Epigenetics and metabolism in 2014: Metabolic programming--knowns, unknowns and possibilities.

Studies published in 2014 have helped in our understanding of the epigenetic mechanisms by which suboptimal nutritional exposures during in utero development are transmitted to subsequent generations through both the maternal and paternal line. Advances include identification of common loci that are vulnerable to in utero under-nutrition and over-nutrition as well as those that occur tissue-wide.S. E. Ozanne is receiving grants from the British Heart Foundation (PG/13/46/30329), Diabetes UK (12/0004508), the European Union (Seventh Framework Programme EarlyNutrition under Grant agreement no. 289346) and Medical Research Council (MRC_MC_UU_12012/4).This is the accepted manuscript. The final version is available from http://www.nature.com/nrendo/journal/v11/n2/full/nrendo.2014.218.html

Non-Genetic Transmission of Obesity - It's in Your Epigenes.

Obesity and its related metabolic comorbidities can be inherited across generations through non-genetic mechanisms. In a recent report, Huypens et al., using an in vitro fertilization approach, provide evidence that exposure to a high-fat diet modifies egg and sperm epigenetic information, rendering the progeny more prone to obesity.Our research is supported by the MRC (MC_UU_12012/4) and the British Heart Foundation (FS/12/64/30001 and PG/14/20/30769).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Elsevier

Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis.

A wealth of animal and human studies demonstrate that perinatal exposure to adverse metabolic conditions - be it maternal obesity, diabetes or under-nutrition - results in predisposition of offspring to develop obesity later in life. This mechanism is a contributing factor to the exponential rise in obesity rates. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of energy homeostasis as an underlying cause. Perinatal development of the hypothalamus (a brain region key to metabolic regulation) is plastic and sensitive to metabolic signals during this critical time window. Recent research in non-human primate and rodent models has demonstrated that exposure to adverse maternal environments impairs the development of hypothalamic structure and consequently function, potentially underpinning metabolic phenotypes in later life. This review summarizes our current knowledge of how adverse perinatal environments program hypothalamic development and explores the mechanisms that could mediate these effects.SEO receives funding from the British Heart Foundation and is a member of the MRC Metabolic Diseases Unit. LD is a Sir Henry Wellcome Post-Doctoral Fellow.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.yfrne.2015.08.00

Early nutrition, epigenetics, and cardiovascular disease.

PURPOSE OF REVIEW: Here, we provide a summary of the current knowledge on the impact of early life nutrition on cardiovascular diseases that have emerged from studies in humans and experimental animal models. The involvement of epigenetic mechanisms in the Developmental Origins of Health and Disease will be discussed in relation to the implications for the heart and the cardiovascular system. RECENT FINDINGS: Environmental cues, such as parental diet and a suboptimal in utero environment can shape growth and development, causing long-lasting cardiometabolic perturbations. Increasing evidence suggest that these effects are mediated at the epigenomic level, and can be passed onto future generations. In the last decade, epigenetic mechanisms (DNA methylation, histone modifications) and RNA-based mechanisms (microRNAs, piRNAs, and tRNAs) have therefore emerged as potential candidates for mediating inheritance of cardiometabolic diseases. SUMMARY: The burden of obesity and associated cardiometabolic diseases is believed to arise through interaction between an individual's genetics and the environment. Moreover, the risk of developing poor cardiometabolic health in adulthood is defined by early life exposure to pathological cues and can be inherited by future generations, initiating a vicious cycle of transmission of disease. Elucidating the molecular triggers of such a process will help tackle and prevent the uncontrolled rise in obesity and cardiometabolic disease.Our research is supported by the Medical Research Council (MRC; MC_UU_12012/4) and the British Heart Foundation (FS/12/64/30001 and PG/14/20/30769).This is the author accepted manuscript. The final version is available from Wolters Kluwer via http://dx.doi.org/10.1097/MOL.0000000000000338

Programming of cardiovascular disease across the life-course.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting both developed and developing countries. Whilst it is well recognized that our risk of CVD can be determined by the interaction between our genetics and lifestyle, this only partly explains the variability at the population level. Based on these well-known risk factors, for many years, intervention and primary prevention strategies have focused on modifying lifestyle factors in adulthood. However, research shows that our risk of CVD can be pre-determined by our early life environment and this area of research is known as the Developmental Origins of Health and Disease. The aim of this review is to evaluate our current understanding of mechanisms underlying the programming of CVD. This article is part of a special issue entitled CV Aging.H.L. Blackmore is funded by the British Heart Foundation. S.E. Ozanne is a member of the MRC Metabolic Diseases Unit and funded by MRC grantMC_UU_12012/4.This is the accepted manuscript of a paper published in the Journal of Molecular and Cellular Cardiology (Blackmore HL, Ozanne SE, Journal of Molecular and Cellular Cardiology 2014, doi:10.1016/j.yjmcc.2014.12.006)

Developmental programming by maternal obesity in 2015: Outcomes, mechanisms, and potential interventions.

