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

Cognitive Function, Mental Health, and Quality of Life in Siblings of Preterm Born Children : Protocol for a Systematic Review

Background: Children and adults born preterm are at increased risk of cognitive impairments, mental health disorders, and poorer quality of life. Epidemiological studies have shown that the impact of preterm birth extends to the immediate family members; however, existing research have focused on parents, and little attention has been given to siblings. Objective: The aim of the systematic review described in this protocol is to synthesize currently available evidence on the impact of exposure to preterm birth (ie, having a sibling born preterm) on cognition, mental health, and quality of life of term born siblings (index child) of preterm born children, and to critically appraise the evidence. Methods: This protocol outlines a systematic review designed in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols) checklist. We will include all studies that assess outcomes in siblings of children born preterm. Quantitative and qualitative studies will be eligible for the systematic review, and only studies in English will be included. Firstly, search will be conducted electronically on PubMed, Scopus, Embase, Mednar, and opengrey.eu databases and, secondly, manually in Google Scholar and reference lists. The search strategy will include keywords and synonyms, Boolean operators, and text words (ie, within title and abstract). The team of reviewers will screen the search results, extract data from eligible studies, and critically appraise the studies. Analysis will involve both descriptive and quantitative approaches. Meta-analysis will be conducted if appropriate. Results: This systematic review was registered on PROSPERO (International Prospective Register of Systematic Reviews) on December 18, 2020, and it is currently in progress. The findings will be synthesized to determine the effect of preterm birth on full-term siblings and the quality of the available evidence. Conclusions: The evidence derived from this study will shed light on gaps and limitations in the field of preterm birth, more specifically, the effect of preterm birth on full-term siblings. In addition, we hope that understanding the impact of preterm birth on family members will inform targeted interventions and policies for those identified at high risk and how to mitigate health risks. International Registered Report Identifier (IRRID): DERR1-10.2196/34987Peer reviewe

Cognitive Function, Mental Health, and Quality of Life in Siblings of Preterm Born Children : Protocol for a Systematic Review

Background: Children and adults born preterm are at increased risk of cognitive impairments, mental health disorders, and poorer quality of life. Epidemiological studies have shown that the impact of preterm birth extends to the immediate family members; however, existing research have focused on parents, and little attention has been given to siblings. Objective: The aim of the systematic review described in this protocol is to synthesize currently available evidence on the impact of exposure to preterm birth (ie, having a sibling born preterm) on cognition, mental health, and quality of life of term born siblings (index child) of preterm born children, and to critically appraise the evidence. Methods: This protocol outlines a systematic review designed in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols) checklist. We will include all studies that assess outcomes in siblings of children born preterm. Quantitative and qualitative studies will be eligible for the systematic review, and only studies in English will be included. Firstly, search will be conducted electronically on PubMed, Scopus, Embase, Mednar, and opengrey.eu databases and, secondly, manually in Google Scholar and reference lists. The search strategy will include keywords and synonyms, Boolean operators, and text words (ie, within title and abstract). The team of reviewers will screen the search results, extract data from eligible studies, and critically appraise the studies. Analysis will involve both descriptive and quantitative approaches. Meta-analysis will be conducted if appropriate. Results: This systematic review was registered on PROSPERO (International Prospective Register of Systematic Reviews) on December 18, 2020, and it is currently in progress. The findings will be synthesized to determine the effect of preterm birth on full-term siblings and the quality of the available evidence. Conclusions: The evidence derived from this study will shed light on gaps and limitations in the field of preterm birth, more specifically, the effect of preterm birth on full-term siblings. In addition, we hope that understanding the impact of preterm birth on family members will inform targeted interventions and policies for those identified at high risk and how to mitigate health risks. International Registered Report Identifier (IRRID): DERR1-10.2196/34987Peer reviewe

Glucose Metabolism in Midlife Is Associated With Preceding 30-Year Employment Trajectories : A Northern Finland Birth Cohort 1966 Study

