LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action.

The adipose tissue-derived hormone, leptin, acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. In order to understand leptin action we have explored the physiological function of LRb signalling pathways, defining important roles for signal transducer and activator of transcription-3 (STAT3) in positive signalling and for LRbTyr(985)-mediated feedback inhibition in leptin signal attenuation. As the cells on which leptin acts are not homogeneous, but rather represent a broadly distributed network of neurones with divergent projections and functions, it is also crucial to consider how each of these populations responds to LRb signals to contribute to leptin action. While well-known LRb-expressing neurones within the arcuate nucleus of the hypothalamus mediate crucial effects on satiety and energy expenditure, other populations of LRb-expressing neurones in the ventral tegmental area and elsewhere likely control the mesolimbic dopamine system. Additional populations of LRb-expressing neurones likely contribute to other aspects of neuroendocrine regulation. It will be important to define the molecular mechanisms by which leptin acts to regulate neurophysiology in each of these LRb-expressing neural populations in order to understand the totality of leptin action.