Leptin and the Blood‐Brain Barrier: Curiosities and Controversies

Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation. As the major site of leptin production is peripheral, and the site of action of greatest interest is the hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain barrier (BBB) has been of great interest. We review here the ongoing research that addresses fundamental questions such as the sites of leptin resistances in obesity and other conditions, the causes of resistances and their relations to one another, the three barrier sites of entry into the CNS, why recent studies using suprapharmacological doses cannot address these questions but give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using leptin therapeutically. The current status of the controversy of whether the short form of the leptin receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is reviewed. Review of these and other topics summarizes in a new appreciation of what leptin may have actually evolved to do and what physiological role leptin resistance may play. © 2021 American Physiological Society. Compr Physiol 11:2351-2369, 2021.