title: Seasonal leptin resistance is associated with impaired signalling via JAK2-STAT3 but not ERK, possibly mediated by reduced hypothalamic GRB2 protein.
abstract: The Siberian hamster, Phodopus sungorus, undergoes a striking seasonal cycle of leptin sensitivity and body weight regulation, but the molecular mechanism and relevance to human leptin insensitivity are unknown. Here we show that nuclear translocation of phospho-STAT3 in the hypothalamus is rapidly stimulated by leptin to a greater extent in hamsters held in short-day length (SD) as compared to long-day length (LD). Intriguingly, effects of leptin on STAT3 appeared to be in part limited to nuclear translocation of phospho-STAT3 associated with the cell surface rather than phosphorylation of STAT3. The number of phospho-ERK cells within the hypothalamus was unaffected by either photoperiod or leptin. However, proximal to ERK phosphorylation, hypothalamic SH2-containing tyrosine phosphatase (SHP2) and the small growth factor receptor-binding protein (GRB2), which act as competitive negative modulators on binding of SOCS3 to leptin receptor (LRb)-associated Tyr⁹⁸⁵, were increased in SD compared to LD. Our findings suggest that activation of STAT3 by leptin may be dependent on interaction of stimulatory SHP2/GRB2 as well as inhibitory SOCS3 on the level of competitive binding to LRb-associated Tyr⁹⁸⁵. This hypothetical mechanism may represent the molecular identity of seasonally induced adjustments in leptin sensitivity and may be applied to investigating leptin sensitivity in other rodent models.
authors.affiliation: Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany. tups@staff.uni-marburg.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Tups
authors.forename: Sigrid
authors.initials: S
authors.lastname: Stöhr
authors.forename: Michael
authors.initials: M
authors.lastname: Helwig
authors.forename: Perry
authors.initials: P
authors.lastname: Barrett
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Krol
authors.forename: Joachim
authors.initials: J
authors.lastname: Schachtner
authors.forename: Julian G
authors.initials: JG
authors.lastname: Mercer
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
mesh_terms: D000818:Animals; D002467:Cell Nucleus; D006224:Cricetinae; D005260:Female; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017111:Phodopus / Q000378:metabolism*; D017440:Photoperiod; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D051380:GRB2 Adaptor Protein; D020738:Leptin; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D053614:Janus Kinase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11