• 1
    Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci 1953; 140: 578596.
  • 2
    Munzberg H, Myers MG Jr. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci 2005; 8: 566570.
  • 3
    Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661671.
  • 4
    Banks WA. Leptin transport across the blood-brain barrier: implications for the cause and treatment of obesity. Curr Pharm Des 2001; 7: 125133.
  • 5
    Banks WA, Farrell CL. Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am J Physiol Endocrinol Metab 2003; 285: E1015.
  • 6
    Myers MG Jr, Munzberg H, Leinninger GM, Leshan RL. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab 2009; 9: 117123.
  • 7
    Munzberg H. Differential leptin access into the brain – a hierarchical organization of hypothalamic leptin target sites? Physiol Behav 2008; 94: 664669.
  • 8
    Irani BG, Le Foll C, Dunn-Meynell A, Levin BE. Effects of leptin on rat ventromedial hypothalamic neurons. Endocrinology 2008; 149: 51465154.
  • 9
    Adam CL, Moar KM, Logie TJ, Ross AW, Barrett P, Morgan PJ, Mercer JG. Photoperiod regulates growth, puberty and hypothalamic neuropeptide and receptor gene expression in female Siberian hamsters. Endocrinology 2000; 141: 43494356.
  • 10
    Mercer JG, Moar KM, Ross AW, Morgan PJ. Regulation of leptin receptor, POMC and AGRP gene expression by photoperiod and food deprivation in the hypothalamic arcuate nucleus of the male Siberian hamster (Phodopus sungorus). Appetite 2000; 34: 109111.
  • 11
    Mercer JG, Moar KM, Ross AW, Hoggard N, Morgan PJ. Photoperiod regulates arcuate nucleus POMC, AGRP, and leptin receptor mRNA in Siberian hamster hypothalamus. Am J Physiol Regul Integr Comp Physiol 2000; 278: R271R281.
  • 12
    Mercer JG, Moar KM, Logie TJ, Findlay PA, Adam CL, Morgan PJ. Seasonally inappropriate body weight induced by food restriction: effect on hypothalamic gene expression in male Siberian hamsters. Endocrinology 2001; 142: 41734181.
  • 13
    Mercer JG, Hoggard N, Williams LM, Lawrence CB, Hannah LT, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 1996; 387: 113116.
  • 14
    Spanswick D, Smith MA, Groppi VE, Logan SD, Ashford ML. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 1997; 390: 521525.
  • 15
    Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG Jr, Schwartz MW. Intracellular signalling Key enzyme in leptin-induced anorexia. Nature 2001; 413: 794795.
  • 16
    Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996; 14: 9597.
  • 17
    Myers MG Jr. Leptin receptor signaling and the regulation of mammalian physiology. Recent Prog Horm Res 2004; 59: 287304.
  • 18
    Tartaglia LA. The leptin receptor. J Biol Chem 1997; 272: 60936096.
  • 19
    Li C, Friedman JM. Leptin receptor activation of SH2 domain containing protein tyrosine phosphatase 2 modulates Ob receptor signal transduction. Proc Natl Acad Sci USA 1999; 96: 96779682.
  • 20
    White DW, Kuropatwinski KK, Devos R, Baumann H, Tartaglia LA. Leptin receptor (OB-R) signaling cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization. J Biol Chem 1997; 272: 40654071.
  • 21
    Banks AS, Davis SM, Bates SH, Myers MG Jr. Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000; 275: 1456314572.
  • 22
    Bjorbaek C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, Gu H, Neel BG, Myers MG Jr, Flier JS. Divergent roles of SHP-2 in ERK activation by leptin receptors. J Biol Chem 2001; 276: 47474755.
  • 23
    Gong Y, Ishida-Takahashi R, Villanueva EC, Fingar DC, Munzberg H, Myers MG Jr. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J Biol Chem 2007; 282: 3101931027.
