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Division of Energy Balance and Obesity, Rowett Research Institute, Aberdeen Center for Energy Regulation and Obesity, Aberdeen, Scotland AB21 9SB, United Kingdom; and Department of Animal Physiology, Philipps University Marburg (M.K.), D-35043 Marburg, Germany
Address all correspondence and requests for reprints to: Dr. Martin Klingenspor, Department of Animal Physiology, Philipps University Marburg, Karl von Frisch Strasse 8, D-35043 Marburg, Germany. E-mail: klingens{at}staff.uni-marburg.de; or Dr. Julian Mercer, Division of Energy Balance and Obesity, Rowett Research Institute, Aberdeen, Scotland AB21 9SB, United Kingdom. E-mail: jgm{at}rri.sari.ac.uk.
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Abstract |
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Introduction |
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The arcuate nucleus of the hypothalamus (ARC) is probably the most important integrative center for mediation of the leptin signal (4). Central transduction of the leptin signal is mediated by the long form of the leptin receptor (LRb) (5), activation of which results in autophosphorylation of the associated Janus kinase type 2 tyrosine kinase and the transmission of downstream phosphotyrosine-dependent signals. The transcription factor, signal transducer and activator of transcription-3 (STAT3), is the most potent intracellular mediator of the leptin signal. Once activated, STAT3 regulates the transcription of leptin-responsive target genes. One particular target gene is SOCS3 (suppressor of cytokine signaling), a broadly acting suppressor of cytokine signaling (6) that suppresses signaling downstream of the receptor by inhibition of STAT3 phosphorylation. SOCS3 has been identified as a potential mediator of central leptin resistance (7, 8).
The hypothesis underlying the present study is that changes in leptin signaling pathways mediated by the inhibitory peptide SOCS3 may be critical to the physiological changes in body weight in the Siberian hamster. We hypothesize that photoperiod has a direct effect on the leptin signaling system at the level of signal transduction, whereby reduced arcuate nucleus SOCS3 expression in SD hamsters activates leptin signaling. Lower SOCS3 expression as an early response to SD could lead to an increased anorexigenic action of leptin levels and trigger the weight loss or growth restriction induced by SD. Here, we address this hypothesis in a series of experiments with hamsters subjected to energetic and hormonal challenges to characterize the impact of energy balance, photoperiod, and leptin on SOCS3 mRNA.
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Materials and Methods |
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Experimental protocols
Experiment 1: effect of extended SD exposure and food deprivation in juvenile female hamsters.
Twenty-four female hamsters were divided into two groups of 12 at weaning, one of which was transferred to SD. After 8 wk, half the animals in each photoperiod group (n = 6) were deprived of food for 48 h, and the remainder continued to feed ad libitum.
Experiment 2: SOCS3 mRNA changes during the time course of SD acclimation.
Archived brain sections were used from juvenile female hamsters killed at weaning or 4, 7, 14, or 21 d postweaning in either photoperiod (11). As before, all animals were gestated and weaned in LD, with transfer to SD at weaning, as appropriate.
Experiment 3: effect of extended SD exposure and food restriction in juvenile female hamsters.
The protocol employed was similar to that previously described for adult males (10), except that the restriction periods were of either 6-wk (experiment 3a) or 12-wk (experiment 3b) duration. For each study duration, hamsters were allocated to one of three groups. One group remained in LD and fed ad libitum throughout the 6-wk (n = 12) or 12-wk (n = 12) experiment (LD-ADLIB). A second group was transferred to SD and was fed ad libitum throughout (SD-ADLIB; n = 12). The third group remained in LD, but received a restricted ration of food (LD-REST; n = 12), such that the group mean body weight tracked that of the SD hamsters. Body weight and food intake were measured daily for all animals during the restriction period. The degree of food restriction imposed on the LD-REST group did not exceed 65% of the LD-ADLIB intake at any point during the study. After 6 wk (experiment 3a) or 12 wk (experiment 3b), hamsters were killed, trunk blood was collected in lithium-heparin tubes, and brains were removed and frozen on dry ice. Selected white and brown adipose tissue depots were excised, among them retroperitoneal white adipose tissue (RWAT), inguinal white adipose tissue (IWAT), reproductive tract white adipose tissue (RTWAT), and interscapular brown adipose tissue (IBAT). The total mass of the dissected white adipose tissue depots was taken as a measure of body adiposity.
