Obesity, diet quality and absenteeism in a working population

The relationship between workplace absenteeism and adverse lifestyle factors (smoking, physical inactivity and poor dietary patterns) remains ambiguous. Reliance on self-reported absenteeism and obesity measures may contribute to this uncertainty. Using objective absenteeism and health status measures, the present study aimed to investigate what health status outcomes and lifestyle factors influence workplace absenteeism. Cross-sectional data were obtained from a complex workplace dietary intervention trial, the Food Choice at Work Study. Four multinational manufacturing workplaces in Cork, Republic of Ireland. Participants included 540 randomly selected employees from the four workplaces. Annual count absenteeism data were collected. Physical assessments included objective health status measures (BMI, midway waist circumference and blood pressure). FFQ measured diet quality from which DASH (Dietary Approaches to Stop Hypertension) scores were constructed. A zero-inflated negative binomial (zinb) regression model examined associations between health status outcomes, lifestyle characteristics and absenteeism. The mean number of absences was 2·5 (sd 4·5) d. After controlling for sociodemographic and lifestyle characteristics, the zinb model indicated that absenteeism was positively associated with central obesity, increasing expected absence rate by 72 %. Consuming a high-quality diet and engaging in moderate levels of physical activity were negatively associated with absenteeism and reduced expected frequency by 50 % and 36 %, respectively. Being in a managerial/supervisory position also reduced expected frequency by 50 %. To reduce absenteeism, workplace health promotion policies should incorporate recommendations designed to prevent and manage excess weight, improve diet quality and increase physical activity levels of employees.

Mammalian cell cultures as a model system for the determination of cytotoxicity induced by cholesterol oxidation products

Oxysterols are products of cholesterol oxidation, which may be produced endogenously or may be absorbed from the diet where they are commonly found in foods of animal origin. Oxysterols are known to be cyctotoxic to cells in culture and mode of toxicity has been identified as apoptosis in certain cell lines. The cytotoxicity of the oxysterols 25-hydroxycholesterol (25-OH) and 7β-hydroxycholesterol (7β-OH) was examined in two human cell lines, HepG2, a hepatoma cell line, and U937, a monocytic cell line. Both 25-OH and 7β-OH were cytotoxic to the HepG2 cell line but apoptotic cells were not detected and it was concluded that cells underwent necrosis. 25-OH was not cytotoxic to the U937 cell line but it was found to have a cytostatic effect. 7β-OH was shown to induce apoptosis in the U937 line. The mechanism of oxysterol-induced apoptosis has not yet been fully elucidated, however the generation of an oxidative stress and the depletion of glutathione have been associated with the initial stages of the apoptotic process. The concentration of cellular antioxidant enzyme, superoxide dismutase (SOD) was increased in association with 7β-OH induced apoptosis in the U937 cell line. There was no change in the glutathione concentration or the SOD activity of HepG2 cells, which underwent necrosis in the presence of 7β-OH. Many apoptotic pathways center on the activation of caspase-3, which is the key executioner protease of apoptosis. Caspase-3 activity was also shown to increase in association with 7β-OH-induced apoptosis in U937 cells but there was no significant increase in caspase-3 activity in HepG2 cells. DNA fragmentation is regarded as the biochemical hallmark of apoptosis, therefore the comet assay as a measure of DNA fragmentation was assessed as a measure of apoptosis. The level of DNA fragmentation induced by 7β-OH, as measured using the comet assay, was similar for both cell lines. Therefore, it was concluded that the comet assay could not be used to distinguish between 7β-OH-induced apoptosis in U937 cells and 7β-OH-induced necrosis in HepG2 cells. The cytotoxicity and apoptotic potency of oxysterols 25-OH, 7β-OH, cholesterol- 5a,6a-epoxide (a-epoxide), cholesterol-5β,6β-epoxide (β-epoxide), 19-hydroxy-cholesterol (19-OH), and 7-ketocholesterol (7-keto) was compared in the U937 cell line. 7 β-OH, β-epoxide and 7-keto were found to induce apoptosis in U937 cells. 7β-OH-induced apoptosis was associated with a decrease in the cellular glutathione concentration and an increase in SOD activity, 7-keto and β-epoxide did not affect the glutathione concentration or the SOD activity of the cells.a-Epoxide, 19-OH and 25-OH were not cytotoxic to the U937 cell line.