  • 24
    Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C, Flier JS. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 2004; 10: 734738.
  • 25
    Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H, Yoshimura A. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 2004; 10: 739743.
  • 26
    Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 1999; 283: 15441548.
  • 27
    Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 2000; 20: 54795489.
  • 28
    Rondinone CM, Trevillyan JM, Clampit J, Gum RJ, Berg C, Kroeger P, Frost L, Zinker BA, Reilly R, Ulrich R, Butler M, Monia BP, Jirousek MR, Waring JF. Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis. Diabetes 2002; 51: 24052411.
  • 29
    Zinker BA, Rondinone CM, Trevillyan JM, Gum RJ, Clampit JE, Waring JF, Xie N, Wilcox D, Jacobson P, Frost L, Kroeger PE, Reilly RM, Koterski S, Opgenorth TJ, Ulrich RG, Crosby S, Butler M, Murray SF, McKay RA, Bhanot S, Monia BP, Jirousek MR. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci USA 2002; 99: 1135711362.
  • 30
    Baskin DG, Breininger JF, Schwartz MW. SOCS-3 expression in leptin-sensitive neurons of the hypothalamus of fed and fasted rats. Regul Pept 2000; 92: 915.
  • 31
    Munzberg H, Flier JS, Bjorbaek C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 2004; 145: 48804889.
  • 32
    Porte D Jr, Baskin DG, Schwartz MW. Leptin and insulin action in the central nervous system. Nutr Rev 2002; 60: S20S29.
  • 33
    Schwartz MW, Porte D Jr. Diabetes, obesity, and the brain. Science 2005; 307: 375379.
  • 34
    Heldmaier G, Ruf T. Body temperature and metabolic rate during natural hypothermia in endotherms. J Comp Physiol [B] 1992; 162: 696706.
  • 35
    Krol E, Tups A, Archer ZA, Ross AW, Moar KM, Bell LM, Duncan JS, Mayer C, Morgan PJ, Mercer JG, Speakman JR. Altered expression of SOCS3 in the hypothalamic arcuate nucleus during seasonal body mass changes in the field vole, Microtus agrestis. J Neuroendocrinol 2007; 19: 8394.
  • 36
    Ladyman SR, Grattan DR. Region-specific reduction in leptin-induced phosphorylation of signal transducer and activator of transcription-3 (STAT3) in the rat hypothalamus is associated with leptin resistance during pregnancy. Endocrinology 2004; 145: 37043711.
  • 37
    Ladyman SR, Grattan DR. Suppression of leptin receptor messenger ribonucleic acid and leptin responsiveness in the ventromedial nucleus of the hypothalamus during pregnancy in the rat. Endocrinology 2005; 146: 38683874.
  • 38
    Rousseau K, Atcha Z, Cagampang FR, Le Rouzic P, Stirland JA, Ivanov TR, Ebling FJ, Klingenspor M, Loudon AS. Photoperiodic regulation of leptin resistance in the seasonally breeding Siberian hamster (Phodopus sungorus). Endocrinology 2002; 143: 30833095.
  • 39
    Tups A, Ellis C, Moar KM, Logie TJ, Adam CL, Mercer JG, Klingenspor M. 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 2004; 145: 11851193.
  • 40
    Tups A, Barrett P, Ross AW, Morgan PJ, Klingenspor M, Mercer JG. 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 2006; 18: 139145.
  • 41
    Klingenspor M, Dickopp A, Heldmaier G, Klaus S. Short photoperiod reduces leptin gene expression in white and brown adipose tissue of Djungarian hamsters. FEBS Lett 1996; 399: 290294.
  • 42
    Klingenspor M, Niggemann H, Heldmaier G. Modulation of leptin sensitivity by short photoperiod acclimation in the Djungarian hamster, Phodopus sungorus. J Comp Physiol [B] 2000; 170: 3743.