Experiment 4: duration-dependent effect of leptin injection in juvenile female hamsters.
Forty-eight juvenile female hamsters were allocated to two weight-matched groups of 24 animals, one of which was transferred to SD for 8 wk. They were subdivided in each photoperiod, with half being injected ip with recombinant mouse leptin (2 mg/kg), and the other half with vehicle. Animals were killed 15, 30, 60, or 120 min after injection with leptin or vehicle (n = 3/group).
Experiment 5: effect of extended SD exposure and leptin injection in adult male hamsters.
Twenty-four adult male hamsters, 4–6 months of age, were allocated to two weight-matched groups of 12 animals, one of which was transferred into SD for 12 wk. These groups were then subdivided so that one group in each photoperiod (n = 6/group) received an ip injection of recombinant mouse leptin (2 mg/kg body weight; R&D Systems, Minneapolis, MN) 1 h before death, and the other group received a control injection of vehicle (15 mM sterile HCl and 7.5 mM sterile NaOH) at the same time point.
RIA
Serum concentrations of leptin were measured using the Linco Multispecies kit (Biogenesis, Poole, UK) according to the manufacturer’s instructions and as validated previously for use with hamster serum (10).
Hypothalamic gene expression
mRNA levels were quantified by in situ hybridization in 20-µm coronal hypothalamic sections using techniques described in detail previously (10). A riboprobe complementary to the suppressor of cytokine signaling-3 (SOCS3) was generated from cloned cDNA from the hypothalamus of the Siberian hamster. cDNA synthesis was performed using the cDNA synthesis kit (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. The 465-bp SOCS3 fragment was amplified by PCR with 35 cycles of 94 C for 1 min, 59 C for 1 min and 40 sec, and 72 C for 2 min, then finally one cycle at 72 C for 10 min. The amplification was performed using the following primers: 5'-ACACCAGCCTGCGCCTCAAGACCT-3' and 5'-TCGCCCCCAGAATAGATGTAGTAA-3'. The DNA fragment was ligated into pGEM-T-Easy, transformed into Escherichia coli DH5
, and sequenced. For cRNA synthesis by in vitro transcription, the SOCS3 cDNA fragment was subcloned into pBluescript II SK-.
As previously described (10), forebrain sections (20 µm) were collected throughout the extent of the ARC onto a set of eight slides, with six or seven sections mounted on each slide. Accordingly, slides spanned the hypothalamic region approximating -2.7 to -1.46 mm relative to Bregma according to the atlas of the mouse brain (11A ). One slide from each animal was hybridized. Briefly, slides were fixed, acetylated, and hybridized overnight at 58 C using 35S-labeled cRNA probes (1–2 x 107 cpm/ml). Slides were treated with ribonuclease A, desalted, with a final high stringency wash (30 min) in 0.1x standard saline citrate at 60 C, dried, and apposed to Kodak Biomax MR Film (Eastman Kodak Co., Rochester, NY). Autoradiographic images were quantified using the Image-Pro Plus system (version 4.5.1, Media Cybernetics, Inc., Silver Spring, MD). Equivalent sections of individual animals were matched according to the atlas of the mouse brain. Four sections from the ARC of each animal spanning from -2.54 to -1.94 mm relative to Bregma were analyzed. Data were manipulated using a standard curve generated from 14C autoradiographic microscales (Amersham Pharmacia Biotech, Arlington Heights, IL), and the integrated intensity of the hybridization signal was computed.
Statistical analysis
Data were analyzed by t test, one- or two-way ANOVA, followed by Student-Newman-Keuls multiple comparison test, as appropriate, using SigmaStat statistical software (Jandel Corp., Erkrath, Germany). Where data failed equal variance or normality tests, they were analyzed by Mann-Whitney rank-sum test or one-way ANOVA on ranks, followed by Dunn’s multiple comparison test. Results are presented as the mean ± SEM, and differences were considered significant at P < 0.05.
