Leptin

It is unknown whether leptin can cross the blood-brain barrier to access receptor neurons, because the blood-brain barrier is somewhat absent in the area of the median eminence, close to where the NPY neurons of the arcuate nucleus are. If it does cross the blood-brain barrier, it is unknown whether this occurs via an active or passive process. It is generally thought that leptin might enter the brain at the choroid plexus, where there is intense expression of a form of leptin receptor molecule that might act as a transport mechanism.

Once leptin has bound to the Ob-Rb receptor, it activates the molecule stat3, which is phosphorylated and travels to the nucleus, it is presumed, to effect changes in gene expression. One of the main effects on gene expression is the down-regulation of the expression of endocannabinoids, responsible—among their many other functions—for increasing appetite. There are other intracellular pathways activated by leptin, but less is known about how they function in this system. Neuronal receptors remodel in response to leptin to have a different number and different types of synapses.

Although leptin is a circulating signal that reduces appetite, in general, obese people have an unusually high circulating concentration of leptin. These people are said to be resistant to the effects of leptin, in much the same way that people with type 2 diabetes are resistant to the effects of insulin. Thus, obesity develops when people take in more energy than they use over a prolonged period of time, and this excess food intake is not driven by hunger signals, occurring in spite of the anti-appetite signals from circulating leptin. The high sustained concentrations of leptin from the enlarged fat stores result in the cells that respond to leptin becoming desensitized.

In mice, leptin is also required for male and female fertility. In mammals generally, and in humans in particular, puberty in females is linked to a critical level of body fat. When fat levels fall below this threshold (as in anorexia), the ovarian cycle stops and females stop menstruating.

Leptin is also strongly linked with angiogenesis, increasing VEGF levels.