Ever since Neel's proposition of the "thrifty gene" hypothesis more than 40 yr ago (1), evolutionary explanations for the origins of human obesity have assumed that our tendency to put on weight in a modern environment is the vestige of a trait that was beneficial under the more austere nutritional conditions of the past. Neel proposed that, for millions of years during the Paleolithic, humans and our hominin ancestors survived as roaming bands of foragers who faced an unpredictable food supply. Given this, an ability to capitalize on any excess energy by efficiently depositing it as fat during periods of "feast" would have boosted the chances of surviving the inevitable future "famine." We inherited our genes from ancestors who survived these recurrent ecological crises, which now leave us prone to obesity and diabetes in a contemporary environment of nutritional abundance.
From: Nutrition and Health: Adipose Tissue and Adipokines in Health and Disease Edited by: G. Fantuzzi and T. Mazzone © Humana Press Inc., Totowa, NJ
Neel's hypothesis was invaluable for stimulating interest in the evolutionary origins of human obesity. In particular, the thrifty gene model heightened awareness that the environment can change more rapidly than the genome, potentially leading to novel diseases through "mismatch" between genes and environment. Despite these important contributions, the hypothesis has difficulty explaining more recent advances in our understanding of the obesity epidemic and its health sequelae. As crosscultural data accumulate, the heterogeneity in the prevalence and health consequences of obesity are not easily reconciled with a purely gene-based model of obesity risk (2). Observations among societies experiencing ongoing nutritional transitions in Asia, Latin America, and elsewhere document a heightened metabolic disease risk for a given level of body mass index or adiposity (3-5). The hypothesis would need to be modified to explain this. Additionally, there is now evidence that famine was less common among our foraging ancestors than presumed by Neel's model (6), raising doubts about its central assumptions (2). Further complexities arise as etiological insights change; for example, current understanding of the pathogenesis of obesity-related disease now includes a significant role for immune activation, and this is not easily encompassed within the model (7).
That human metabolism is not primarily crafted to survive famine is suggested by a closer examination of the developmental trends in body composition that characterize the human lifecycle. As illustrated in Fig. 1, body fat in humans constitutes a larger percentage of weight at birth than in any other mammal so far studied (8). This is followed by a continued fast pace of fat deposition during the early postnatal months. In well-nourished populations, adiposity reaches peak levels at around the age of weaning before gradually declining to a nadir in childhood, when humans reach their lowest level of adiposity in the lifecycle before again increasing in the prepubertal phase. If the threat of famine is what molded the human metabolic propensity to deposit and maintain extra body fat, it is not obvious why children's bodies should do so little to prepare for these difficult periods. These developmental changes in body composition suggest that the evolutionary forces that selected for the size of the energy buffer during early life were primarily aimed at defending against nutritional stress that has largely subsided by mid-childhood. Indeed, the low priority placed on maintaining an energy reserve during childhood suggests that the background risk of starvation faced by our ancestors may have been smaller than often thought.
This chapter first reviews the nutritional ecology of the period spanning mid-gestation through early childhood and consider the influence that natural selection operating at this age may have had on the modern human genome and the risk of metabolic disease. We adopt a developmental perspective to move beyond Neel's model and take into account the sources and age-specific intensity of nutritional stress and natural selection. There is now substantial evidence that developmental responses to early nutritional environments can modify our genetic pattern of ontogenesis (developmental plasticity), with lasting effects on our physiology and metabolism. Secondly, we discuss evidence for several developmental pathways now known to link early environmental experiences, including nutrition, to later metabolism, weight gain, and disease. Just as Neel emphasized the past adaptive significance of genes, these newly discovered and potentially adaptive modes of developmental response may provide greater flexibility in the face of ecological change than can be achieved through the slow process of genetic change.
These considerations underscore the need to take development seriously in studies of metabolic disease. We conclude by speculating that the accelerating pace of the global obesity epidemic and its rising disease burden may be the result of two related forms of mismatch: that between the human genome and the novel lifestyle of contemporary human populations and, in more rapidly changing environments, that between the constraints imposed by developmental processes together with early nutrition and the environment and lifestyle subsequently experienced in adulthood.
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