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Results |
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). In addition to the hypothalamus, SOCS3 mRNA was detected in the pyriform cortex and the CA 1–3 region of the hippocampus (Fig. 1). Cross-hybridization of the hamster SOCS3 fragment with other members of the SOCS family is unlikely, as sequence comparison revealed low identities with other SOCS cDNAs; the highest identity was 25.5% to SOCS 1 of M. musculus. A sense probe synthesized from the cloned cDNA generated a low intensity, nonspecific signal.
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). Over the 8-wk period, SD hamsters gained 10.9 ± 1.0 g, whereas hamsters in LD gained 16.8 ± 0.8 g. Animals maintained in LD had significantly (P < 0.05) higher reproductive tract weights than animals in SD, independent of feeding status (LD-ADLIB, 260.6 ± 16.4; SD-ADLIB, 146.8 ± 16.6; LD-FD, 269.5 ± 16.0; SD-FD, 155.3 ± 13.2). Food deprivation for 48 h led to a loss in body weight of 13.4 ± 2.3% in LD hamsters and 17.9 ± 2.3% in SD hamsters. There were significant differences in serum leptin concentration between the groups. Both short photoperiod (by two-way ANOVA: F = 46.20; P < 0.001) and food deprivation (by two-way ANOVA: F = 21.92; P < 0.001) suppressed serum leptin concentrations (Fig. 2B). A highly significant reduction of SOCS3 mRNA levels was observed in the ARC (Fig. 2B; see also Fig. 1
) in response to SD acclimation (by two-way ANOVA: F = 91.96; P < 0.001) as well as in response to food deprivation (by two-way ANOVA: F = 19.40; P < 0.001; Fig. 2C). However, there were no marked differences in SOCS3 gene expression in other hypothalamic nuclei (Fig. 1; data not shown).
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); in comparison with the weaning control group, SOCS3 mRNA expression in SD was maintained at a level similar to that observed at weaning, whereas LD hamsters had elevated SOCS3 mRNA expression. There was a significant effect of postweaning photoperiod (F = 26.95; P < 0.001). The differences in SOCS3 mRNA expression between LD and SD at individual time points attained significance (P < 0.01) on d 14 and 21 postweaning. Furthermore, after only 4 d, LD animals revealed a significant increase in SOCS3 expression compared with the weaning group on LD (P < 0.05).
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) and 12 wk (Fig. 4B) for hamsters maintained in either LD or SD (LD-ADLIB and SD-ADLIB groups). The body weight gains of the SD group were mimicked by gradual incremental food intake restriction in LDs (LD-REST). At the end of the restriction periods, body masses of SD-ADLIB and LD-REST hamsters were 76.9% and 71.9% of those in respective LD-ADLIB controls at 6 and 12 wk postweaning. Body mass differentials were accompanied by differences in weight of adipose tissue (Table 1). There were linear correlations between body mass and adipose tissue mass among animals of the same age (6 wk: rs= 0.879; P < 0.0001; 12 wk: rs= 0.942, P < 0.0001). Hamsters at 6 wk postweaning had a higher body fat content at the same body weight than hamsters at 12 wk postweaning (Fig. 4C). Differences between LD-REST and SD-ADLIB hamsters were restricted to the mass of the reproductive tract (Table 1), although LD-REST hamsters had slightly more adipose tissue than SD-ADLIB at both 6 and 12 wk postweaning at a similar body weight. However, although LD-REST had an intermediate serum leptin level at 6 wk (LD-ADLIB > SD-ADLIB = LD-REST; P 
0.05; Fig. 4A), the 12 wk group had serum leptin concentrations below the level observed in SD-ADLIB animals (LD-ADLIB > SD-ADLIB > LD-REST; P 0.05; Fig. 4, B and D). There was a significant correlation between adipose tissue weight and serum leptin concentration (Fig. 4D). Food restriction for either 6 or 12 wk had no effect on SOCS3 mRNA expression; there were no differences between LD-ADLIB and LD-REST hamsters (Fig. 4, E and F). Significant differences were observed between LD-ADLIB and SD-ADLIB groups (6 wk, F = 6.28; 12 wk, F = 25.9; P < 0.05). After 6- and 12-wk SD exposure, SOCS3 mRNA expression was suppressed 42% (Fig. 4E) and 52%, respectively (Fig. 4F) relative to that in LD-ADLIB hamsters.
