Metabolic Signaling to the Central Nervous System: Routes Across the Blood Brain Barrier

In order to maintain an ideal body weight, an organism must balance energy intake with energy expenditure. It is well known that metabolic signals derived in the periphery act in well-defined hypothalamic and brainstem neuronal circuits to control energy homeostasis. As such, peripheral signals that convey information regarding nutritional and metabolic status of the individual must be able to access and control these neuronal circuits in order to direct both food intake and energy expenditure. Within the hypothalamus, the arcuate nucleus of the hypothalamus has become recognized as a critical center in this integrated circuitry. Although there is considerable anatomical evidence indicating that the arcuate is protected by the blood brain barrier, neurons in this region have been repeatedly suggested to directly sense many circulating signals which do not readily diffuse across this barrier. In this review we will describe the hypothalamic circuitry involved in the regulation of energy homeostasis and will discuss data indicating that the arcuate nucleus is, in fact, protected by the blood brain barrier. We will then consider alternative mechanisms through which one specific circulating adipokine, leptin, can gain access to and influence central nervous sites involved in the regulation of energy homeostasis without the requirement for direct access from the peripheral circulation to arcuate neurons.