In the absence of leptin signaling, mice, like humans, grow extremely obese and develop many of the common sequellae of obesity in humans, such as diabetes and steatosis of the liver. Introduction of leptin directly into the hypothalamus potently reverses the overeating and obesity seen in leptin-deficient animals. Still, expression of the leptin receptor ObR is not limited to the hypothalamus and other regions of the brain, but also occurs in the liver and many other sites. Hence, the possibility remains that some of aspects of the leptin-deficient phenotype reflect the absence of peripheral signaling. To test the significance of various sites of central and peripheral leptin signaling, Cohen et al. have used Cre-lox technology to generate mice in which particular cell types delete the ObR gene by somatic recombination. Here, they describe the effects of ObR deficiency in the brain or the liver. Absence of neuronal ObR greatly increases body weight and induces the accumulation of fat in the liver, effects that are not seen when the ObR defect is restricted to the liver. Because obesity in the brain-specific knockout is not as severe as that in simple knockouts, it may be that OBR signaling in organs helps regulate energy homeostasis?effects that may still be revealed in other Cre/lox experiments . However, the authors note that there was considerable scatter in their data and that those animals that had most efficiently removed the ObR gene from their neurons weighed the most. The complete absence of neuronal ObR might, if it could be achieved using this technology, might therefore recapitulate all of the effects observed in Ob- or ObR-deficient animals.