The gut microbiota as a contributing factor to antipsychotic-induced weight gain and metabolic dysfunction

Schizophrenia represents one of the world’s most devastating illnesses due to its often lifelong course and debilitating nature. The treatment of schizophrenia has vastly improved over recent decades with the discovery of several antipsychotic compounds; however these drugs are not without adverse effects that must be addressed to maximize their therapeutic value. Newer, atypical, antipsychotics are associated with a compilation of serious metabolic side effects including weight gain, insulin resistance, fat deposition, glucose dysregulation and ensuing co-morbidities such as type II diabetes mellitus. The mechanisms underlying these side effects remain to be fully elucidated and adequate interventions are lacking. Further understanding of the factors that contribute these side effects is therefore required in order to develop effective adjunctive therapies and to potentially design antipsychotic drugs in the future with reduced impact on the metabolic health of patients. We investigated if the gut microbiota represented a novel mechanism contributing to the metabolic dysfunction associated with atypical antipsychotics. The gut microbiota comprises the bacteria that exist symbiotically within the gastrointestinal tract, and has been shown in recent years to be involved in several aspects of energy balance and metabolism. We have demonstrated that administration of certain antipsychotics in the rat results in an altered microbiota profile and, moreover, that the microbiota is required for the full scale of metabolic dysfunction to occur. We have further shown that specific antibiotics can attenuate certain aspects of olanzapine and risperidone–induced metabolic dysfunction, in particular fat deposition and adipose tissue inflammation. Mechanisms underlying this novel link appear to involve energy utilization via expression of lipogenic genes as well as reduced inflammatory tone. Taken together, these data indicate that the gut microbiota is an important factor involved in the myriad of metabolic complications associated with antipsychotic therapy. Furthermore, these data support the future investigation of microbial-based therapeutics for not only antipsychotic-induced weight gain but also for tackling the global obesity epidemic.

The impact of a variety of factors on the obesity associated gut microbiota

The obesity pandemic has become perhaps the most prevalent health issue of our time, with more than 10% of the world’s population now being obese. Obesity can be defined as abnormal or excess fat accumulation that may impair health and results from an imbalance between energy intake and energy expenditure. A decrease in physical activity due to an increase in sedentary forms of work, changing modes of transport and increasing urbanization is likely a major contributory factor. Diet is another major factor with the increased availability and intake of calorie dense, high fat foods being of global concern. Notably, with respect to this thesis, over the last decade advances in the field of next generation sequencing (NGS) have facilitated investigations to determine the relationship between the gut microbiota and obesity. This thesis examines the impact of a variety of factors on the obesity associated gut microbiota. Overall the results presented in this thesis highlight that microbial diversity is influenced by diet, exercise, antibiotics and disease state, however it is only through further understanding of the structure and function that we can identify targets that can impact on health.