This article is part of a Special Issue "SBN 2014". Obesity in women of child-bearing age is a growing problem in developed and developing countries. Evidence from human studies indicates that maternal BMI correlates with offspring adiposity from an early age and predisposes to metabolic disease in later life. Thus the early life environment is an attractive target for intervention to improve public health. Animal models have been used to investigate the specific physiological outcomes and mechanisms of developmental programming that result from exposure to maternal obesity in utero. From this research, targeted intervention strategies can be designed. In this review we summarise recent progress in this field, with a focus on cardiometabolic disease and central control of appetite and behaviour. We highlight key factors that may mediate programming by maternal obesity, including leptin, insulin, and ghrelin. Finally, we explore potential lifestyle and pharmacological interventions in humans and the current state of evidence from animal models.NCP holds a Wellcome Trust PhD studentship; SEO is a member of the MRC Metabolic Diseases Unit and is funded by MRC grant MC_UU_12012/4.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.yhbeh.2015.06.01

Nutrition in early life and age-associated diseases.

The prevalence of age-associated disease is increasing at a striking rate globally. It is known that a strong association exists between a suboptimal maternal and/or early-life environment and increased propensity of developing age-associated disease, including cardiovascular disease (CVD), type-2 diabetes (T2D) and obesity. The dissection of underlying molecular mechanisms to explain this phenomenon, which is known as 'developmental programming' is still emerging; however three common mechanisms have emerged in many models of developmental programming. These mechanisms are (a) changes in tissue structure, (b) epigenetic regulation and (c) accelerated cellular ageing. This review will examine the epidemiological evidence and the animal models of suboptimal maternal environments, focusing upon these molecular mechanisms and will discuss the progress being made in the development of safe and effective intervention strategies which ultimately could target those 'programmed' individuals who are known to be at-risk of age-associated disease.British Heart Foundation [Grant IDs: PG/09/037/27387, FS/09/029/27902]; Medical Research Council [Grant ID: MC UU 12012/4]This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.arr.2016.08.00

Maternal diet, aging and diabetes meet at a chromatin loop.

We have recently demonstrated that exposure to a suboptimal diet during early development leads to abnormal epigenetic regulation of a promoter-enhancer interaction at the gene encoding HNF-4α, a key transcription factor required for pancreatic β-cell differentiation and glucose homeostasis. In addition, our studies revealed that the suboptimal maternal diet amplifies the age-associated epigenetic silencing of this locus. In this research perspective we discuss these novel findings in the context of the growing list of epigenetic mechanisms by which the environment can affect gene activity and emphasize their implications for the understanding of the mechanistic basis of the development of type 2 diabetes with age.This work was supported by the Biotechnology and Biological Sciences Research Council, the British Heart Foundation, the FP6 Epigenome Network of Excellence programme, GlaxoSmithKline, the Nuffield Foundation, the Royal Society, the National Institute for Health Research Cambridge Biomedical Research Centre, and the Medical Research Council Centre for Obesity and Related Metabolic Disease

Sex and gender differences in developmental programming of metabolism.

BACKGROUND: The early life environment experienced by an individual in utero and during the neonatal period is a major factor in shaping later life disease risk-including susceptibility to develop obesity, diabetes, and cardiovascular disease. The incidence of metabolic disease is different between males and females. How the early life environment may underlie these sex differences is an area of active investigation. SCOPE OF REVIEW: The purpose of this review is to summarize our current understanding of how the early life environment influences metabolic disease risk in a sex specific manner. We also discuss the possible mechanisms responsible for mediating these sexually dimorphic effects and highlight the results of recent intervention studies in animal models. MAJOR CONCLUSIONS: Exposure to states of both under- and over-nutrition during early life predisposes both sexes to develop metabolic disease. Females seem particularly susceptible to develop increased adiposity and disrupted glucose homeostasis as a result of exposure to in utero undernutrition or high sugar environments, respectively. The male placenta is particularly vulnerable to damage by adverse nutritional states and this may underlie some of the metabolic phenotypes observed in adulthood. More studies investigating both sexes are needed to understand how changes to the early life environment impact differently on the long-term health of male and female individuals.Wellcome Trust, MRC, NIH, Foundation for Prader-Willi Research, The Saban Research Institut

DNA damage, cellular senescence and organismal ageing: causal or correlative?

Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing