Mechanism of attenuation of leptin signaling under chronic ligand stimulation

Abstract

BackgroundLeptin is an adipocyte-derived hormone that acts via its hypothalamic receptor (LEPRb) to regulate energy balance. A downstream effect essential for the weight-regulatory action of leptin is the phosphorylation and activation of the latent transcription factor STAT3 by LEPRb-associated Janus kinases (JAKs). Obesity is typically associated with chronically elevated leptin levels and a decreased ability of LEPRb to activate intracellular signal transduction pathways (leptin resistance). Here we have studied the roles of the intracellular tyrosine residues in the negative feedback regulation of LEPRb-signaling under chronic leptin stimulation.ResultsMutational analysis showed that the presence of either Tyr985 and Tyr1077 in the intracellular domain of LEPRb was sufficient for the attenuation of STAT3 phosphorylation, whereas mutation of both tyrosines rendered LEPRb resistant to feedback regulation. Overexpression and RNA interference-mediated downregulation of suppressor of cytokine signaling 3 (SOCS3) revealed that both Tyr985 and Tyr1077 were capable of supporting the negative modulatory effect of SOCS3 in reporter gene assays. In contrast, the inhibitory effect of SOCS1 was enhanced by the presence of Tyr985 but not Tyr1077. Finally, the reduction of the STAT-phosphorylating activity of the LEPRb complex after 2 h of leptin stimulation was not accompanied by the dephosphorylation or degradation of LEPRb or the receptor-associated JAK molecule, but depended on Tyr985 and/or Tyr1077.ConclusionsBoth Tyr985 and Tyr1077 contribute to the negative regulation of LEPRb signaling. The inhibitory effects of SOCS1 and SOCS3 differ in the dependence on the tyrosine residues in the intracellular domain of LEPRb.

Recent scenario of obesity and male fertility

“…LEPR-B is membrane bound isoform with longest intracellular domain and is the functional isoform in the hypothalamus and its inactivation generates phenotype characteristic of complete leptin or leptin receptor deficiency (Henson & Castracane, 2006) which induces leptin resistance with main candidates being SOCS3 and STAT 3 pathways downstream of leptin receptor (Knobelspies et al, 2010).…”

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

“…This strain-specific regulation of Socs3 expression by the CAF diet is highly relevant for the functionality of leptin signalling because Socs3 acts as a negative-feedback regulator of leptin signal transduction (Mori et al 2004). Thus, while the enhanced expression of Socs3 in the hypothalamus of CAF-fed LEW rats confirms the attenuation of central leptin signalling, a hallmark feature of leptin resistance (Knobelspies et al 2010, Olofsson et al 2013, the downregulation of Socs3 expression observed in CAF-fed WKY rats is associated with an increase in central leptin sensitivity. Therefore, the hyperleptinaemia in WKY rats was not translated to an attenuation of the leptin signalling, but the opposite.…”

“…We can therefore hypothesize that the maintenance of STAT3 activation through its phosphorylation consequence of SOCS3 is an essential step for the phenotypic response to diet. Moreover, LepRb and its intracellular tyrosine residues may also play a pivotal role in the regulation of STAT3 activation under chronic leptin stimulation (Knobelspies et al 2010).…”

The Role of Angiotensin in Obesity and Metabolic Disease

“…This is of physiological importance as phosphorylation of STAT3 is necessary for leptin-mediated modulation of energy homeostasis and body weight [66]. Tyr 985 is then involved in feedback inhibition of STAT3 signalling mediated via the leptin receptor through inhibitory molecules binding to the phosphorylated receptor to abrogate signal transduction [67,69]. PTP-1b functions as a negative modulator of phosphorylation of critical tyrosine residues in leptin signal transduction and has been directly linked to attenuation of insulin and leptin signalling via these transient dephosphorylation events [70].…”