Recent advances in understanding leptin signaling and leptin resistance

Abstract

The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.

Fig. 1.

A model of leptin regulation of energy balance and body weight. Leptin is secreted by adipose tissue in proportion to adipose mass and relays information about peripheral energy storage and availability to the brain. Leptin regulates neuronal activity in multiple regions of the hypothalamus, including the arcuate nucleus (ARC), ventromedial hypothalamus (VMH), and paraventricular hypothalamus (PVH). Leptin suppresses appetite (energy intake) and promotes energy expenditure primarily by regulating these neuronal activities. Leptin resistance causes an imbalance between energy intake and expenditure, resulting in obesity. 3V, 3rd ventricle.

Fig. 2.

A model of leptin signaling and leptin resistance. Leptin binds to the long form of the leptin receptor (LEPRb) and activates LEPRb-associated JAK2. JAK2 phosphorylates LEPRb on Tyr^{985/1077/1138}. SH2-containing protein tyrosine phosphatase 2 (SHP2) binds to phospho-Tyr⁹⁸⁵ and mediates the activation of the MAPK pathway. Suppressor of cytokine signaling-3 (SOCS3) also binds to phospho-Tyr⁹⁸⁵ and inhibits leptin signaling in a negative feedback manner. STAT5 and STAT3 bind to phospho-Tyr¹⁰⁷⁷ and phospho-Tyr¹¹³⁸, respectively, and are subsequently phosphorylated and activated by JAK2. STAT3 and STAT5 activate their target genes, which mediate leptin's anorexigenic effect. JAK2 autophosphorylates on Tyr⁸¹³, which binds to SH2B1. SH2B1 simultaneously binds to insulin receptor substrate (IRS)-1 and IRS-2 and recruits IRS proteins to the LEPRb/JAK2 complex, which results in JAK2-mediated tyrosine phosphorylation of IRS-1 and IRS-2 and subsequent activation of the phosphoinositide 3-kinase (PI3K) pathway. Leptin also stimulates a JAK2-independent pathway involving the Src tyrosine kinase family members. The JAK2-dependent and -independent pathways act coordinately and synergistically to promote STAT3 activation. Leptin also regulates the CaMKK2/AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and the mammalian target of rapamycin (mTOR)/ribosomal S6 kinase (S6K) pathways; however, the molecular steps from the LEPRb to these 2 pathways are not clear. These diverse pathways act coordinately as a network to fully mediate leptin responses. LEPRb signaling is negatively regulated by SOCS3, protein tyrosine phosphatase 1B (PTP1B), and endoplasmic reticulum (ER) stress but positively regulated by SH2B1.