  • 43
    Krol E, Duncan JS, Redman P, Morgan PJ, Mercer JG, Speakman JR. Photoperiod regulates leptin sensitivity in field voles, Microtus agrestis. J Comp Physiol [B] 2006; 176: 153163.
  • 44
    Steinlechner S, Heldmaier G. Role of photoperiod and melatonin in seasonal acclimatization of the Djungarian hamster, Phodopus sungorus. Int J Biometeorol 1982; 26: 329337.
  • 45
    Heldmaier G, Steinlechner S, Rafael J, Latteier B. Photoperiod and ambient temperature as environmental cues for seasonal thermogenic adaptation in the Djungarian hamster, Phodopus sungorus. Int J Biometeorol 1982; 26: 339345.
  • 46
    Morgan PJ, Ross AW, Mercer JG, Barrett P. Photoperiodic programming of body weight through the neuroendocrine hypothalamus. J Endocrinol 2003; 177: 2734.
  • 47
    Atcha Z, Cagampang FR, Stirland JA, Morris ID, Brooks AN, Ebling FJ, Klingenspor M, Loudon AS. 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 2000; 141: 41284135.
  • 48
    Mrosovsky N. Rheostasis: the physiology of change. New York: Oxford University Press, 1990.
  • 49
    Bartness TJ, Wade GN, Goldman BD. Are the short-photoperiod-induced decreases in serum prolactin responsible for the seasonal changes in energy balance in Syrian and Siberian hamsters? J Exp Zool 1987; 244: 437454.
  • 50
    Yellon SM, Goldman BD. Influence of short days on diurnal patterns of serum gonadotrophins and prolactin concentrations in the male Djungarian hamster, Phodopus sungorus. J Reprod Fertil 1987; 80: 167174.
  • 51
    Duncan MJ, Goldman BD. Hormonal regulation of the annual pelage color cycle in the Djungarian hamster, Phodopus sungorus II role of prolactin. J Exp Zool 1984; 230: 97103.
  • 52
    Niklowitz P, Hoffmann K. Pineal and pituitary involvement in the photoperiodic regulation of body weight, coat color and testicular size of the Djungarian hamster, Phodopus sungorus. Biol Reprod 1988; 39: 489498.
  • 53
    Badura LL, Goldman BD. Central sites mediating reproductive responses to melatonin in juvenile male Siberian hamsters. Brain Res 1992; 598: 98106.
  • 54
    Anderson GM, Beijer P, Bang AS, Fenwick MA, Bunn SJ, Grattan DR. Suppression of prolactin-induced signal transducer and activator of transcription 5b signaling and induction of suppressors of cytokine signaling messenger ribonucleic acid in the hypothalamic arcuate nucleus of the rat during late pregnancy and lactation. Endocrinology 2006; 147: 49965005.
  • 55
    Kokay IC, Grattan DR. Expression of mRNA for prolactin receptor (long form) in dopamine and pro-opiomelanocortin neurones in the arcuate nucleus of non-pregnant and lactating rats. J Neuroendocrinol 2005; 17: 827835.
  • 56
    Peraldi P, Filloux C, Emanuelli B, Hilton DJ, Van Obberghen E. Insulin induces suppressor of cytokine signaling-3 tyrosine phosphorylation through janus-activated kinase. J Biol Chem 2001; 276: 2461424620.
  • 57
    Pi XJ, Grattan DR. Differential expression of the two forms of prolactin receptor mRNA within microdissected hypothalamic nuclei of the rat. Brain Res Mol Brain Res 1998; 59: 112.
  • 58
    Pi XJ, Grattan DR. Distribution of prolactin receptor immunoreactivity in the brain of estrogen-treated, ovariectomized rats. J Comp Neurol 1998; 394: 462474.
  • 59
    Steyn FJ, Anderson GM, Grattan DR. Hormonal regulation of suppressors of cytokine signaling (SOCS) messenger ribonucleic acid in the arcuate nucleus during late pregnancy. Endocrinology 2008; 149: 32063214.
