Leptin receptor signaling and the regulation of mammalian physiology

Abstract

The adipocyte-derived hormone, leptin, signals the status of body energy stores to the central nervous system to regulate appetite and energy expenditure. A specific long-form leptin receptor (LepRb), a type I cytokine receptor, mediates leptin action on LepRb-expressing neurons in the brain. Leptin binding to LepRb activates the associated Janus kinase-2 (Jak2) tyrosine kinase to promote the phosphorylation of Jak2 and three residues on LepRb; each of these sites mediates a distinct aspect of downstream LepRb signaling, with differing physiologic functions. Tyr 1138 -STAT3 signaling suppresses feeding, but is not required for a number of other leptin actions. Tyr 985 binds SH2-containing tyrosine phosphatase-2 and suppressor of cytokine signaling-3 and primarily mediates the attenuation of LepRb signaling in vivo. The role for Tyr 1077 , the major regulator of signal transducer and activator of transcription-5 (STAT5) during leptin signaling, in the physiologic response to leptin remains unclear, although the obese phenotype of animals deleted for STAT5 in the brain suggests the potential importance of this signaling pathway. Leptin also modulates a number of other signaling pathways in the brain, including PI 3-kinase, mammalian target of rapamycin and AMP-dependent protein kinase; the pathways by which leptin controls these signals remain unclear, however, and may involve some indirect mechanisms. Important issues regarding leptin action and LepRb signaling in the future include not only the more thorough analysis of intracellular signaling pathways, but the neural substrate by which leptin acts, as most major populations of LepRb neurons remain poorly studied.

Role of leptin in female reproduction

“…Phosphorylation of each of these residues leads to the recruitment of a distinct set of downstream signaling molecules. By example, phosphorylated Tyr985 recruits the SH2-containing tyrosine phosphatase 2(SHP2), which presents the first step in the activation of the extracellular signal-regulated kinase (MAPK) cascade [19]. Additionally, phosphorylated Tyr985 also recruits SOCS3, a negative regulator of leptin action.…”

“…It has been reported that hypothalamic leptin control of reproduction is regulated by signals independent of STAT3 signaling [20]. Finally, the phosphorylation of Tyr1077, the major phosphorylation site mediating leptin's effects on reproduction, promotes the recruitment and transcriptional activation of STAT5 [19] and is required for ongoing appropriate function of the female reproductive function [21].…”

Leptin and insulin growth factor 1: diagnostic markers of the refeeding syndrome and mortality

“…This is not surprising as several nutritional factors regulate leptin and IGF1 production (8,9) . Both decline significantly in conditions of starvation (7) , through potentially independent mechanisms (10) .…”

Altered long non-coding RNA expression profile in patients with IgA-negative mesangial proliferative glomerulonephritis

“…Renal biopsies were obtained from IgA-unassociated MsPGN in patients (ages, [18][19][20][21][22][23][24][25][26][27][28][29] at the 181 Hospital in Gulin, China, between March and September 2010. The diagnosis of IgA-unassociated MsPGN was confirmed through pathological diagnosis and the presence of other clinical evidence.…”