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Associate Professor Department of Psychiatry McGill University Douglas Institute in Mental Health Montreal, Quebec, Canada
Address all correspondence and requests for reprints to: Claire-Dominique Walker, Ph.D., Associate Professor, Department of Psychiatry, McGill University, Douglas Institute in Mental Health, 6875 LaSalle Boulevard, Montreal, Quebec, Canada H4H 1R3. E-mail: waldom{at}douglas.mcgill.ca.
With the growing epidemics of childhood and adult obesity and the increasing social and medical burden for our societies, research into the long-term effects of early nutrition has become critical to understanding the underlying mechanisms and to curbing, if at all possible, the progression of the epidemics. Most of the studies in the last decades have focused on models of restricted intrauterine growth and/or maternal diabetes and neonatal overfeeding, as both these extremes are known to lead to the same adult phenotype (metabolic syndrome), which includes insulin and leptin resistance, diabetes, obesity, and hypertension (1, 2, 3). To understand the early "programming" effects of caloric intake on adult pathology, many crucial questions need answers. For instance, when is the critical timing for the fetal/neonatal dietary changes to exert enduring effects, what is the duration of the effects, what is the nature of the interactions between predisposing genes and the environmental changes that will lead to adult pathology, and what are the underlying mechanisms? In this issue of Endocrinology, Xiao et al. (4) address some of these questions by demonstrating that overfeeding during the suckling period in rat pups might permanently impair energy expenditure through altering the functional activity of brown adipose tissue (BAT). This particular adipose tissue and its specific expression of uncoupling proteins (mainly UCP1) is recognized to represent an important "gate" against obesity in rodents, although less so in humans (5). Because UCP1 uncouples mitochondrial oxidation from phosphorylation, BAT can oxidize energy substrates, particularly fatty acids, to produce heat instead of ATP.
In the report by Xiao et al., overfed pups growing in small litters display, as adults, clear impairment in BAT function and its ability to dissipate excess energy intake. Whether the primary site of action is a reduction in biochemical markers of BAT function (UCP1 expression, lipogenic enzymes supplying fuel sources, transcriptional factors, and coactivators) or a modified hypothalamic control of sympathetic outflow to this important tissue, the net consequence is that, even in a situation where the animal is not exposed to a high caloric diet, reprogramming of its BAT function by early neonatal overfeeding will be associated with an increased risk for obesity in adult life (Fig. 1
). Moreover, all is in the timing, as earlier studies using a similar overfeeding paradigm after the weaning period have failed to demonstrate such a negative effect on BAT thermogenic capacity (6). In fact, rats overfed after weaning exhibit improved thermogenic capacity as adults, consistent with the diet-induced activation of BAT that is observed in adults.
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The postnatal nutritional environment in rodents is so critical that it can even override genetic predisposing factors in the development of the obesity phenotype (8). Elegant cross-fostering experiments in which obesity-resistant pups were cross-fostered to obesity-sensitive mothers revealed that changes in milk composition, possibly changes in insulin, leptin, and fatty acid concentrations, from the obese-prone mothers were sufficient to increase adiposity and lead to insulin resistance in adulthood, despite the endogenous "obesity-resistant" genotype. Hyperinsulinemia and hyperleptinemia in pups from small litters might reprogram more extensively all hypothalamic circuits involved in energy balance (9, 10) in addition to adipose tissue metabolism (11) and energy expenditure mechanisms in the BAT, as found by Xiao et al. (4).
With the development of the various experimental models of neonatal overfeeding (7, 12, 13, 14) (small litters or higher caloric content of the maternal diet), it will be possible to differentiate whether it is the modality through which increased caloric intake occurs in pups that matters or whether the long-term outcome is independent from either increased total caloric intake or increased specific nutrient intake. In the case of small litters, increased total caloric intake by pups is likely to occur, although dams have been shown to spend less time with well-nourished pups compared with control or underfed pups (15). In the case of nutrient-specific alterations in the maternal diet (high-fat diets, high-carbohydrate diets, or combinations of both), the increased caloric intake in the offspring would reflect increased exposure to the targeted nutrient rather than overall increased caloric intake. Subtle differences in the phenotypic makeup of adults might tell us a great deal about the potential mechanisms and preferred targets.
So, what are the potential implications of these studies for the developing human baby, and should mothers dramatically reduce their caloric intake while nursing their infants? In the last decade, several studies have looked at obesity risk factors associated with breast- and bottle-feeding during different postpartum periods, and the debate is still raging. Although it is agreed that breast-feeding generally allows for a slower rate of weight gain in infants and a better distribution of calories across time of the day, both a lack of effect (16) or a beneficial effect (17) on the risk for childhood obesity have been reported. Moreover, it is possible that the benefits of breastfeeding are attenuated or reversed in children whose mothers have diabetes or are obese because the increases in caloric content and/or changes in milk composition might outweigh the benefits of breast-feeding (18, 19, 20).
With respect to the specific mechanisms related to energy expenditure such as those described by Xiao et al., it is unknown whether, in human infants, the BAT is as sensitive to the reprogramming effects of overfeeding as the rodent BAT appears to be. In humans, however, thermogenic capacity is more widely distributed over several tissues (5), and the contribution of BAT to energy expenditure in adults is smaller compared with rodents as many routes allow for energy dissipation in humans (21). In premature and term newborns, BAT function and thermogenic capacity are closely linked to feeding cycles (22, 23, 24). Termination of feeding is suggested to be caused by high temperatures brought about by stimulated BAT thermogenesis (24). The studies by Xiao et al. (4) demonstrating a proximal effect of high caloric intake to increase UCP1 expression in suckling pups would indicate a similar capacity to reach high temperatures faster in overfed pups, although this mechanism might not be so critical to turn off food intake in young pups. The contrast between high expression of UCP1 in neonates and its reduction in adult offspring suggests that the central and peripheral systems controlling BAT activity have exhausted their homeostatic capacity with time, resulting in impaired adult thermogenic responses (Fig. 1
). Maintenance of high activity in BAT might be costly after weaning off the high caloric input of maternal milk supply and, thus, adult BAT thermogenic capacity might pay the price of the neonatal suckling feast. This is not so hot after all... .
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Footnotes |
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Abbreviations: BAT, Brown adipose tissue; UCP, uncoupling protein.
Received June 4, 2007.
Accepted for publication June 18, 2007.
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