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Several observations indicate that leptin has a more important role than insulin in the CNS control of energy homeostasis. For example, leptin deficiency causes severe obesity, with hyperphagia that persists despite high insulin levels. In contrast, obesity is not inducedbyinsulindeficiency.Butsuchcomparisonsarecomplicated by the critical role that insulin has in promoting both fat storage and leptin synthesis by fat cells. Because fat deposition requires insulin, weight gain cannot occur when insulin deficiency is present, even if food is consumed in large amounts. For example, in uncontrolled diabetes mellitus (the disease induced by the loss of insulin), food intake increases markedly27, but levels of both body adiposity and plasma leptin remain low in rats28 and humans29. Rather than being stored as fat, excess calories ingested in this context contribute to elevated blood glucose levels, and ultimately, much of this glucose is lost in the urine. Because both insulin and leptin levels are low in this type of diabetes, the long-recognized syndrome of ‘diabetic hyperphagia’27 could potentially result from reduced CNS signalling by insulin, leptin, or by both hormones. A recent study sought to clarify this issue by selectively replenishing leptin (but not insulin) to nondiabetic levels through exogenous leptin infusion in a rat model of uncontrolled, insulin-deficient diabetes30. Because this intervention prevented the development of diabetic hyperphagia, it was concluded that deficiency of leptin, but not insulin, is required for hyperphagia in this model. Thus, although both leptin and insulin probably participate in the CNS control of energy homeostasis, available data indicate that leptin has the more critical role. Leptin resistance and obesity The hypothesis that leptin resistance can occur in association with obesity was first suggested by the finding of elevated plasma leptin levels in obese humans13. This hypothesis suggests that some cases of human obesity may be due to reduced leptin action in the brain, andthat affected individuals are unlikely to respond to pharmacological treatment with leptin. Resistance to leptin is clearly documented in mice (for example, db/db)19 and rats (for example, fa/fa)31 bearing mutant leptin receptors, but also in mice that develop obesity for other reasons. These include mice with genetic ablation of thermogenic brown adipose tissue32, mice that lack melanocortin-4 (MC4) receptors33, agouti (Ay/a) mice34 (see later) and mice fed a highly palatable high-fat diet19. Several mechanisms may contribute to leptin resistance.