The developmental origins hypothesis The developmental origi

The developmental origins hypothesis The “developmental origins of adult disease” hypothesis originated from epidemiological studies conducted by David Barker and colleagues in Hertfordshire, England in 1989. They found that being born small for gestational age was a major risk factor for the development of cardiovascular disease later in life with significantly increased the risk of mortality from XMU-MP-1 failure [1,2]. These studies were the first of many epidemiological and animal studies that have rigorously investigated the impact of altered fetal, early postnatal and childhood growth on the development of later life diseases. Indeed, it is now unequivocally accepted that early life insults increase the susceptibility of the offspring to developing a plethora of adverse conditions in later life including, but not limited to, type 2 diabetes [3–5], insulin resistance [4–8], hypertension [1] and osteoporosis [9,10]. These early life insults to the offspring primarily originate from an adverse maternal condition prior to and/or during pregnancy, such as gestational diabetes, obesity, excessive weight gain, pre-eclampsia, smoking, undernutrition and uteroplacental insufficiency. Each of these abnormal conditions imposes negative impact on the gestational milieu and leads to important consequences for the growth and development of the fetus and health of the offspring in adulthood. Early life origins of later life disease is often referred to as ‘programming’. Defined by Hales and Barker, ‘programming’ is the “permanent or long term change in the structure or function of an organism resulting from a stimulus or insult acting at a critical period of early life” [11]. Furthermore, the adult outcomes of early life ‘programming’ are characterized by the nature of the insult and developmental responses, the timing in which the insult occurs, and the duration of the insult [12,13]. The insult most adversely affects the organs that undergo rapid growth in the offspring at the time of the insult occurring. Another phenomenon that likely contributes to early life programming events is the “predictive adaptive response”. This occurs when the fetus undergoes or initiates adaptations during gestation or early postnatal development based on the predicted postnatal nutritional environment [14–16]. For example, poor nutritional conditions during gestation may trigger metabolic adaptations in the fetus in preparation for poor nutrition after birth in order to ensure survival. However, if the resultant postnatal nutrition is abundant, then the programmed metabolic adaptations that occurred in utero will become detrimental and likely result in excess energy storage, altered postnatal growth, altered body composition (e.g. increased fat mass:lean mass) and subsequent metabolic dysfunction in later life [11,12,17]. The remainder of this review will primarily focus on 2 important and relevant questions: (1) the impact of maternal obesity and/or high fat diet during gestation on the development of metabolic disease in the adult offspring; and (2) the role of epigenetic modifications as the underlying mechanism responsible for the developmental programming of later disease. Although developmental programming is a well-established phenomenon, much of the literature is concerned with the impact of maternal undernutrition and uteroplacental insufficiency that often result in small birth weight and later life disease. However, it is becoming more apparent that the correlation between birth weight and later disease is presented with a U shaped curve; and being born large for gestational age is also a significant risk factor for later disease [18–20]. Furthermore, maternal obesity and high-fat diet are increasing in prevalence and the impact on offspring health warrants attention. Epigenetics is a relatively new field of research that is primarily concerned with the regulation of gene transcription through modifications of DNA structure, such as DNA methylation and histone methylation/acetylation. Changes in epigenetic regulation have been shown to occur in early life development in response to environmental cues and unveils new possibilities in the programming field as to the long-term impact and mechanistic insight into developmental programming.