  • 60
    Roy AF, Benomar Y, Bailleux V, Vacher CM, Aubourg A, Gertler A, Djiane J, Taouis M. Lack of cross-desensitization between leptin and prolactin signaling pathways despite the induction of suppressor of cytokine signaling 3 and PTP-1B. J Endocrinol 2007; 195: 341350.
  • 61
    Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 1994; 13: 11771185.
  • 62
    Tups A, Helwig M, Stohr S, Barrett P, Mercer JG, Klingenspor M. Photoperiodic regulation of insulin receptor mRNA and intracellular insulin signaling in the arcuate nucleus of the Siberian hamster, Phodopus sungorus. Am J Physiol Regul Integr Comp Physiol 2006; B: R643650.
  • 63
    Merchenthaler I. Neurons with access to the general circulation in the central nervous system of the rat: a retrograde tracing study with fluoro-gold. Neuroscience 1991; 44: 655662.
  • 64
    Shaver SW, Pang JJ, Wainman DS, Wall KM, Gross PM. Morphology and function of capillary networks in subregions of the rat tuber cinereum. Cell Tissue Res 1992; 267: 437448.
  • 65
    Augustine RA, Grattan DR. Induction of central leptin resistance in hyperphagic pseudopregnant rats by chronic prolactin infusion. Endocrinology 2008; 149: 10491055.
  • 66
    Augustine RA, Ladyman SR, Grattan DR. From feeding one to feeding many: hormone-induced changes in bodyweight homeostasis during pregnancy. J Physiol 2008; 586: 387397.
  • 67
    Henson MC, Castracane VD. Leptin in pregnancy: an update. Biol Reprod 2006; 74: 218229.
  • 68
    Naef L, Woodside B. Prolactin/leptin interactions in the control of food intake in rats. Endocrinology 2007; 148: 59775983.
  • 69
    Gouilleux F, Pallard C, Dusanter-Fourt I, Wakao H, Haldosen LA, Norstedt G, Levy D, Groner B. Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-Stat5 DNA binding activity. EMBO J 1995; 14: 005013.
  • 70
    Barclay JL, Anderson ST, Waters MJ, Curlewis JD. SOCS3 as a tumor suppressor in breast cancer cells, and its regulation by PRL. Int J Cancer 2009; 124: 17561766.
  • 71
    Ladyman SR, Tups A, Augustine RA, Swahn-Azavedo AM, Kokay IC, Grattan DR. Loss of hypothalamic response to leptin during pregnancy associated with development of melanocortin resistance. J Neuroendocrinol 2009; 21: 449456.
  • 72
    Levin BE, Hogan S, Sullivan AC. Initiation and perpetuation of obesity and obesity resistance in rats. Am J Physiol 1989; 256: R766R771.
  • 73
    Irani BG, Le FollC, Dunn-Meynell AA, Levin BE. Ventromedial nucleus neurons are less sensitive to leptin excitation in rats bred to develop diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 2009; 296: R521R527.
  • 74
    Bouret SG, Gorski JN, Patterson CM, Chen S, Levin BE, Simerly RB. Hypothalamic neural projections are permanently disrupted in diet-induced obese rats. Cell Metab 2008; 7: 179185.
  • 75
    Levin BE, Dunn-Meynell AA, Banks WA. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am J Physiol Regul Integr Comp Physiol 2004; 286: R143R150.
  • 76
    Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG, Heinecke JW, Woods SC, Schwartz MW, Niswender KD. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab 2009; 296: E1003E1012.
  • 77
    Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008; 135: 6173.
  • 78
    Moraes JC, Coope A, Morari J, Cintra DE, Roman EA, Pauli JR, Romanatto T, Carvalheira JB, Oliveira AL, Saad MJ, Velloso LA. High-fat diet induces apoptosis of hypothalamic neurons. PLoS ONE 2009; 4: e5045.