Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition

Abstract

Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause. Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences that are induced by fetal programming. Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a behavioral trigger of adult disease. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (AD group) or at 30% of ad libitum intake, or undernutrition (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [a control diet or a hypercaloric (30% fat) diet]. Food intake in offspring from UN mothers was significantly elevated at an early postnatal age. It increased further with advancing age and was amplified by hypercaloric nutrition. UN offspring also showed elevated systolic blood pressure and markedly increased fasting plasma insulin and leptin concentrations. This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal programming and a key contributing factor in adult pathophysiology. We hypothesize that hyperinsulinism and hyperleptinemia play a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development.

Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats

“…There was no clear evidence of obesity, either defined as excess weight or excess body fat in any of the animals exposed to LP diets in utero. This is in direct contrast to the studies of Vickers et al 14,26 Although ageing brought out some subtle differences in the amount of fat relative to body weight and the distribution of fat between subcutaneous and abdominal sites, the data favour the view that undernutrition in fetal life does not programme obesity, consistent with the findings in mice. 28 However, as shown by other studies, this is a situation that may change if the animals were challenged with a high fat diet in postnatal life.…”

“…[7][8][9] The range of nutritional exposures capable of eliciting programmed responses in the developing offspring is broad, including micronutrient deficiency, [10][11][12] excess of saturated fat 13 and restriction of food intake (global nutrient restriction). 14,15 In the present paper, we report findings from a model of low protein feeding in rat pregnancy. 16 This intervention is known to promote hypertension 17 and renal dysfunction 18 in the offspring and has also been shown to shorten lifespan, 19 disturb glucose metabolism 20 and increase susceptibility to oxidative injury.…”

“…The early period (days 0-7) corresponds to the embryonic phase of development in the rat and in fact embryos only implant at around day 4.5. 7 The mid-gestation period (days [8][9][10][11][12][13][14] largely corresponds to the period of organogenesis, while late gestation (days [15][16][17][18][19][20][21][22] is the period of most rapid growth and differentiation of key structures. By feeding at these targeted periods, it is possible to identify when nutritional programming occurs and this can provide important indicators of potential mechanisms.…”

“…25 In general, the feeding behaviour of young adult rats is altered by exposure to prenatal LP diets, with hypophagia noted when a low fat diet is provided, contrasting with hyperphagia when allowed to self-select macronutrients. 25 In contrast, Vickers et al 14 have reported that the restriction of maternal food intake to pregnant rats to just 30% of ad libitum produces marked hyperphagia and clear increases in adiposity in their offspring. When provided with a high fat diet, such animals develop obesity.…”

The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

“…37 As obesity treatment entails huge costs, the development of effective strategies for primary prevention is particularly attractive. Despite epidemiological evidence from a variety of sources that perinatal nutritional factors have long-term effects on obesity predisposition, 38,39 nothing is known about which specific food components are responsible for that. The novel and main finding of this study is that the intake of moderate amounts of leptin by suckling rats prevents the development of overweight/obesity in later life.…”