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). Leptin only had an effect on SOCS3 mRNA expression in SD-acclimated hamsters. One hour after leptin injection, a clear increase in SOCS3 mRNA expression was observed (Fig. 5A). This effect was still apparent after 2 h. In contrast, LD-acclimated hamsters did not exhibit marked changes in SOCS3 mRNA expression at either 1 or 2 h after leptin injection (Fig. 5, A and B). The animals that received a control injection exhibited higher SOCS3 gene expression in LD than in SD (by one-way ANOVA: F = 45.3; P < 0.001).
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Adult male hamsters exhibited a highly significant effect of photoperiod on SOCS3 expression (by two-way ANOVA: F = 22.36; P < 0.001; Fig. 5C), with a reduction to 36.6% in the SD compared with the LD control group. Consistent with experiment 4, 1 h after leptin injection, SOCS3 mRNA expression was significantly increased in SD hamsters to 94.0% of the LD control value (by two-way ANOVA: F = 16.09; P < 0.001), whereas no significant effect was observed in LD (Fig. 5C).
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Discussion |
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The distribution of SOCS3 mRNA in the hypothalamus of the Siberian hamster was similar to that in other mammals (14) with the most intense hybridization in the ARC, an important integrative center in body weight regulation, and less intense, but distinct, hybridization to the VMH and DMH. The present study focuses on SOCS3 mRNA expression in the ARC, a nucleus that is assumed to play the most important role in transduction of the leptin signal into a neuronal response (14, 15) and where SOCS3 mRNA is coexpressed with NPY and POMC mRNA (Tups, A., unpublished observations). The localization of SOCS3 mRNA within the hamster brain is consistent with the distribution of leptin receptor mRNA (3) and the leptin-responsive transcription factor, STAT3 (Tups, A., unpublished observations). This implies that SOCS3 is involved in transduction of the leptin signal within the hamster hypothalamus, and differential SOCS3 mRNA expression may thus represent a marker for changes in leptin sensitivity.
In the present study we focused on hypothalamic SOCS3 expression in juvenile female hamsters in which photoperiod manipulations were performed at weaning. The duration of acclimation to opposite photoperiods was varied to allow determination of changes in SOCS3 mRNA expression longitudinally throughout SD acclimation. This facilitated investigation of both the molecular basis of catabolic drive early in SD photoperiod in animals whose body weight trajectories had not begun to diverge (4–21 d postweaning) and the importance of leptin signal transduction to the maintenance of SD adaptations over longer periods during which SD hamsters gained less weight than LD animals. The effect of leptin injection in female P. sungorus was substantiated in adult male hamsters, suggesting that the leptin signal is regulated similarly in adult and prepubertal hamsters of either sex.
It is known that food deprivation for 48 h down-regulates SOCS3 gene expression in the ARC of nonseasonal rodent species [e.g. rats (14)]. The present study confirms this effect for the first time in the seasonal animal, Phodopus sungorus. The decline in SOCS3 mRNA levels mediated by acute catabolic intervention is independent of the photoperiod in which the hamster is maintained and may be the consequence of the abrupt fall in circulating leptin in response to acute food deprivation. However, in contrast to food deprivation, more gradual changes in serum leptin resulting from chronic food restriction do not affect SOCS3 mRNA levels. In these studies and in states of energy balance, photoperiod is the prime modulator of SOCS3 gene expression.