AbstractObjective: The aim of the study is to evaluate how glucose metabolism in midlife is related to preceding 30-year-long employment trajectories.Methods: In the Northern Finland Birth Cohort 1966, we compared glucose metabolism at 46 to employment trajectories (previously defined for men and women and named as high-educated, traditional, self-employed, delayed, and floundering; n = 6399).Results: Compared with individuals in high-educated trajectories, odds ratios for type 2 diabetes (T2D, 95% confidence interval) in traditional and floundering trajectories in men were 1.65 (1.02–2.68) and 2.42 (1.38–4.23) and in women 1.89 (1.04–3.43) and 2.60 (1.46–4.62), respectively. In self-employed trajectory in women, odds ratios for prediabetes and T2D were 1.66 (1.09–2.51) and 2.47 (1.21–5.04).Conclusions: The highest risks for T2D in midlife were associated after traditional and floundering trajectories in men and women and after self-employment trajectory in women.Abstract Objective: The aim of the study is to evaluate how glucose metabolism in midlife is related to preceding 30-year-long employment trajectories. Methods: In the Northern Finland Birth Cohort 1966, we compared glucose metabolism at 46 to employment trajectories (previously defined for men and women and named as high-educated, traditional, self-employed, delayed, and floundering; n = 6399). Results: Compared with individuals in high-educated trajectories, odds ratios for type 2 diabetes (T2D, 95% confidence interval) in traditional and floundering trajectories in men were 1.65 (1.02–2.68) and 2.42 (1.38–4.23) and in women 1.89 (1.04–3.43) and 2.60 (1.46–4.62), respectively. In self-employed trajectory in women, odds ratios for prediabetes and T2D were 1.66 (1.09–2.51) and 2.47 (1.21–5.04). Conclusions: The highest risks for T2D in midlife were associated after traditional and floundering trajectories in men and women and after self-employment trajectory in women

A bidirectional Mendelian randomisation study to evaluate the relationship between body constitution and hearing loss

Abstract Hearing loss and hearing disorders represent possible mediating pathways in the associations between noise exposures and non-auditory health outcomes. In this context, we assessed whether the noise-obesity associations should consider hearing functions as possible mediators and applied Mendelian randomisation (MR) to investigate causal relationships between body constitution and hearing impairments. We obtained genetic associations from publicly available summary statistics from genome-wide association studies in European ancestry adult populations (N= from 210,088 to 360,564) for (i) body constitution: body mass index (BMI), waist circumference (WC) and body fat percentage (BFP), and (ii) hearing loss: sensorineural hearing loss, noise-induced hearing loss, and age-related hearing impairment (ARHI). We employed colocalisation analysis to investigate the genetic associations for BMI and ARHI liability within an FTO locus. We conducted bi-directional MR for the ‘forward’ (from body constitution to hearing) and ‘reverse’ directions. We applied the random effects inverse variance-weighted method as the main MR method, with additional sensitivity analyses. Colocalisation analysis suggested that BMI and ARHI shared a causal variant at the FTO gene. We did not find robust evidence for causal associations from body constitution to hearing loss and suggested that some associations may be driven by FTO variants. In the reverse analyses, ARHI was negatively associated with BMI [effect size – 0.22 (95% CI – 0.44 to – 0.01)] and BFP [effect size – 0.23 (95% CI – 0.45 to 0.00)], supporting the notion that ARHI may diminish body constitution. Finally, our data suggest that there is no strong evidence that hearing explains the association between noise exposure and body constitution.Abstract Hearing loss and hearing disorders represent possible mediating pathways in the associations between noise exposures and non-auditory health outcomes. In this context, we assessed whether the noise-obesity associations should consider hearing functions as possible mediators and applied Mendelian randomisation (MR) to investigate causal relationships between body constitution and hearing impairments. We obtained genetic associations from publicly available summary statistics from genome-wide association studies in European ancestry adult populations (N= from 210,088 to 360,564) for (i) body constitution: body mass index (BMI), waist circumference (WC) and body fat percentage (BFP), and (ii) hearing loss: sensorineural hearing loss, noise-induced hearing loss, and age-related hearing impairment (ARHI). We employed colocalisation analysis to investigate the genetic associations for BMI and ARHI liability within an FTO locus. We conducted bi-directional MR for the ‘forward’ (from body constitution to hearing) and ‘reverse’ directions. We applied the random effects inverse variance-weighted method as the main MR method, with additional sensitivity analyses. Colocalisation analysis suggested that BMI and ARHI shared a causal variant at the FTO gene. We did not find robust evidence for causal associations from body constitution to hearing loss and suggested that some associations may be driven by FTO variants. In the reverse analyses, ARHI was negatively associated with BMI [effect size – 0.22 (95% CI – 0.44 to – 0.01)] and BFP [effect size – 0.23 (95% CI – 0.45 to 0.00)], supporting the notion that ARHI may diminish body constitution. Finally, our data suggest that there is no strong evidence that hearing explains the association between noise exposure and body constitution

