Photoperiodic Regulation of Leptin Sensitivity in the Siberian Hamster, Phodopus sungorus, Is Reflected in Arcuate Nucleus SOCS-3 (Suppressor of Cytokine Signaling) Gene Expression

Abstract

We present the first evidence that suppressor of cytokine signaling-3 (SOCS3), a protein inhibiting Janus kinase/signal transducer and activator of transcription (STAT) signaling distal of the leptin receptor, conveys seasonal changes in leptin sensitivity in the Siberian hamster. Food deprivation (48 h) reduced SOCS3 gene expression in hamsters acclimated to either long (LD) or short (SD) photoperiods, suggesting that leptin signals acute starvation regardless of photoperiod. However, SOCS3 mRNA levels were substantially lower in the hypothalamic arcuate nucleus of hamsters acclimated to SD than in those raised in LD. In juveniles raised in LD, a rapid increase in SOCS3 mRNA was observed within 4 d of weaning, which was completely prevented by transfer to SD on the day of weaning. The early increase in SOCS3 gene expression in juvenile hamsters in LD clearly preceded the establishment of different body weight trajectories in LD and SD. In adult LD hamsters, SOCS3 mRNA was maintained at an elevated level despite the chronic food restriction imposed to lower body weight and serum leptin to or even below SD levels. A single injection of leptin in SD hamsters elevated SOCS3 mRNA to LD levels, whereas leptin treatment had no effect on SOCS3 gene expression in LD hamsters. Our results suggest that the development of leptin resistance in LD-acclimated hamsters involves SOCS3-mediated suppression of leptin signaling in the arcuate nucleus. Increased SOCS3 expression in LD hamsters is independent of body fat and serum leptin levels, suggesting that the photoperiod is able to trigger the biannual reversible switch in leptin sensitivity.

Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of leptin resistance

“…The distribution of SOCS3, NPY, AgRP, POMC and CART mRNAs in the field vole hypothalamus was consistent with other rodent species , Peacock et al2004, Tups et al 2004. Although the probe for SOCS3 hybridized to the ARC, ventromedial and dorsomedial nuclei, expression outside the ARC was highly variable and generally not strong enough to allow quantification by image analysis.…”

“…Specifically, transfer of male Siberian hamsters from LD to SD conditions was associated with rapid down-regulation of hypothalamic SOCS3 mRNA followed by a decrease in body mass (Tups et al 2004), whereas transfer back from SD to LD induced an increase in SOCS3 expression that preceded any changes in body mass by at least 2 weeks (Tups et al 2006). Furthermore, neural cell-specific SOCS3 conditional knockout mice have greater responsiveness to the weight-and appetite-reducing effects of exogenous leptin than their wild-type littermates (Mori et al 2004).…”

“…mRNA levels were quantified by in situ hybridization in 20 mm coronal sections using techniques described previously (Simmons et al 1989, Mercer et al 1995. Antisense riboprobes complementary to fragments of hamster SOCS3 (Tups et al 2004), rat NPY (Mercer et al 1995), hamster AgRP and POMC and rat CART (Adam et al 2000) were transcribed from cloned cDNA templates. Coronal hypothalamic sections of vole brains were cut on a cryostat and collected throughout the extent of the ARC onto a set of eight slides, with six or seven sections mounted on each slide.…”

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

“…For instance, we recently showed that leptin exhibits a potent acute glucose-lowering capacity in Lep ob/ob mice, which was associated with increasing the number of pAKT immunoreactive cells in the ARC, thereby sensitizing insulin action (26). It is conceivable that diet-induced hypothalamic inflammation leads to relative leptin insensitivity, involving NF-kB-mediated transcription of the most prominent leptin inhibitor, SOCS-3 (34,35), which is a target gene regulated by this transcription factor (14). Inhibition of IKKb/NF-kB signaling in the ARC was associated with a reduction of SOCS-3 expression in this nucleus.…”

“…To test whether ARC-directed AAV overexpression of IkBa-mt might alter leptin sensitivity on a molecular level, we investigated the expression of SOCS-3 as the most prominent inhibitor of leptin signaling (34,35). In situ hybridization analysis revealed that SOCS-3 mRNA was decreased by 35% in the ARC of AAV2-IkBa-mt mice relative to controls (P = 0.029) (Fig.…”