R. Uher and I. A. Campbell are concerned about the generalizability of our findings, derived as they were from the study of very rare individuals with complete congenital leptin deficiency. Their comments illustrate a commonly held belief, which we believe to be largely false, that because certain human disorders are rare, they cannot valuably illuminate normal physiology. The great advantage of studying subjects in whom a hormone is completely absent, is that their physiology can be studied before and after its restoration, so that one can be more confident about the precise nature of the explanation for the phenomena observed. The history of endocrinology potently illustrates how unusual patients, often with inherited disorders, have provided important new insights into normal hormonal physiology.
The reasons for the apparent discrepancies between our study (1) and that of Uher and Campbell (2) are clear to us. The shape of the leptin “dose-response curve” is such that while its complete absence results in marked hyperphagia, even low levels of leptin dramatically correct this (3). However with plasma leptin levels within the normal range there is little relationship between leptin concentrations and food intake (3). While depriving humans of food for 24 hours results in a fall in circulating leptin, levels remain well within those seen in the normal population (2). It is therefore not surprising that no systematic changes in neuronal activation could be linked to alterations in leptin levels. We suggest that there is no conflict between our results and those of Uher et al. because these studies asked fundamentally different questions. Uher et al. addressed the question of whether 24 hours of food deprivation in humans systematically altered neuronal activation patterns to food-related visual and gustatory stimuli. Interpretation of their results is, however, challenging, as starvation results in complex endocrine and metabolic changes. We asked a simpler question, specifically focused on the biological actions of leptin. Because of the specificity of the perturbation we were able to clearly discern dramatic and specific effects of leptin on neuronal activation.
Furthermore, we would contest the assertion of Uher and colleagues that the neuroimaging methodology across the two studies was very similar. We used a blocked design (showing a total of 150 images) in order to boost power to detect food-related activations (1). It is possible that the presentation of a total of 40 images in their experiment, with a stimulus onset asynchrony of 15 seconds (2), led to reduced power to detect brain activation responses and differences in these activations between sessions. Although Uher et al. (2) recorded subjective liking they did not apparently seek to correlate state-related changes in food liking with state-related changes in food-stimulus-related activation. This association and its perturbation by leptin was one of the key findings in our study (1).
Uher and Campbell also express concern that the effects we see may be the result of developmental consequences unique to congenital leptin deficiency. Developmental effects of leptin on hypothalamic circuitry actually seem to have little relevance to humans as the life-long hyperphagia and severe obesity seen in adults with congenital leptin deficiency are entirely normalized by leptin replacement therapy, even if this is commenced in the fourth or fifth decade of life (4).
The explanatory power of rare human diseases has long been recognized. In a letter to a Dutch physician in 1657, William Harvey wrote, "nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of Nature, by careful investigation of cases of rarer forms of disease" (5).
Sadaf Farooqi, Edward Bullmore, Stephen O’ Rahilly, Paul Fletcher
Institute of Metabolic Science, Addenbrooke’s Hospital, Metabolic Research Laboratories, University of Cambridge, Cambridge CB2 2QQ, UK.
References
1. I. S. Farooqi et al., Science 341, 879 (1999).
2. R. Uher et al., Behav. Brain Res. 169, 111 (2006).
3. A. P. Coll, I. S. Farooqi, S. O'Rahilly, Cell 129(2), 251 (2007).
4. J. Licinio et al., PNAS 101(13), 4531 (2004).
5. K. Peters, Clin. Med. 4(6), 551 (2004).
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