Leptin-signaling pathways and leptin resistance

Abstract

Leptin acts as an anorexigenic hormone in the brain, where the long form of the leptin receptor (LRb) is widely expressed in hypothalamic and extra-hypothalamic sites that are known to participate in diverse feeding circuits. The important role of leptin in energy homeostasis is demonstrated by the profound hyperphagia and morbid obesity in humans and rodents null for leptin or LRb. However, common forms of obesity are associated with high leptin levels and a failure to respond effectively to exogenous leptin; indicating a state of leptin resistance. Leptin resistance is thought to be an important component in the development of obesity. Several defects may contribute to the leptin resistant state, including a defective leptin transport across the blood-brain barrier, which reduces the availability of leptin at its receptor. Furthermore, defects in LRb signal transduction involving reduced LRb expression or the induction of feedback inhibitors have been found in leptin resistance; these defects are commonly termed cellular leptin resistance,. Finally, reduced leptin action can result in the disruption of proper neuronal interactions, by altering neuronal wiring. Interestingly, some leptin functions remain intact in the leptin-resistant state, such as cardiovascular leptin effects. The appearance of selective leptin resistance is mirrored by the observation that cellular leptin resistance has been found only in some subpopulations of hypothalamic LRb neurons. Current efforts to dissect leptin function in specific populations of LRb neurons will increase our understanding of these complexities of leptin physiology.

Fig. 1.

Immunohistochemical visualization of green fluorescent protein expressing LRb neurons in the hypothalamus (a), midbrain (b) and brainstem (c). LRb neurons are found in central sites that contribute importantly to the control of eating. LHA = Lateral hypothalamic area; fx = fornix; DMH = dorsomedial hypothalamus; VMH = ventromedial hypothalamus; Arc = arcuate nucleus; VTA = ventral tegmental area; AP = area postrema; NTS = nucleus of the solitary tract.

Fig. 2.

The intracellular LRb signaling cascade involves the binding, phosphorylation and activation of JAK2 (janus kinase 2) as well as phosphorylation of conserved tyrosine residues on LRb. These initiate distinct signaling pathways to mediate the diverse functions of leptin, including the transcriptional regulation of SOCS-3 (suppressor-of-cytokine-signaling-3) and PTP1B (phosphotyrosine phosphatase 1B) which are negative regulator or LRb signaling and are involved in the development of leptin resistance in the obese state.