The geometry of leptin action in the brain: more complicated than a simple ARC

Abstract

Leptin signals the repletion of fat stores, acting in the CNS to permit energy utilization by a host of autonomic and neuroendocrine processes and to decrease feeding. While much recent research has focused on the leptin-regulated circuitry of the hypothalamic arcuate nucleus (ARC), the majority of brain leptin receptor (LepRb)-expressing neurons lie outside the ARC in other CNS regions known to modulate energy balance. Each set of LepRb neurons throughout the brain presumably mediates unique aspects of leptin action, and understanding the function for LepRb-expressing neurons throughout the brain represents a crucial next step in the study of energy homeostasis.

Figure 1. Proposed model for the integrative regulation of the ARC→ PVH circuit by leptin

A simplified model “wiring” diagram of the medial hypothalamic circuitry as described in the text is shown superimposed upon an image of green fluorescent protein (GFP)-containing LepRb neurons (green) from sagittal sections of the medial hypothalamus and brainstem of mice that express GFP in LepRb neurons (Leshan et al., 2006). Each set of LepRb neurons responds not only to leptin, but also to additional stimuli. Thus, leptin acts at a number of points to enable the integration of signals of body energy status with other physiologic variables that dictate the strength of the final output signal. Note that while the PVH contains many GFP-reactive projections, few LepRb neurons reside in this output nucleus. Physiologic inputs to each nucleus are shown in yellow and putative projections from LepRb-containing neurons are denoted as green arrows.

Figure 2. Neural mechanisms by which leptin may modulate the mesolimbic DA system

Components of the mesolimbic DA system are shown superimposed upon an image of GFP-containing LepRb neurons as in Figure 1. At its core, this system contains a set of DA neurons within the VTA and that project to the striatum (including the nucleus accumbens (NAc), amygdala, and PFC) to encode the incentive salience of natural and artificial rewards. Leptin may modify the activity of the mesolimbic DA system in a number of ways, including by the direct regulation of a LepRb-expressing population of VTA DA neruons. Additionally, leptin regulates the lateral hypothalamic area (LHA- a major upstream regulator of the mesolimbic DA system) via a number of mechanisms. In addition to containing a set of LepRb-expressing neurons, the LHA contains OX neurons (pink) that project to and regulate VTA DA neurons and MCH neurons (light blue) that project to the striatum. Putative projections from LepRb-containing neurons are denoted as green arrows.