Minireview: CNS Mechanisms of Leptin Action

Abstract

Leptin is an adipocytokine that circulates in proportion to body fat to signal the repletion of long-term energy stores. Leptin acts via its receptor, LepRb, on specialized neuronal populations in the brain (mainly in the hypothalamus and brainstem) to alter motivation and satiety, as well as to permit energy expenditure and appropriate glucose homeostasis. Decreased leptin, as with prolonged caloric restriction, promotes a powerful orexigenic signal, decreases energy use via a number of neuroendocrine and autonomic axes, and disrupts glucose homeostasis. Here, we review what is known about cellular leptin action and focus on the roles for specific populations of LepRb-expressing neurons for leptin action.

Figure 1.

LepRb signaling. Leptin binds to the extracellular domain of LepRb, activating the associated Jak2 tyrosine kinase and promoting the Jak2-mediated phosphorylation of tyrosine residues 985, 1077, and 1138 of LepRb (note, numbering is that of the murine receptor). Phosphorylated Tyr985 recruits PTPN11, which initiates the ERK signaling cascade. Phosphorylated Tyr1077 and Tyr1138 recruit STAT5 and STAT3, respectively, permitting their trafficking to the nucleus to mediate the control of cognate gene expression. In addition, mechanisms that limit LepRb signaling have been defined: Socs3, whose expression is increased by leptin, binds to phosphorylated Tyr985 to blunt LepRb signaling. Also, the tyrosine phosphatases, PTP1B and TCPTP, dephosphorylate Jak2 and/or LepRb to terminate LepRb signaling. In addition, Rho kinase 1, adenosine monophosphate activated protein kinase, insulin receptor substrate (IRS)2, and SH2B1 have been shown to act downstream of LepRb, although the mechanisms by which LepRb controls these pathways have yet to be defined.

Figure 2.

Major leptin-regulated neural systems and their outputs. Shown is a schematic diagram of major leptin-regulate brain systems, in a ventral (from the bottom) view of the rodent brain. Although all structures are bilateral, they are shown on only 1 side of the brain for the sake of simplicity. Note that the ARC, NTS, and PVH are bilateral but straddle the midline. Three major roles for leptin include the control of food intake and energy expenditure (red pathways), glucose homeostasis (green pathways), and motivated behavior (blue pathways). In the hindbrain, leptin action on the NTS increases satiety; these NTS LepRb neurons make reciprocal connections with hypothalamic nuclei (ARC, DMH, and PVH) that control food intake. Leptin also acts directly on the ARC and DMH, which (in addition to their reciprocal connections with each other) share strong reciprocal connections with the major output nucleus of the hypothalamus, the PVH. Leptin acts on these circuits to reduce food intake and increase energy expenditure. Direct leptin action on the ARC and VMH contribute to the suppression of glucose production and the stimulation of glucose disposal. Leptin action on the PBN also contributes to glycemic control, by suppressing glucose production during the CRR; PBN LepRb neurons mediate this effect via projections to the VMH. Leptin acts on LepRb neurons in the LHA to control the mesolimbic DA system. Not only do LHA LepRb neurons project to the VTA but also they modulate the activity of LHA HCRT neurons that project to the VTA. Thus, LHA LepRb neurons control the VTA neurons that project to the NAc to modulate the activity of the mesolimbic DA system and motivated behavior.