Maternal and infant prediction of the child BMI trajectories : studies across two generations of Northern Finland birth cohorts

AbstractBackground/objective: Children BMI is a longitudinal phenotype, developing through interplays between genetic and environmental factors. Whilst childhood obesity is escalating, we require a better understanding of its early origins and variation across generations to prevent it.Subjects/methods: We designed a cross-cohort study including 12,040 Finnish children from the Northern Finland Birth Cohorts 1966 and 1986 (NFBC1966 and NFBC1986) born before or at the start of the obesity epidemic. We used group-based trajectory modelling to identify BMI trajectories from 2 to 20 years. We subsequently tested their associations with early determinants (mother and child) and the possible difference between generations, adjusted for relevant biological and socioeconomic confounders.Results: We identified four BMI trajectories, ‘stable-low’ (34.8%), ‘normal’ (44.0%), ‘stable-high’ (17.5%) and ‘early-increase’ (3.7%). The ‘early-increase’ trajectory represented the highest risk for obesity. We analysed a dose-response association of maternal pre-pregnancy BMI and smoking with BMI trajectories. The directions of effect were consistent across generations and the effect sizes tended to increase from earlier generation to later. Respectively for NFBC1966 and NFBC1986, the adjusted risk ratios of being in the early-increase group were 1.08 (1.06–1.10) and 1.12 (1.09–1.15) per unit of pre-pregnancy BMI and 1.44 (1.05–1.96) and 1.48 (1.17–1.87) in offspring of smoking mothers compared to non-smokers. We observed similar relations with infant factors including birthweight for gestational age and peak weight velocity. In contrast, the age at adiposity peak in infancy was associated with the BMI trajectories in NFBC1966 but did not replicate in NFBC1986.Conclusions: Exposures to adverse maternal predictors were associated with a higher risk obesity trajectory and were consistent across generations. However, we found a discordant association for the timing of adiposity peak over a 20-year period. This suggests the role of residual environmental factors, such as nutrition, and warrants additional research to understand the underlying gene–environment interplay.Abstract Background/objective: Children BMI is a longitudinal phenotype, developing through interplays between genetic and environmental factors. Whilst childhood obesity is escalating, we require a better understanding of its early origins and variation across generations to prevent it. Subjects/methods: We designed a cross-cohort study including 12,040 Finnish children from the Northern Finland Birth Cohorts 1966 and 1986 (NFBC1966 and NFBC1986) born before or at the start of the obesity epidemic. We used group-based trajectory modelling to identify BMI trajectories from 2 to 20 years. We subsequently tested their associations with early determinants (mother and child) and the possible difference between generations, adjusted for relevant biological and socioeconomic confounders. Results: We identified four BMI trajectories, ‘stable-low’ (34.8%), ‘normal’ (44.0%), ‘stable-high’ (17.5%) and ‘early-increase’ (3.7%). The ‘early-increase’ trajectory represented the highest risk for obesity. We analysed a dose-response association of maternal pre-pregnancy BMI and smoking with BMI trajectories. The directions of effect were consistent across generations and the effect sizes tended to increase from earlier generation to later. Respectively for NFBC1966 and NFBC1986, the adjusted risk ratios of being in the early-increase group were 1.08 (1.06–1.10) and 1.12 (1.09–1.15) per unit of pre-pregnancy BMI and 1.44 (1.05–1.96) and 1.48 (1.17–1.87) in offspring of smoking mothers compared to non-smokers. We observed similar relations with infant factors including birthweight for gestational age and peak weight velocity. In contrast, the age at adiposity peak in infancy was associated with the BMI trajectories in NFBC1966 but did not replicate in NFBC1986. Conclusions: Exposures to adverse maternal predictors were associated with a higher risk obesity trajectory and were consistent across generations. However, we found a discordant association for the timing of adiposity peak over a 20-year period. This suggests the role of residual environmental factors, such as nutrition, and warrants additional research to understand the underlying gene–environment interplay

Genetic fine-mapping from summary data using a nonlocal prior improves the detection of multiple causal variants

