Evidence for the intra-uterine programming of adiposity in later life

Abstract

Aim: Research in animals has shown that altering foetal nutrition by under-nourishing or over-nourishing the mother or rendering her diabetic or foetal exposure to glucocorticoids and toxins can programme obesity in later life. The increased adiposity is mediated by permanent changes in appetite, food choices, physical activity and energy metabolism. In humans, increased adiposity has been shown in people who experienced foetal under-nutrition due to maternal famine or over-nutrition due to maternal diabetes. Lower birth weight (a proxy for foetal under-nutrition) is associated with a reduced adult lean mass and increased intra-abdominal fat. Higher birth-weight caused by maternal diabetes is associated with increased total fat mass and obesity in later life. There is growing evidence that maternal obesity, without diabetes, is also a risk factor for obesity in the child, due to foetal over-nutrition effects. Maternal smoking is associated with an increased risk of obesity in the children, although a causal link has not been proven. Other foetal exposures associated with increased adiposity in animals include glucocorticoids and endocrine disruptors.

Conclusions: Reversing the current obesity epidemic will require greater attention to, and better understanding of, these inter-generational (mother-offspring) factors that programme body composition during early development.

Figure 1. The fetal programming hypothesis; adult chronic disease resulting from the effects of fetal under-nutrition on the development of different tissues

Fetal under-nutrition can occur because of an inadequate maternal diet, inability of the mother to mobilise and transport sufficient nutrients, or an impaired vascular and placental supply line to the fetus. It can also occur if there is high fetal demand, for example because of faster growth. Changes in fetal structure and physiology occur because of a simple lack of the nutrients or building blocks required to construct high-quality organs and tissues, or because of adaptations to reduce nutrient demand eg by slowing fetal growth or prioritising essential organs. Endocrine systems (especially for hormones that regulate fetal growth and maturation) are re-set, and tissues are supported or sacrificed differentially. It is hypothesised that the resulting metabolic changes persist and increase the risk of developing diabetes and cardiovascular disease, especially if additional stressors are acquired in later life (such as obesity and physical inactivity).

Figure 2. Increased adiposity in adult offspring of dams fed on a globally restricted diet during pregnancy

Offspring from undernourished (UN) mothers are shorter and lighter at birth than those born from ad-libitum (AD) fed mothers. UN animals remain shorter as adults but exhibit increased fat mass compared to AD animals. The increased adiposity is amplified in the presence of a postnatal high fat (HF) diet. Reproduced with permission from Bentham Science Publishers Ltd: Vickers MH et al. Current Drug Targets 2007; 8: 923-34.

Figure 3. Animal models showing fetal programming of body composition and cardio-metabolic outcomes

There is an extensive literature on research in animal models showing that a variety of maternal exposures during pregnancy influence body composition and metabolism in the adult offspring. The maternal exposures include both under-nutrition and over-nutrition, and may or may not be associated with changes in birth weight (Gardner et al. 1998, Vickers et al. 2007, Taylor and Poston 2007, Warner and Ozanne 2010).

Figure 4. The muscle-thin but adipose (‘thin-fat’) Indian newborn

Newborns in India are lighter than white Caucasian babies born in the UK (mean birth weight 2.7-2.9 kg v 3.5 kg) and have a reduced abdominal circumference (suggesting smaller viscera) and arm circumference (less muscle) but similar skinfold thickness. They are thus muscle-thin but relatively adipose. These features are also present in Indian children and adults, and contribute to an increased risk of insulin resistance and diabetes (Yajnik et al. 2003; Krishnaveni et al. 2005).

Figure 5. The prevalence of obesity among young Dutch men whose mothers were exposed or unexposed to famine during pregnancy

Men whose mothers lived in famine-affected areas during early pregnancy had an increased risk of obesity compared with controls whose mothers lived outside the famine areas or whose mothers were exposed to famine before pregnancy. Maternal exposure during late pregnancy or the early post-natal period was associated with a lower risk of obesity. Obesity was defined by a weight for height 120% or more above the (then) WHO standard. Reproduced with permission from the Massachusetts Medical Society (MMS): Ravelli et al. NEJM 1976;295:349-353

Figure 6. Adult body mass index according to categories of birth weight among Hertfordshire men aged 60-70 (n=845)

Adult body mass index and the prevalence of obesity increase with increasing birth weight. There is a small increase in BMI in the lowest birth weight categories.

Figure 7. Differences in triceps skinfold thickness (TSF), subscapular skinfold thickness (SSF) and arm fat area (AFA) among Nepali children aged 6-8 y whose mothers received supplements containing vitamin A and other micronutrients in pregnancy compared with the control group (vitamin A alone)

Children of mothers who were randomised to receive vitamin A, iron, folic acid and zinc during pregnancy had thinner skinfolds and smaller arm fat area at age 6-8 years than children of control mothers (vitamin A alone, represented by the zero line). Reproduced with permission from Stewart CP et al. Am J Clin Nutr 2009;90:132-40.

Figure 8. Subscapular skinfold thickness from birth to age 9 years among the daughters of South Indian mothers who developed gestational diabetes compared with controls

Children of GDM mothers were more adipose at birth than children born to non-diabetic mothers. The difference in adiposity diminished between birth and the age of one year, but increased again, and progressively widened after 2 years. Copyright 2003 American Diabetes Association. From Krishnaveni et al. Diabetes Care, Vol 33:402-4. Reproduced by permission of The American Diabetes Association.

Figure 9. Maternal obesity and offspring obesity

Maternal adiposity and obesity could be linked to child adiposity and obesity by a number of mechanisms.

Figure 10. The prevalence of childhood obesity according to weight categories of mothers and fathers

Studies comparing mother-child and father-child BMI associations show similar effects from both parents. Reproduced with permission from Whitaker 2010 KL et al. Am J Clin Nutr 2010;91:1560-7.

Figure 11. Prevalence of overweight and obesity among children born before and after maternal bariatric surgery

The prevalence of overweight and obesity is higher among children born to obese mothers before they underwent bariatric surgery than among children born after surgery. Reproduced with permission from Kral JG et al. Pediatrics 2006;118:e1644-9.

Figure 12. Meta-analysis of studies linking maternal smoking and child overweight

The risk of overweight and obesity is increased in children of mothers who smoked during pregnancy. Reproduced by permission from Macmillan Publishers Ltd: Oken E et al. Int J Obes 2008;32:201-10.

Figure 13. Hypothalamic pathways regulating appetite and feeding behaviour

Appetite and feeding behaviour are regulated by the arcuate nucleus and other hypothalamic nuclei, which respond to leptin, insulin and other incoming signals of the individual’s nutritional status. During intra-uterine life, fetal leptin and insulin play a role in the development of these nuclei and their connections. Research in animal models has shown altered hypothalamic structure and function in offspring according to nutritional exposures in the mother.