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The protein encoded by the obese (ob) gene, leptin, is secreted from adipose tissue and is proposed to act in the brain as an important regulator of food intake and body weight. To investigate the direct effects of leptin within the CNS, we injected 3.5 microg of either mouse or human leptin into the third ventricle (ICV) of lean Long-Evans rats or obese (fa/fa) Zucker rats, in which obesity results from a mutation in the leptin receptor gene. ICV administration of leptin reduced 4-h food intake in both deprived and non-deprived lean rats. In addition, repeated ICV administration produced a long-lasting reduction in body weight while peripheral administration of the same dose had no effect. ICV administration of the same dose of leptin into the third ventricle of obese Zucker rats did not reduce food intake. These results are consistent with the hypothesis that leptin has direct actions in the CNS as an afferent signal related to the state of energy stores in adipose tissue. Furthermore, insensitivity to these central effects of leptin may be an important determinant of obesity.

Kennedy hypothesized nearly 50 y ago that negative feedback regulation of body fat stores involves hormones that circulate in proportion to adiposity and enter the brain, where they exert inhibitory effects on food intake and energy balance. Recent studies implicate leptin and insulin as 'adiposity signals' to the brain that promote negative energy balance in two ways: by inhibiting 'anabolic' hypothalamic neuronal circuits that stimulate food intake and promote weight gain, and by activating 'catabolic' pathways that reduce food intake and body weight. Chief among candidate 'anabolic' effector pathways is the NPY=AgRP neuron, found only in the hypothalamic arcuate nucleus. These neurons make peptides that potently stimulate food intake not only by increasing neuropeptide Y (NPY) signaling, but by reducing melanocortin signaling via the release of agoutirelated peptide (AgRP), an endogenous melanocortin 3=4 receptor antagonist. Since NPY=AgRP neurons express receptors for leptin and insulin and are inhibited by these hormones, they are activated by a decrease of leptin or insulin signaling. Fasting, uncontrolled diabetes, and genetic leptin deficiency are examples of conditions in which food intake increases via a mechanism hypothesized to involve NPY=AgRP neurons. Data are reviewed which illustrate the role of these neurons in adaptive and maladaptive states characterized by hyperphagia and weight gain.