AbstractMotivation: Genome-wide association studies (GWAS) have been successful in identifying genomic loci associated with complex traits. Genetic fine-mapping aims to detect independent causal variants from the GWAS-identified loci, adjusting for linkage disequilibrium patterns.Results: We present “FiniMOM” (fine-mapping using a product inverse-moment prior), a novel Bayesian fine-mapping method for summarized genetic associations. For causal effects, the method uses a nonlocal inverse-moment prior, which is a natural prior distribution to model non-null effects in finite samples. A beta-binomial prior is set for the number of causal variants, with a parameterization that can be used to control for potential misspecifications in the linkage disequilibrium reference. The results of simulations studies aimed to mimic a typical GWAS on circulating protein levels show improved credible set coverage and power of the proposed method over current state-of-the-art fine-mapping method SuSiE, especially in the case of multiple causal variants within a locus.Abstract Motivation: Genome-wide association studies (GWAS) have been successful in identifying genomic loci associated with complex traits. Genetic fine-mapping aims to detect independent causal variants from the GWAS-identified loci, adjusting for linkage disequilibrium patterns. Results: We present “FiniMOM” (fine-mapping using a product inverse-moment prior), a novel Bayesian fine-mapping method for summarized genetic associations. For causal effects, the method uses a nonlocal inverse-moment prior, which is a natural prior distribution to model non-null effects in finite samples. A beta-binomial prior is set for the number of causal variants, with a parameterization that can be used to control for potential misspecifications in the linkage disequilibrium reference. The results of simulations studies aimed to mimic a typical GWAS on circulating protein levels show improved credible set coverage and power of the proposed method over current state-of-the-art fine-mapping method SuSiE, especially in the case of multiple causal variants within a locus

The association between diabetes and cognitive changes during aging

AbstractBackground/Objectives:Worldwide, we are observing a rising prevalence of dementia and mild cognitive impairments that often co-occur with the heightened incidence of non-communicable diseases in the elderly. It is suggested that type 2 diabetes and defects in glucose metabolism might predispose to poorer cognitive performances and more rapid decline in old age.Methods:To address existing knowledge gaps in this area, we systematically reviewed the literature to identify whether patients with type 2 diabetes (T2DM) and pre-diabetes are at a higher risk of poorer cognitive performance, and whether the risk (if any) might affect specific cognitive abilities. We concentrated the review on elderly individuals (65 years or older) at intake. In total, 3251 original articles were retrieved, of which 17 met our inclusion and quality control criteria, which comprised 12 structured questions used to define the articles.Results:11 of 17 studies found a statistically significant decline in cognition among individuals who had T2DM or pre-diabetes compared to their non-diabetic counterparts. The association between diabetes and cognitive decline was not always clear, and the extent of the cognitive tests used seemed to have the greatest effect on the results.Conclusion:Focusing on a population age 65 years and over, we found insufficient evidence to support an association between pre-diabetes stages and mild cognitive impairment. However, there is consistent evidence to support diabetes as an independent risk factor for low cognitive ability in the elderly. Finally, we found insufficient evidence to support effect of T2DM on distinct cognitive ability due to the scarcity of comparable findings.Abstract Background/Objectives:Worldwide, we are observing a rising prevalence of dementia and mild cognitive impairments that often co-occur with the heightened incidence of non-communicable diseases in the elderly. It is suggested that type 2 diabetes and defects in glucose metabolism might predispose to poorer cognitive performances and more rapid decline in old age. Methods:To address existing knowledge gaps in this area, we systematically reviewed the literature to identify whether patients with type 2 diabetes (T2DM) and pre-diabetes are at a higher risk of poorer cognitive performance, and whether the risk (if any) might affect specific cognitive abilities. We concentrated the review on elderly individuals (65 years or older) at intake. In total, 3251 original articles were retrieved, of which 17 met our inclusion and quality control criteria, which comprised 12 structured questions used to define the articles. Results:11 of 17 studies found a statistically significant decline in cognition among individuals who had T2DM or pre-diabetes compared to their non-diabetic counterparts. The association between diabetes and cognitive decline was not always clear, and the extent of the cognitive tests used seemed to have the greatest effect on the results. Conclusion:Focusing on a population age 65 years and over, we found insufficient evidence to support an association between pre-diabetes stages and mild cognitive impairment. However, there is consistent evidence to support diabetes as an independent risk factor for low cognitive ability in the elderly. Finally, we found insufficient evidence to support effect of T2DM on distinct cognitive ability due to the scarcity of comparable findings

