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Endocrinology Vol. 149, No. 11 5345-5347
Copyright © 2008 by The Endocrine Society

Fetal Programming from Maternal Obesity: Eating Too Much for Two?

David R. Grattan

Centre for Neuroendocrinology and Department of Anatomy and Structural Biology University of Otago, Dunedin, New Zealand

Address all correspondence and requests for reprints to: David R. Grattan, Centre for Neuroendocrinology, and Department of Anatomy and Structural Biology, University of Otago, P.O. Box 913, Dunedin, New Zealand. E-mail: dave.grattan{at}anatomy.otago.ac.nz.

The marked increase in the prevalence of obesity over the past 20 yr has focused research attention on mechanisms underlying the control of body weight. The relatively rapid onset of the "obesity epidemic" suggests that it is a consequence of environmental or epigenetic influences on a susceptible genome rather than the result of a major genetic change. A combination of epidemiological studies, which have shown strong associations between birth weight and subsequent bodyweight phenotype (1), and animal models using altered maternal or neonatal food intake (2), have convincingly shown that low birth weight is associated with increased risk to the life-long health of the offspring (3). Intrauterine growth restriction, either from maternal undernutrition or placental insufficiency, appears to program the offspring for conditions of energy insufficiency, resulting in obesity and metabolic syndrome in the offspring when exposed to normal postnatal nutrition. This effect is even more dramatic if the offspring are then exposed to an environmental challenge, such as a high-fat diet. The fetal programming effect may be associated with methylation of some genes (3) and is characterized by leptin resistance and reduced expression of anorectic peptides in the hypothalamus (4).

Although much attention has been focused on the effects of maternal undernutrition, such a condition may be relatively rare in Western societies, and the opposite problem may be more likely to occur (2). Consistent with the rising incidence of obesity in adult populations worldwide, there has been a 2-fold rise in women identified as obese during pregnancy (5). Over 40% of women exceed the Institute of Medicine Guidelines for optimal weight gain during pregnancy (6), and maternal obesity increases the risk of pregnancy complications, including hypertension, preeclampsia, and gestational diabetes (7). In fact, obesity is now considered "the most common clinical risk factor encountered in obstetric practice" (8). Moreover, it is becoming clear that maternal overnutrition, like maternal undernutrition, can also predispose offspring to develop obesity and type 2 diabetes (2, 9). Whether fetal programming by maternal obesity involves the same mechanisms as that of maternal undernutrition remains to be fully characterized.

In the current issue of Endocrinology, Margaret Morris and colleagues (10) provide new insights into the mechanisms underlying fetal programming effects of maternal overnutrition. They found that female rats that develop obesity due to a high-fat diet before and during pregnancy have offspring that are profoundly susceptible to obesity. At 20 d of age, male offspring bred from obese dams were over 40% heavier than control animals, with increased fat and elevated levels of leptin. If these animals were further subjected to postnatal overnutrition, by reducing the pup number to three per lactating female, then the effect on their body weight phenotype as adults was even more profound. Maternal obesity also had a detrimental impact on glucose metabolism in the offspring, reflected by impaired glucose tolerance and reduced expression of glucose sensors and glucose transporters in the hypothalamus. The fetal programming effect of maternal obesity during pregnancy appeared to be mediated by long-term changes in peptide expression in the hypothalamic circuits that regulate food intake. Maternal obesity was associated with increased levels of the orexigenic peptide, neuropeptide Y (NPY), in the offspring, together with reduced levels of proopiomelanocortin (POMC), the precursor for the major anorectic neuropeptide, {alpha}-MSH (10). These changes may be secondary to the development of leptin resistance in the neonate (11).

Interestingly, fetal programming induced by maternal undernutrition (4) and post natal overnutrition (12), have also been associated with long-term changes in hypothalamic NPY and POMC, similar to those observed by Morris and colleagues (10). Hence, both forms of metabolic imbalance during pregnancy seem to result in permanent alteration in the same hypothalamic circuits, suggesting that there might be a common mechanism. Neurons expressing POMC and NPY continue to mature for up to three weeks after birth in rats (13, 14), providing a developmental window in which maternal and fetal hormones could permanently program appetite regulatory centers (15, 16). The critical player is likely to be leptin itself. Absence of leptin, such as occurs in ob/ob mice, has been shown to permanently alter neuronal projections from the arcuate nucleus, and this can be prevented by administration of leptin during a critical period of neonatal development (15). The adverse metabolic programming effect of maternal undernutrition can also be prevented by neonatal administration of leptin (17, 18), suggesting that a lack of leptin is responsible for the programming effect in that model. Neonatal mice from underfed mothers experience a premature activation of the neonatal leptin surge, rather than a complete lack of leptin (19), perhaps altering the timing or duration of this developmental signal. Unlike maternal undernutrition, maternal obesity is associated with elevated leptin in the neonate (10). The high leptin, associated with elevated NPY and reduced POMC, is suggestive of leptin resistance. Interestingly, rats that are genetically prone to diet-induced obesity (20) also show leptin resistance early in life, before the development of obesity, associated with impaired development of arcuate projections to the paraventricular nucleus (21). Thus, it seems likely that perinatal perturbations of leptin action, either through reduced leptin availability or through hypothalamic leptin resistance, might be a common mechanism by which either low or high perinatal nutrition could permanently alter hypothalamic circuits (see Fig. 1Go).


Figure 1
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  		FIG. 1. The U-shaped curve represents the relationship between perinatal nutrition and subsequent risk of metabolic syndrome in adulthood, with increased risk of developing obesity coming from both under- and overnutrition in the perinatal period. Expression of appetite regulatory peptides in the hypothalamus are altered in a similar manner in offspring from both under- and overnutrition models, suggesting that common mechanisms might underlie each phenotype. Perinatal perturbations in leptin action may underlie both phenotypes, due to reduced leptin or leptin resistance during critical developmental stages resulting in permanent alterations in hypothalamic circuitry.

 
Although pre- and postnatal overnutrition had an additive effect on the metabolic phenotype of the offspring (10), in utero overnutrition from maternal obesity appeared to exert a stronger influence than postnatal overnutrition alone. Similarly, maternal undernutrition can cause the development of obesity in the adult offspring, even when postnatal nutrition during lactation and after weaning is normal (22). Thus, it is becoming clear that optimal maternal body weight during pregnancy, associated with appropriate levels of fetal nutrition, are absolutely critical to the short and long term well-being of both mother and child. For the mother, this represents a significant challenge to her body weight homeostasis. Under most conditions, body weight is tightly regulated to match energy intake with energy expenditure to an extraordinary degree of accuracy (23, 24). Hyperphagia and leptin resistance (25, 26) occur during pregnancy, however, resulting in increased deposition of adipose tissue. In lean individuals, this is an adaptive response driven by the hormonal changes associated with pregnancy (27, 28, 29), allowing the mothers to store energy in preparation for the high metabolic demands of the forthcoming lactation (30). In the current "obesogenic" environment, however, this adaptation will make it extremely hard for women to regulate their food intake, especially those already predisposed to obesity. It is now clear that this prenatal state of hypernutrition may have long-term consequences on the developing offspring, and this knowledge must impact on obstetric practice.


   Footnotes
 
Disclosure Statement: The author has nothing to disclose.

See article p. 5348.

Abbreviations: NPY, Neuropeptide Y; POMC, proopiomelanocortin.

Received July 24, 2008.

Accepted for publication August 6, 2008.


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