Seasonal leptin resistance is associated with impaired signalling via JAK2-STAT3 but not ERK, possibly mediated by reduced hypothalamic GRB2 protein
- 405 Downloads
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.
KeywordsArcuate nucleus Body weight regulation Suppressor of cytokine signalling Leptin receptor
This collaborative study was funded by the Scottish Executive Environment and Rural Affairs Department (J.G. Mercer), EC FP6 funding (contract no. LSHM-CT-2003-503041 to J.G. Mercer), the German Research Foundation (DFG Kl 973/5; M. Klingenspor) and the National Genome Research Network (NGFN 01GS0483; M. Klingenspor). A. Tups received a fellowship from the European Commission to attend the ObeSechool EU Marie Curie Training Site (HPMT-2001-00410) at the Rowett Research Institute and was a fellow of the Boehringer Ingelheim Fonds (Heidesheim, Germany).
- Atcha Z, Cagampang FR, Stirland JA, Morris ID, Brooks AN, Ebling FJ, Klingenspor M, Loudon AS (2000) Leptin acts on metabolism in a photoperiod-dependent manner, but has no effect on reproductive function in the seasonally breeding Siberian hamster (Phodopus sungorus). Endocrinology 141:4128–4135PubMedCrossRefGoogle Scholar
- Barrett P, Ivanova E, Graham ES, Ross AW, Wilson D, Ple H, Mercer JG, Ebling FJ, Schuhler S, Dupre SM, Loudon A, Morgan PJ (2006) Photoperiodic regulation of cellular retinol binding protein, CRBP1 [corrected] and nestin in tanycytes of the third ventricle ependymal layer of the Siberian hamster. J Endocrinol 191:687–698PubMedCrossRefGoogle Scholar
- Paxinos G, Franklin K (2002) The mouse brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
- Schuster C, Gauer F, Guerrero H, Lakhdar-Ghazal N, Pevet P, Masson-Pevet M (2000) Photic regulation of mt1 melatonin receptors in the Siberian hamster pars tuberalis and suprachiasmatic nuclei: involvement of the circadian clock and intergeniculate leaflet. J Neuroendocrinol 12:207–216PubMedCrossRefGoogle Scholar
- Tups A, Ellis C, Moar KM, Logie TJ, Adam CL, Mercer JG, Klingenspor M (2004) Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression. Endocrinology 145:1185–1193PubMedCrossRefGoogle Scholar