Leptin signalling pathways in hypothalamic neurons

Abstract

Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways.

Keywords: Cilia; Hypothalamus; Leptin; Neurons; Obesity; Signaling.

Fig. 1

Schematic representation of mouse leptin receptor isoforms. The mouse leptin receptor has six isoforms, LepRa–f with a common extracellular domain but diverse intracellular domains. JAK interaction and activation is mediated through the box 1 motif. The long form, LepRb, is the only isoform that contains motifs enabling the leptin-induced activation of the JAK-STAT pathway

Fig. 2

Signaling pathways of leptin and its downstream effectors. Leptin binds to its receptor and activates the JAK–STAT3, PI3K–FoxO1, and ERK pathways. For JAK–STAT activation, activated JAK2 tyrosine kinase induces the phosphorylation of Tyr985 and Tyr1138 of LepRb, which leads to the activation of STAT3/STAT5. Phosphorylated Tyr985 strongly recruits SHP-2 and GRB2 resulting in the activation of ERK signaling. Leptin also activates PI3K by recruiting IRS proteins leading to the inactivation of FoxO1 by sequestering them in the cytoplasm. On the other hand, leptin has been reported to inhibit AMPK activity. AMPK is activated by upstream signaling, including LKB1 and CaMKKβ. In addition, leptin treatment activates mTOR/S6K signaling in the hypothalamus, which phosphorylates Ser491 of AMPK α-subunit and inhibits AMPK activity. AgRP agouti-related protein, FoxO1 forkhead box protein O1, IRS insulin receptor substrate, JAK Janus kinase, PI3K phosphatidylinositol 3-OH kinase, POMC proopiomelanocortin, PTP1B protein-tyrosine phosphatase 1B, SOCS3 suppressor of cytokine signaling 3, STAT signal transducer and activator of transcription

Fig. 3

Association of cilia signaling and leptin signaling. Primary cilia are associated with leptin signaling in hypothalamic neurons. BBS proteins form a protein complex called BBSome, which is involved in the trafficking of vesicles laden with ciliary proteins from the Golgi to cilia–basal bodies. The BBSome, especially BBS1, may mediate the trafficking of LepRb to the cellular surface or periciliary area as the deletion of BBS1 causes the aberrant distribution of LepRb in the perinuclear area. Another ciliary gene, RPGRIP1L, interacts with LepRb and mediates LepRb trafficking to the periciliary area. RPGRIP1L expression is regulated by CUX1, which binds to the first intron of FTO gene and stimulates the transcription of RPGRIP1L and FTO. BBS Bardet–Biedl syndrome, CUX1 cut-like homeobox 1, FTO fat mass and obesity associated, RPGRIP1L retinitis pigmentosa GTPase regulator-interacting protein-1 like

Fig. 4

Signaling molecules which negatively regulate leptin signaling. Several signaling pathways are activated in the hypothalamus of DIO mice and attenuate signaling cascades downstream from the leptin receptors via interactions with JAK2, STAT3, IRS2, and PI3K. IKKβ IκB kinase-β, NFκB nuclear factor-κB, PKC-θ protein kinase-θ, PPARγ peroxisome proliferator activated transcript-γ, PTP1B protein tyrosine phosphatase 1B, SOCS3 suppressor of cytokine signaling 3