Abstract
The profound seasonal cycle in body weight exhibited by the Djungarian hamster (Phodopus sungorus) is associated with the development of hypothalamic leptin resistance during long day photoperiod (LD, 16:8 h light dark cycle), when body weight is elevated relative to short day photoperiod (SD, 8:16 h light dark cycle). We previously have shown that this seasonal change in physiology is associated with higher levels of mRNA for the potent inhibitor of leptin signaling, suppressor of cytokine signaling-3 (SOCS3), in the arcuate nucleus (ARC) of LD hamsters relative to hamsters in SD. The alteration in SOCS3 gene expression preceded the body weight change suggesting that SOCS3 might be the molecular switch of seasonal body weight changes. To functionally characterize the role of SOCS3 in seasonal body weight regulation, we injected SOCS3 expressing recombinant adeno-associated virus type-2 (rAAV2-SOCS3) constructs into the ARC of leptin sensitive SD hamsters immediately after weaning. Hamsters that received rAAV2 expressing enhanced green fluorescent protein (rAAV2-EGFP) served as controls. ARC-directed SOCS3 overexpression led to a significant increase in body weight over a period of 12 weeks without fully restoring the LD phenotype. This increase was partially due to elevated brown and white adipose tissue mass. Gene expression of pro-opiomelanocortin was increased while thyroid hormone converting enzyme DIO3 mRNA levels were reduced in SD hamsters with SOCS3 overexpression. In conclusion, our data suggest that ARC-directed SOCS3 overexpression partially overcomes the profound seasonal body weight cycle exhibited by the hamster which is associated with altered pro-opiomelanocortin and DIO3 gene expression.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barrett P, Ebling FJ, Schuhler S, Wilson D, Ross AW, Warner A, Jethwa P, Boelen A, Visser TJ, Ozanne DM, Archer ZA, Mercer JG, Morgan PJ (2007) Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction. Endocrinology 148:3608–3617
Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, Lai CF, Tartaglia LA (1996) The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci USA 93:8374–8378
Benzler J, Ganjam GK, Kruger M, Pinkenburg O, Kutschke M, Stohr S, Steger J, Koch CE, Olkrug R, Schwartz MW, Shepherd PR, Grattan DR, Tups A (2012) Hypothalamic glycogen synthase kinase 3beta has a central role in the regulation of food intake and glucose metabolism. Biochem J 447:175–184
Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS (1998) Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1:619–625
Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellecchia M, Blomgren K, Plesnila N (2005) Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen–glucose deprivation and focal cerebral ischemia. J Neurosci 25:10262–10272
Duncan MJ, Goldman BD (1984a) Hormonal regulation of the annual pelage color cycle in the Djungarian hamster, Phodopus sungorus. I. Role of the gonads and pituitary. J Exp Zool 230:89–95
Duncan MJ, Goldman BD (1984b) Hormonal regulation of the annual pelage color cycle in the Djungarian hamster, Phodopus sungorus. II. Role of prolactin. J Exp Zool 230:97–103
Figala J, Hoffmann K, Goldau G (1973) Annual cycle in Djungarian hamster Phodopus sungorus Pallas. Oecologia 12:89–118
Grimm D, Kay MA (2003) From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy. Curr Gene Ther 3:281–304
Grimm D, Kay MA, Kleinschmidt JA (2003) Helper virus-free, optically controllable, and two-plasmid-based production of adeno-associated virus vectors of serotypes 1 to 6. Mol Ther 7:839–850
Herwig A, Ross AW, Nilaweera KN, Morgan PJ, Barrett P (2008) Hypothalamic thyroid hormone in energy balance regulation. Obes Facts 1:71–79
Herwig A, Wilson D, Logie TJ, Boelen A, Morgan PJ, Mercer JG, Barrett P (2009) Photoperiod and acute energy deficits interact on components of the thyroid hormone system in hypothalamic tanycytes of the Siberian hamster. Am J Physiol Regul Integr Comp Physiol 296:R1307–R1315
Hoffmann K (1978) Effects of short photoperiods on puberty, growth and moult in the Djungarian hamster (Phodopus sungorus). J Reprod Fertil 54:29–35
Jethwa PH, Warner A, Fowler MJ, Murphy M, de Backer MW, Adan RA, Barrett P, Brameld JM, Ebling FJ (2010) Short-days induce weight loss in Siberian hamsters despite overexpression of the agouti-related peptide gene. J Neuroendocrinol 22:564–575
Kievit P, Howard JK, Badman MK, Balthasar N, Coppari R, Mori H, Lee CE, Elmquist JK, Yoshimura A, Flier JS (2006) Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab 4:123–132
Klingenspor M, Niggemann H, Heldmaier G (2000) Modulation of leptin sensitivity by short photoperiod acclimation in the Djungarian hamster, Phodopus sungorus. J Comp Physiol B 170:37–43
Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S (1998) Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393:72–76
Kugler S, Kilic E, Bahr M (2003) Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Ther 10:337–347
Lerchl A, Schlatt S (1993) Influence of photoperiod on pineal melatonin synthesis, fur color, body weight, and reproductive function in the female Djungarian hamster, Phodopus sungorus. Neuroendocrinology 57:359–364
Mercer JG, Moar KM, Ross AW, Hoggard N, Morgan PJ (2000) Photoperiod regulates arcuate nucleus POMC, AGRP, and leptin receptor mRNA in Siberian hamster hypothalamus. Am J Physiol Regul Integr Comp Physiol 278:R271–R281
Mercer JG, Ellis C, Moar KM, Logie TJ, Morgan PJ, Adam CL (2003) Early regulation of hypothalamic arcuate nucleus CART gene expression by short photoperiod in the Siberian hamster. Regul Pept 111:129–136
Metlakunta AS, Sahu M, Yasukawa H, Dhillon SS, Belsham DD, Yoshimura A, Sahu A (2011) Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling. Am J Physiol Regul Integr Comp Physiol 300:R1185–R1193
Munzberg H, Huo L, Nillni EA, Hollenberg AN, Bjorbaek C (2003) Role of signal transducer and activator of transcription 3 in regulation of hypothalamic proopiomelanocortin gene expression by leptin. Endocrinology 144:2121–2131
Murphy M, Jethwa PH, Warner A, Barrett P, Nilaweera KN, Brameld JM, Ebling FJ (2012) Effects of manipulating hypothalamic triiodothyronine concentrations on seasonal body weight and torpor cycles in Siberian hamsters. Endocrinology 153:101–112
Myers MG Jr (2004) Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 59:287–304
Paxinos G, Franklin KBJ (1997) The mouse brain in stereotaxic coordinates. Academic press, Harcourt Brace and Co., San Diego
Ramadoss P, Unger-Smith NE, Lam FS, Hollenberg AN (2009) STAT3 targets the regulatory regions of gluconeogenic genes in vivo. Mol Endocrinol 23:827–837
Robson AJ, Rousseau K, Loudon AS, Ebling FJ (2002) Cocaine and amphetamine-regulated transcript mRNA regulation in the hypothalamus in lean and obese rodents. J Neuroendocrinol 14:697–709
Rousseau K, Atcha Z, Loudon AS (2003) Leptin and seasonal mammals. J Neuroendocrinol 15:409–414
Tartaglia LA (1997) The leptin receptor. J Biol Chem 272:6093–6096
Tups A (2009) Physiological models of leptin resistance. J Neuroendocrinol 21:961–971
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 145:1185–1193
Tups A, Barrett P, Ross AW, Morgan PJ, Klingenspor M, Mercer JG (2006) The suppressor of cytokine signalling 3, SOCS3, may be one critical modulator of seasonal body weight changes in the Siberian hamster, Phodopus sungorus. J Neuroendocrinol 18:139–145
Tups A, Stohr S, Helwig M, Barrett P, Krol E, Schachtner J, Mercer JG, Klingenspor M (2012) Seasonal leptin resistance is associated with impaired signalling via JAK2-STAT3 but not ERK, possibly mediated by reduced hypothalamic GRB2 protein. J Comp Physiol B 182:553–567
Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434–5446
White DW, Kuropatwinski KK, Devos R, Baumann H, Tartaglia LA (1997) Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization. J Biol Chem 272:4065–4071
Acknowledgments
This study was funded by the German Ministry of Education and Research (Ref. No: 0315087, to AT). Isolation and culturing of primary rat cortical cells was performed with support of Sandra Engel under supervision of Prof. Carsten Culmsee at the Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by G. Heldmaier.
Rights and permissions
About this article
Cite this article
Ganjam, G.K., Benzler, J., Pinkenburg, O. et al. Overexpression of suppressor of cytokine signaling 3 in the arcuate nucleus of juvenile Phodopus sungorus alters seasonal body weight changes. J Comp Physiol B 183, 1101–1111 (2013). https://doi.org/10.1007/s00360-013-0772-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00360-013-0772-1