The human camel: the concept of predictive adaptive responses and the obesity epidemic (2003)

There is an epidemic of obesity, with associated type 2 diabetes and metabolic syndrome, in developed societies and in some developing societies such as parts of the Indian sub-continent and China. The consequences of this are well reviewed by Anne Dornhorst in this issue of Practical Diabetes International (pages 283–289). The epidemic brings an enormous burden of chronic disease in addition to type 2 diabetes, for example cardiovascular disease and bone and joint disorders, which will have tremendous economic and humanitarian cost. Prevention of disease is difficult if its causes are not known. As Dr Dornhorst points out, the speed of development of this problem rules out a genetic origin, although the action of early environmental factors on gene expression must be involved. It clearly results from some environmental change, and this underlines its greatest prominence in populations in transition. In part, of course, the changing environment relates to nutrition, or probably more likely the balance between energy expenditure and calorific intake. The focus on the prenatal origins of such disease has drawn attention to the ways in which developmental adaptive responses may play a part in its origin. They may involve epigenetic mechanisms of gene/environment interactions, such that gene polymorphisms that confer susceptibility produce disease in affected individuals when coupled with prenatal restriction of growth. In addition, animal studies have shown that both the metabolic and the cardiovascular effects of an impaired intrauterine environment can be passed across two or more generations, questioning the ways in which we have traditionally thought about ‘inherited’ components of disease risk. Our two research centres, along with several others worldwide, are actively involved in research into the mechanisms underlying the developmental origins of cardiovascular and metabolic disease. In addition, we feel it important to view the phenomenon from the wider perspective of human biology. In the mists of time, Homo sapiens evolved as a hunter-gatherer, adapted to surviving periods of uncertain nutrient availability and having to undertake considerable physical activity to gain food. When food was available he would deposit it as fat, as insurance against later deprivation. In developed societies we now enjoy readily available food of high caloric value, which requires little expenditure of energy to obtain. We have not evolved to cope with this change, and it seems unlikely that we will, as we now control our environment to an unprecedented degree. We are therefore to a large extent stuck with our biology and, as we strive to extend our longevity, we suffer the consequences of malfunction or impaired repair processes that evolution has not deselected because they occur after reproductive age. One of the fundamental aspects of human biology, which we share with many other species, concerns the ability of the developing organism to respond to changes in the environment by altering its body size, structure and physiological homeostatic control processes during periods of developmental plasticity. Because the embryo and fetus cannot sense the external environment directly, mechanisms have evolved for the transmission of environmental cues from the mother via the placenta. Such cues include glucocorticoids and other hormones, and also nutrients themselves, e.g. glucose and oxygen. The responses evoked in the conceptus are part of a spectrum of predictive adaptive responses (PARs). If the prediction of the postnatal environment is correct, then all is well: the PARs should confer a survival advantage to reproductive age over other members of the species. If the prediction is inappropriate, then postnatal risk of disease is greater. The most well-known example of the wider phenomenon of PARs is the thrifty phenotype – born small, with reduced skeletal muscle mass and muscle capillary density, and a tendency to insulin resistance. When such an individual is faced with the high-calorie diet/low energy demand environment of the developed world, obesity is likely in childhood and adolescence. But the processes underlying PARs also encompass the normal maternal constraint of fetal growth. This favours the maternal versus the paternal genomic drive to grow prenatally, and we are learning how this may operate at the epigenetic level via the processes of imprinting, which control expression of maternal and paternal alleles of the genes determining early growth trajectory. These processes operate even in normal pregnancies, although they are accentuated in primigravidae, in twinning and in adolescent pregnancy. We believe that such mechanisms to constrain fetal growth became necessary when Homo species adopted upright walking, so that the pelvic floor need not be too big, yet obstructed labour (with high risk of death of the mother) was avoided by ensuring that the fetus did not outgrow its mother. But these processes have a second important purpose in evolution – namely to signal to the fetus that it is likely to be born into a nutritionally deprived environment, so that it adjusts its physiology accordingly. This was essential as humans evolved as hunter-gatherers, needing to survive periods of famine as well as plenty, and to lay down fat deposits when nutrition was plentiful. It is important to remember that such maternal constraint always reduces fetal growth and induces PARs appropriate for a relatively poor postnatal environment. This may have given the advantage of a fail-safe mechanism during our evolutionary past, but it carries increased risk of disease now. If the change in the postnatal environment were the whole story underlying the epidemic of obesity, then better education and regulation of diet in youngsters, and placing a greater accent on physical activity, should do much to arrest this increase in prevalence of obesity and in its sequelae. But in fact there is evidence that the very members of the population we would wish to help are physiologically resistant to weight loss by these means. It appears that the problem not only lies in the energy-rich environment but in their response to it. Animal studies now support this idea: nutritional restriction of the rat during pregnancy leads to offspring that are not only hypertensive, have endothelial dysfunction and glucose intolerance, but that have enhanced appetite for a cafeteria diet, become obese and show low levels of physical activity. Their resemblance to the human couch-potato is striking. Thus, although lifestyle modification may help obese individuals to a degree, the seeds for the condition may have been sown before birth. In fact they may have been sown in our evolutionary past, and it is striking that our tendency to deposit truncal fat characterises the condition. Perhaps we evolved this pattern of deposition as it provided a reserve for periods of food scarcity with the minimal hindrance to movement. This is rather like the camel's hump – a fat reserve for long periods of desert survival, placed to permit movement and not to interfere with thermoregulation. It is likely that further insights into the origins of type 2 diabetes and the metabolic syndrome will come from consideration of human evolutionary and developmental biology.