Body size during adulthood, but not in childhood, associates with endometriosis, specifically in the peritoneal subtype : population-based life-course data from birth to late fertile age

AbstractIntroduction:Endometriosis is a common gynecological condition causing chronic pain and infertility. Only limited data exist on body size during childhood and adolescence in affected women. A leaner body shape has been associated with endometriosis in adults. However, longitudinal follow-up data from birth to adulthood are lacking. The aim of this study was to assess the association between body size and endometriosis from birth to age 46 years. We also performed in-depth analysis of the endometriosis subtypes.Material and methods:This was a population-based study including 96% of the children born in Northern Finland in 1966. Endometriosis case identification was based on (a) the World Health Organization’s International Statistical Classification of Diseases code documentation from national hospital discharge registers and (b) self-reported diagnosis. A total of 348 women with endometriosis (203 in subtype analysis) and 3487 women without endometriosis were identified. Pregnancy, birth, and growth data up to adolescence were collected from welfare clinical records. Follow-up data of the Northern Finland Birth Cohort 1966 were collected at ages 14, 31, and 46 years through postal questionnaires and clinical examinations and included height, weight, and waist and hip circumference measurements. The associations between endometriosis and body size were assessed using logistic regression models.Results:Body sizes in childhood and adolescence were comparable between women developing endometriosis and those not developing endometriosis. On average, the risk for endometriosis was 2% lower for every kilogram of weight (odds ratio [OR] 0.98, 95% CI 0.97–1.00) and 6% lower for every body mass index unit (OR 0.94, 95% CI 0.90–0.99) at age 31. By age 46, a lower risk for peritoneal endometriosis was observed with greater weight (OR 0.95, 95% CI 0.92–0.98), weight gain from age 14 to age 46 years (OR 0.97, 95% CI 0.93–1.00), body mass index (OR 0.90, 95% CI 0.82–0.98), waist circumference (OR 0.95, 95% CI 0.92–0.99), and waist-hip ratio (OR 0.41, 95% CI 0.21–0.78).Conclusions:This study provides further evidence of the associations between endometriosis and body size and adiposity, specifically in women with peritoneal endometriosis. The associations are evident in adulthood but not in childhood or adolescence.Abstract Introduction:Endometriosis is a common gynecological condition causing chronic pain and infertility. Only limited data exist on body size during childhood and adolescence in affected women. A leaner body shape has been associated with endometriosis in adults. However, longitudinal follow-up data from birth to adulthood are lacking. The aim of this study was to assess the association between body size and endometriosis from birth to age 46 years. We also performed in-depth analysis of the endometriosis subtypes. Material and methods:This was a population-based study including 96% of the children born in Northern Finland in 1966. Endometriosis case identification was based on (a) the World Health Organization’s International Statistical Classification of Diseases code documentation from national hospital discharge registers and (b) self-reported diagnosis. A total of 348 women with endometriosis (203 in subtype analysis) and 3487 women without endometriosis were identified. Pregnancy, birth, and growth data up to adolescence were collected from welfare clinical records. Follow-up data of the Northern Finland Birth Cohort 1966 were collected at ages 14, 31, and 46 years through postal questionnaires and clinical examinations and included height, weight, and waist and hip circumference measurements. The associations between endometriosis and body size were assessed using logistic regression models. Results:Body sizes in childhood and adolescence were comparable between women developing endometriosis and those not developing endometriosis. On average, the risk for endometriosis was 2% lower for every kilogram of weight (odds ratio [OR] 0.98, 95% CI 0.97–1.00) and 6% lower for every body mass index unit (OR 0.94, 95% CI 0.90–0.99) at age 31. By age 46, a lower risk for peritoneal endometriosis was observed with greater weight (OR 0.95, 95% CI 0.92–0.98), weight gain from age 14 to age 46 years (OR 0.97, 95% CI 0.93–1.00), body mass index (OR 0.90, 95% CI 0.82–0.98), waist circumference (OR 0.95, 95% CI 0.92–0.99), and waist-hip ratio (OR 0.41, 95% CI 0.21–0.78). Conclusions:This study provides further evidence of the associations between endometriosis and body size and adiposity, specifically in women with peritoneal endometriosis. The associations are evident in adulthood but not in childhood or adolescence

Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity