Cota and colleagues (9) have provided an insightful look into the mechanism of cannabinoid action. It is particularly intriguing that a system known to be an essential part of CNS mechanisms controlling reward and memory functions has now been identified as one of the very few orexigenic components of energy-balance regulation, in which targeted gene disruption is followed by a lean phenotype. Intriguingly, the other orexigenic system that demonstrates a similar phenotype after ablation is that which produces MCH (16), which Cota et al. now directly connect to the endogenous cannabinoid system. On the other hand, the arcuate nucleus neuropeptide Y/agouti-related protein (NPY/AgRP) system, which Cota et al. demonstrate is not directly targeted by endocannabinoid action, appears to be a less critical (or a functionally more redundant) player in the chronic maintenance of energy balance (17). However, disruption of NPY Y1 or Y2 receptors, which are intricately related to some of the peptidergic neurons (18–21) that are shown by Cota et al. to express CB1 receptors, attenuate the development of type 2 diabetes (22, 23).

The hedonic component of hypercaloric nutrition (24) could possibly be targeted by a CB1 antagonist, which might be able to diminish the possibly addictive aspect of food intake in some individuals, in combination with decreasing orexigenic drive and lipogenesis. As depicted in Figure 1, there is a redundancy of connectivity among hypothalamic peptidergic systems, some of which simultaneously utilize other neurotransmitters and peptides as well (25). An intricate relationship exists between axonal processes and postsynaptic targets of the various systems, but interactions also occur between different axon terminals presynaptically. Thus, to understand endocannabinoid signaling within the hypothalamus, it will be necessary to combine classical light and electron microscopic analyses of chemically identified anatomical interactions with state-of-the-art electrophysiological approaches. Such approaches have recently been used to better understand the hypothalamic signaling of two other metabolic hormones, ghrelin and leptin (26, 27). Determining the central action of these molecules will most likely require the application of interdisciplinary techniques that include neurophysiology, molecular biology, biochemistry, and pharmacology. Regarding the cannabinoid system and obesity therapies, it will be particularly important to expand experimental studies to include other brain sites, including the cortex and basal forebrain, and their functions. The anecdotal and experimental evidence of marijuana’s appetite-regulating effects also shows clear alterations of other CNS mechanisms, such as learning, memory, aggression, and addiction (10). While experimental design generally demands that one focus on only one type of behavior in the experimental system, this approach may have grave consequences for therapeutics. For example, the weight-reducing effects of an antagonist of CB1 could enhance attention, drive, and focus at the expense of emotions and social behavior. Nevertheless, as the smoke continues to clear, the cannabinoid system may prove to be an extremely promising target for the development of medications for obesity and cachexia (9).