Fetal programming of appetite for macronutrients and obesity

Abstract

Epidemiological studies have demonstrated that poor intrauterine growth is linked to non- communicable diseases in adulthood, such as type II diabetes, hypertension and coronary heart disease (Barker 1993). Obesity is a major risk factor for both these diseases and also appears to be related to early growth. Using a rat model, previous studies have demonstrated that nutritional inadequacy in utero induces hypertension in rats maintained on standard laboratory chow (SLC) post-weaning (Langley & Jackson 1994). The mediator(s) of this hypertension is unknown, but dietary and/or endocrine factors could be involved. This thesis was designed to investigate the effects on metabolism, dietary intake and body composition by manipulating the pre and postnatal diets in a rat model.

All offspring were produced by feeding rat dams either 9% or 18% casein diets during pregnancy. In both male and female offspring, glucose tolerance test profiles were similar between 9% casein and 18% (control) groups. The whole glucose load had been cleared by 60 minutes in both groups. Initial peak insulin response was lower in the 9% group however, in this group, a second peak in plasma insulin concentration (PIC) such that after 60 minutes, PIC was significantly higher than the 18% group. This suggests a degree of insulin resistance in these animals. Total carcass energy and %fat were both significantly greater in the 9% group following macronutrient self-selection feeding (MSS). These results show that exposure to a low-protein diet in utero alters fetal programming which manifests itself as an increase in body weight due to an increase in body fat.

Systolic blood pressure (SBP) was significantly elevated in the 9% group upon weaning, but this difference was only sustained when rats were maintained on standard laboratory chow (SLC). A MSS diet lowered SBP in rats from the 9% group without affecting SBP of rats from the 18% group. The relative hypertension of the 9% group was expressed again when SLC was consumed. The effects appeared more pronounced in male offspring although the trend was clearly visible in female offspring. These results indicate that diet during adulthood is critical for the expression of hypertension in this model. Since the major difference between SLC and MSS is the ratio of carbohydrate : fat ingested, it is likely that the metabolic handling of these macronutrients may, in part, underlie the expression of hypertension in this model. As these studies appeared to show similarities with the present rat model and SHR, the macronutrient intake was compared. The SHR consumed significantly less protein than both the 9% and 18% Wistar groups, and weighed significantly lighter by the end of the study. The SHR male offspring consumed less energy than the Wistar group, although this was not the case in the female offspring.

The final study compared pre-natal and post-natal diets. The SLC results confirmed those shown previously. The high-carbohydrate diet also maintains high SBP in the 9% offspring indicating that it is not a specific component in SLC causing the increase in SBP. The high- fat feeding quickly abolished and high-protein feeding gradually reversed the hypertension in the 9% group without affecting the age-related increase in SBP in the 18% group. Post-natal diet had a greater effect on PIC with the high-fat fed females requiring higher insulin levels return the glucose levels towards baseline. In female offspring there was a significant move towards an increase in the proportion of type II fibres as a result of feeding a high-protein or high-fat diet in the 9% groups which was not seen in the 18% group. These results support that both pre- and postnatal diet influence the expression of the hypertension and possibly carbohydrate metabolism in this model. This suggests that a low dietary carbohydrate intake may underlie the hypotensive effect.

To summarise, the changes which have been seen in these studies occurred without moving to the extremes of deficiency during pregnancy and could therefore be of great importance in understanding the possibility of the onset of factors which could lead to obesity and Type II diabetes in the next generation.

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