Childhood obesity in Ireland: recent trends and modifiable determinants

Background: Childhood obesity is a global epidemic posing a significant threat to the health and wellbeing of children. To reverse this epidemic, it is essential that we gain a deeper understanding of the complex array of driving factors at an individual, family and wider ecological level. Using a social-ecological framework, this thesis investigates the direction, magnitude and contribution of risk factors for childhood overweight and obesity at multiple levels of influence, with a particular focus on diet and physical activity. Methods: A systematic review was conducted to describe recent trends (from 2002-2012) in childhood overweight and obesity prevalence in Irish school children from the Republic of Ireland. Two datasets (Cork Children’s Lifestyle [CCLaS] Study and the Growing Up in Ireland [GUI] Study) were used to explore determinants of childhood overweight and obesity. Individual lifestyle factors examined were diet, physical activity and sedentary behaviour. The determinants of physical activity were also explored. Family factors examined were parental weight status and household socio-economic status. The impact of food access in the local area on diet quality and body mass index (BMI) was investigated as an environmental level risk factor. Results: Between 2002 and 2012, the prevalence of childhood overweight and obesity in Ireland remained stable. There was some evidence to suggest that childhood obesity rates may have decreased slightly though one in four Irish children remained either overweight or obese. In the CCLaS study, overweight and obese children consumed more unhealthy foods than normal weight children. A diet quality score was constructed based on a previously validated adult diet score. Each one unit increase in diet quality was significantly associated with a decreased risk of childhood overweight and obesity. Individual level factors (including gender, being a member of a sports team, weight status) were more strongly associated with physical activity levels than family or environmental factors. Overweight and obese children were more sedentary and less active than normal weight children. There was a dose response relationship between time spent at moderate to vigorous physical activity (MVPA) and the risk of childhood obesity independent of sedentary time. In contrast, total sedentary time was not associated with the risk of childhood obesity independent of MVPA though screen time was associated with childhood overweight and obesity. In the GUI Study, only one in five children had 2 normal weight parents (or one normal weight parent in the case of single parent families). Having overweight and obese parents was a significant risk factor for overweight and obesity regardless of socio-economic characteristics of the household. Family income was not associated with the odds of childhood obesity but social class and parental education were important risk factors for childhood obesity. Access to food stores in the local environment did not impact dietary quality or the BMI of Irish children. However, there was some evidence to suggest that the economic resources of the family influenced diet and BMI. Discussion: Though childhood overweight and obesity rates appear to have stabilised over the previous decade, prevalence rates are unacceptably high. As expected, overweight and obesity were associated with a high energy intake and poor dietary quality. The findings also highlight strong associations between physical inactivity and the risk of overweight and obesity, with effect sizes greater than what have been typically found in adults. Important family level determinants of childhood overweight and obesity were also identified. The findings highlight the need for a multifaceted approach, targeting a range of modifiable determinants to tackle the problem. In particular, policies and interventions at the shared family environment or community level may be an effective mean of tackling this current epidemic.

Steroid induced neuroprotection of damaged photoreceptor cells

Retinitis Pigmentosa (RP) is the name given to a group of hereditary diseases causing progressive and degenerative blindness. RP affects over 1 in 4000 individuals, making it the most prevalent inherited retinal disease worldwide, yet currently there is no cure. In 2011, our group released a paper detailing the protective effects of the synthetic progestin ‘Norgestrel’. A common component of the female oral contraceptive pill, Norgestrel was shown to protect against retinal cell death in two distinct mouse models of retinal degeneration: in the Balb/c light damage model and the Pde6brd10 (rd10) model. Little was known of the molecular workings of this compound however and thus this study aimed to elucidate the protective manner in which Norgestrel worked. To this aim, the 661W cone photoreceptor-like cell line and ex vivo retinal explanting was utilised. We found that Norgestrel induces a increase in neuroprotective basic fibroblast growth factor (bFGF) with subsequent downstream actions on the inhibition of glycogen synthase kinase 3β. Progesterone receptor expression was subsequently characterised in the C57 and rd10 retinas and in the 661W cell line. Norgestrel caused nuclear trafficking of progesterone receptor membrane complex one (PGRMC1) in 661W cells and thus Norgestrel was hypothesised to work primarily through the actions of PGRMC1. This trafficking was shown to be responsible for the critical upregulation of bFGF and PGRMC1- Norgestrel binding was proven to cause a neuroprotective bFGF-mediated increase in intracellular calcium. The protective properties of Norgestrel were further studied in the rd10 mouse model of retinitis pigmentosa. Using non-invasive diet supplementation (80mg/kg), we showed that Norgestrel gave significant retinal protection out to postnatal day 40 (P40). Overactive microglia have previously been shown to potentiate photoreceptor cell loss in the degenerating rd10 retina and thus we focussed on Norgestrel-mediated changes in photoreceptor-microglial crosstalk. Norgestrel acted to dampen pro-inflammatory microglial cell reactivity, decreasing chemokine (MCP1, MCP3, MIP-1α, MIP-1β) and subsequent damaging cytokine (TNFα, Il-1β) production. Critically, Norgestrel up-regulated photoreceptor-microglial, fractalkine-CX3CR1 signalling 1000-fold in the P20 rd10 mouse. Known to prevent microglial activation, we hypothesise that Norgestrel acts as a vital anti-inflammatory in the diseased retina, driving fractalkine-CX3CR1 signalling to delay retinal degeneration. This study stands to highlight some of the neuroprotective mechanisms utilised by Norgestrel in the prevention of photoreceptor cell death. We identify for the first time, not only a pro-survival pathway activated directly in photoreceptor cells, but also a Norgestreldriven mediation of an otherwise damaging microglial cell response. All taken, these results form the beginning of a case to bring Norgestrel to clinical trials, as a potential therapeutic for the treatment of RP.