We determined elevated expression of SOCS3 mRNA in hamsters maintained in LD compared with animals kept in SD. This photoperiodic difference is present in hamsters of both sexes and becomes manifest after limited exposure to different photoperiods; the maximum difference occurs between 8 and 12 wk of exposure. Our results support the hypothesis that SOCS3, as a potential inhibitor of leptin signaling, may contribute to the reduction in leptin sensitivity in hamsters acclimated to a LD photoperiod, as reported previously (1). Comparatively high intracellular SOCS3 mRNA levels, which most likely result in elevated SOCS3 protein concentrations, may suppress the anorectic action of the leptin signal in LD by inhibiting phosphorylation of the transcription factor, STAT3. The finding that SOCS3 mRNA expression in SD juvenile female hamsters over the period up to 3 wk postweaning remains close to the level observed at weaning, whereas gene expression in LD is already augmented after 4 d postweaning, suggests that exposure to LD is accompanied by a gain of leptin resistance, whereas SD exposure does not change leptin sensitivity compared with that of animals at weaning. However, body weight trajectories for animals in opposite photoperiods did not start to diverge within the first 3 wk postweaning. Thus, changes in SOCS3 mRNA preceded body weight changes, raising the possibility that SOCS3 may be involved in the induction of these changes. Disinhibition of the leptin signal, represented by decreased SOCS3 mRNA expression in SD, may enhance the anorectic action of leptin in SD. In juvenile females, the early blockade of SOCS3 up-regulation observed in LD by SD exposure suggests that SOCS3 may be involved in the induction and maintenance of an appropriate body weight trajectory.
The study revealed differential SOCS3 expression independent of body weight change in young female hamsters immediately postweaning (i.e. 4–21 d). This suggests that body weight is unlikely to play a substantial role in SOCS3 regulation. To investigate the relationship between body weight and SOCS3 expression, we analyzed LD animals that were food restricted to mimic SD weight trajectory. Chronic food-restricted LD hamsters exhibited SOCS3 expression levels that were unaffected by this long-term catabolic intervention. The fact that LD-REST hamsters had significantly reduced adipose tissue mass and serum leptin compared with their ad libitum-fed conspecifics indicates that leptin plays a minor role in mediating SOCS3 mRNA expression in this photoperiodic state, as substantiated by the serum leptin levels recorded in this restriction experiment. In contrast to ad libitum-fed hamsters, in which serum leptin levels were proportional to adipose tissue mass, in the 12-wk LD-REST group, leptin levels were lower than expected from adipose tissue mass, indicating altered leptin secretion or turnover in response to long-term food restriction. To our knowledge this is the first indication that leptin resistance, as indicated by high expression of SOCS3, can also be associated with low endogenous leptin levels. These findings imply that SOCS3 in LD is expressed constitutively and is unaffected by chronic changes in serum leptin levels; thus, SOCS3 is still expressed at a high level despite a low serum leptin concentration due to food restriction. A functional central leptin resistance in LD could be mediated by constitutive inhibition of the anorexigenic action of leptin. This implies that either the low leptin concentration is sufficient for activating SOCS3 mRNA expression, or degradation of SOCS3 mRNA is reduced, which may lead to decreased turnover of this inhibitory peptide. Furthermore, up-regulation of LRb, as observed in male hamsters after food restriction in LD (10), provides a possible mechanism for compensating for declining leptin levels to keep SOCS3 mRNA expression on a high constitutive level.
Our findings imply that aside from acute energetic challenges, photoperiod is a major parameter triggering adjustments in leptin sensitivity in P. sungorus. The molecular transducer of photoperiodic information is the pineal hormone, melatonin, and interaction between photoperiod, melatonin, and the leptin system may occur, but there is also evidence for photoperiodic responses not mediated by melatonin (16). However, the importance of photoperiod, rather than leptin, as a key regulator of leptin sensitivity in the seasonal hamster was also supported by a functional study by Rousseau et al. (17). In this experiment, chronic peripheral leptin infusion was given to hamsters with low body weight, fat reserves, and circulating leptin, brought about by either SD exposure or imposed food restriction in LD. This treatment caused body weight and fat loss in SD, but had no such effects in LD. Furthermore, by performing studies in ovariectomized, steroid-clamped hamsters, the Rousseau study also strongly suggested that whole body and hypothalamic responses to leptin are primarily induced by photoperiod rather than by seasonal changes in sex steroids.
