Molecular mechanisms and neural mediators of leptin action

Abstract

The adipose-derived hormone leptin signals the adequacy of body triglyceride stores to specialized leptin receptor (LepRb)-containing cells, which modulate physiology and behavior appropriately for the status of energy reserves. Decreased leptin action initiates a program that restrains a host of energy-intensive processes, promotes food seeking and consumption, and supports the continued availability of glucose and other metabolic fuels in the face of diminished fat stores. In addition to activating the STAT3-dependent transcriptional regulation that mediates most leptin action in vivo, LepRb mediates some leptin effects via a poorly understood second intracellular signaling pathway. Leptin also activates feedback pathways that restrain LepRb signaling in the face of high leptin, as in obesity. Leptin mediates most of its metabolic effects via multiple populations of Lepr-expressing hypothalamic neurons, each of which controls different aspects of leptin action. Although most of these neuron populations contribute only modestly to the control of food intake and body weight by leptin, Glp1r-expressing Lepr neurons inhibit Agrp neurons and strongly suppress feeding and body weight. Going forward, it will be important to define the potentially distinct intracellular responses to leptin for individual Lepr neuron populations, along with the cell type-specific roles for these responses in the physiologic effects of leptin.