of parents of 5–6-year-olds and 43% of parents of 10–12-year-olds were taking action to prevent unhealthy weight gain in their children, less-educated parents were less likely to do so.
Conclusions: Public health programmes are required to raise parental recognition of childhood overweight and of related risk behaviours, and to provide parents with practical strategies to prevent unhealthy weight gain in their children.

Whose socioeconomic status influences a women's obesity risk: her mother's, her father's, or her own?

Background Evidence on the relative influence of childhood vs adulthood socioeconomic conditions on obesity risk is limited and equivocal. The objective of this study was to investigate associations of several indicators of mothers', fathers', and own socioeconomic status, and intergenerational social mobility, with body mass index (BMI) and weight change in young women.

Methods This population-based cohort study used survey data provided by 8756 women in the young cohort (aged 18–23 years at baseline) of the Australian Longitudinal Study on Women's Health. In 1996 and 2000, women completed mailed surveys in which they reported their height and weight, and their own, mother's, and father's education and occupation.

Results Multiple linear regression models showed that both childhood and adulthood socioeconomic status were associated with women's BMI and weight change, generally in the hypothesized (inverse) direction, but the associations varied according to socioeconomic status and weight indicator. Social mobility was associated with BMI (based on father's socioeconomic status) and weight change (based on mother's socioeconomic status), but results were slightly less consistent.

Conclusions Results suggest lasting effects of childhood socioeconomic status on young women's weight status, independent of adult socioeconomic status, although the effect may be attenuated among those who are upwardly socially mobile. While the mechanisms underlying these associations require further investigation, public health strategies aimed at preventing obesity may need to target families of low socioeconomic status early in children's lives.