Leptin - Mechanism of Action

Mechanism of Action

Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), that in turn are encoded by a single gene, LEPR. Ob-Rb is the only receptor isoform that can signal intracellularly via the Jak-Stat and MAPK signal transduction pathways, and is present in hypothalamic nuclei.

Whether leptin can cross the blood–brain barrier to access receptor neurons is unknown, because the blood–brain barrier is attenuated in the area of the median eminence, close to where the NPY neurons of the arcuate nucleus are located. Leptin is generally thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.

Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to presumably effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of endocannabinoids, responsible for increasing appetite. Other intracellular pathways are activated by leptin, but less is known about how they function in this system. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.

Leptin action is recognized to be more decentralized than previously assumed. In addition to its endocrine action at a distance (from adipose tissue to brain), leptin also acts as a paracrine mediator.