SOCS3 gene expression is not exclusively regulated by leptin. It is known, for example, that insulin can induce phosphorylation of SOCS3 through Janus-activated kinase (18). Nevertheless it is very unlikely that photoperiodic regulation of the SOCS3 gene is mediated via insulin; the current experiments demonstrate the direct induction of SOCS3 mRNA by exogenous leptin and continuing elevated SOCS3 gene expression in LD-REST hamsters, which, due to their negative energy balance, are presumably hypoinsulinemic.
SOCS3 mRNA expression in the ARC of SD hamsters was increased 1 h after leptin injection. This was demonstrated in adult male hamsters as well as in juvenile female hamsters, with maximum induction after injection occurring at 30–60 min. These data are consistent with SOCS3 induction in cell culture. Auernhammer et al. (19) demonstrated that SOCS3 gene expression was induced several-fold by the ligand leukemia inhibitory factor within 30 min. This finding can be compared with SOCS3 activation by leptin, because both ligands use the same Janus kinase-STAT pathway. Our data are the first to provide a time scale for SOCS3 gene activation by leptin in vivo. However, central signaling induced by exogenous leptin seems to be processed differently in long and short photoperiods, with further indication that the SOCS3 gene may be activated constitutively in LD. Even leptin concentrations well above the physiological range (and consistently higher in LD compared with SD) had only a minor effect on SOCS3 mRNA expression in LD, providing further evidence of leptin resistance in LD.
Intriguingly, the present study provides evidence that seasonal leptin resistance, as represented by P. sungorus, seems not to be associated with obesity as such. The significant positive correlation between body weight and total adipose tissue weight represented by IWAT, RWAT, and RTAT indicates that LD hamsters are appropriately fat for their body mass, suggesting that increased leptin resistance in LD is not a result of a disproportional elevation in adiposity.
In summary, our studies suggest that changes in SOCS3 mRNA within the ARC contribute to adjustments in leptin sensitivity, leading to a different reading of the leptin signal in LD and SD hamsters. These observed changes in SOCS3 gene expression are informative of the way in which the animal uses the leptin signal. The LD-acclimated and thus leptin-resistant hamster does not regulate SOCS3 gene expression via leptin under all circumstances; even a substantial decline in endogenous leptin levels after chronic food restriction did not affect SOCS3 mRNA expression. However, an abrupt decline in leptin levels caused by complete food deprivation decreases SOCS3 gene expression in both photoperiods, suggesting that leptin acts as a starvation signal regardless of photoperiod. This finding also suggests that manipulations leading to such acute reductions in blood leptin may effectively resensitize the brain to the leptin signal. In contrast, our data imply that the reading of gradual changes in circulating leptin is photoperiod dependent. This suggests that there may be an interaction between the leptin and melatonin signaling systems, with melatonin being elevated within the hierarchy of signaling. However, as some studies have demonstrated photoperiodic responses not mediated by melatonin (16), future experiments should address a potential role of melatonin in the control of SOCS3 expression. Nevertheless, in the seasonal animal, SOCS3 may be an early mediator of an appropriate body weight trajectory. The inhibition of leptin signal transduction by SOCS3 is regarded as a highly conserved mechanism. Thus, the biannual switch from leptin sensitivity in SD to leptin resistance in LD, which is manifested by ARC SOCS3 gene expression in P. sungorus, provides a basis for elucidating mechanisms of human leptin resistance and ways of manipulating the leptin system to overcome this central resistance.
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Footnotes |
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A.T. was the recipient of a fellowship from the European Commission to attend the ObeSechool European Union Marie Curie Training Site (HPMT-2001-0410) at the Rowett Research Institute and is in receipt of funding from Boehringer Ingelheim Fonds (Heidesheim, Germany).
Abbreviations: ARC, Arcuate nucleus; DMH, dorsomedial nucleus; IWAT, inguinal white adipose tissue; LD, long day photoperiod; PVN, paraventricular nucleus; RTWAT, reproductive tract white adipose tissue; RWAT, retroperitoneal white adipose tissue; SCN, suprachiasmatic nucleus; SD, short day photoperiod; SOCS3, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; VMH, ventromedial nucleus.
Received October 15, 2003.
Accepted for publication November 18, 2003.
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