The brain has been recognized as a prominent site of peptide biosynthesis for more than 30 years, and many neuropeptides are now known to be common to gut and brain. With these precedents in mind it is remarkable that adipose-derived peptides like leptin have attracted minimal attention as brain-derived putative neuromodulators of energy balance. This review outlines the evidence that several adipose-specific genes are also expressed in the central nervous system and pituitary gland. We, and others, confirmed that the genes for leptin, resistin, adiponectin, FIAF (fasting-induced adipose factor) and adiponutrin are expressed and regulated in these tissues. For example, leptin mRNA was readily detectable in human, rat, sheep and pig brain, but not in the mouse. Leptin expression in rat brain and pituitary was regulated through development, by food restriction, and following traumatic brain injury. In contrast, hypothalamic resistin mRNA was unaffected by age or by fasting, but was significantly depleted by food restriction in mouse pituitary gland. Similar results were seen in the ob/ob mouse, and we noted a marked reduction in resistin-positive hypothalamic nerve fibres. Resistin and fiaf mRNA were also upregulated in hypoxic/ischaemic mouse brain. Our studies on the regulation of neuronal adipokines were greatly aided by the availability of clonal hypothalamic neuronal cell lines. One of these, N-1, expresses both rstn and fiaf together with several other neuropeptides and receptors involved in energy homeostasis. Selective silencing of rstn revealed an autocrine/paracrine regulatory system, mediated through socs-3 expression that may influence the feedback effects of insulin and leptin in vivo. A similar convergence of signals in the pituitary gland could also influence anterior pituitary hormone secretion. In conclusion, the evidence is suggestive that brain and pituitary-derived adipokines represent a local regulatory circuit that may fine tune the feedback effects of adipose hormones in the control of energy balance.

Keywords:
Leptin, Resistin, Adiponectin, Fasting-induced adipose factor, Blood-brain barrier, Hypothalamus, RNA interference, Cephalokines
1.
Krieger DT: Brain peptides: What, where, and why? Science 1983;222:975–985.
2.
Bryant MG, Polak MM, Modlin I, Bloom SR, Albuquerque RH, Pearse AG: Possible dual role for vasoactive intestinal peptide as gastrointestinal hormone and neurotransmitter substance. Lancet 1976;1:991–993.
3.
Dockray GJ: The G.L. Brown lecture. Regulatory peptides and the neuroendocrinology of gut-brain relations. Q J Exp Physiol 1988;73:703–727.
4.
Polak JM, Bloom SR: Regulatory peptides of the gastrointestinal and respiratory tracts. Arch Int Pharmacodyn Ther 1986;280:16–49.
5.
Sato T, Fukue Y, Teranishi H, Yoshida Y, Kojima M: Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-D-glucose administration. Endocrinology 2005;146:2510–2516.
6.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–432.
7.
Trayhurn P, Bing C, Wood IS: Adipose tissue and adipokines – energy regulation from the human perspective. J Nutr 2006;136:1935S–1939S.
8.
Lafontan M: Fat cells: afferent and efferent messages define new approaches to treat obesity. Annu Rev Pharmacol Toxicol 2005;45:119–146.
9.
Koerner A, Kratzsch J, Kiess W: Adipocytokines: Leptin – the classical, resistin – the controversical, adiponectin – the promising, and more to come. Best Pract Res Clin Endocrinol Metab 2005;19:525–546.
10.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature 2001;409:307–312.
11.
Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF: A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995;270:26746–26749.
12.
Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B, Wahli W: Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem 2000;275:28488–28493.
13.
Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I: Visfatin: A protein secreted by visceral fat that mimics the effects of insulin. Science 2005;307:426–430.
14.
Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS: Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci USA 2005;102:10610–10615.
15.
Bullo M, Peeraully MR, Trayhurn P: Stimulation of ngf expression and secretion in 3T3-1 adipocytes by prostaglandins PGD2, PGJ2, and Δ12-PGJ2. Am J Physiol 2005;289:E62–E67.
16.
Kratchmarova I, Kalume DE, Blagoev B, Scherer PE, Podtelejnikov AV, Molina H, Bickel PE, Andersen JS, Fernandez MM, Bunkenborg J, Roepstorff P, Kristiansen K, Lodish HF, Mann M, Pandey A: A proteomic approach for identification of secreted proteins during the differentiation of 3T3-L1 preadipocytes to adipocytes. Mol Cell Proteomics 2002;1:213–222.
17.
Yang YS, Song HD, Li RY, Zhou LB, Zhu ZD, Hu RM, Han ZG, Chen JL: The gene expression profiling of human visceral adipose tissue and its secretory functions. Biochem Biophys Res Commun 2003;300:839–846.
18.
Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB: Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 1998;395:535–547.
19.
Funahashi H, Yada T, Suzuki R, Shioda S: Distribution, function, and properties of leptin receptors in the brain. Int Rev Cytol 2003;224:1–27.
20.
Burguera B, Couce ME, Long J, Lamsam J, Laakso K, Jensen MD, Parisi JE, Lloyd RV: The long form of the leptin receptor (OB-Rb) is widely expressed in the human brain. Neuroendocrinology 2000;71:187–195.
21.
Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV: Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab 1999;84:2903–2911.
22.
Cai A, Hyde JF: The human growth hormone-releasing hormone transgenic mouse as a model of modest obesity: differential changes in leptin receptor (OBR) gene expression in the anterior pituitary and hypothalamus after fasting and obr localization in somatotrophs. Endocrinology 1999;140:3609–3614.
23.
Morash B, Li A, Murphy PR, Wilkinson M, Ur E: Leptin gene expression in the brain and pituitary gland. Endocrinology 1999;140:5995–5998.
24.
Wilkinson M, Morash B, Ur E: The brain is a source of leptin. Front Horm Res 2000;26:106–125.
25.
Wiesner G, Vaz M, Collier G, Seals D, Kaye D, Jennings G, Lambert G, Wilkinson D, Esler M: Leptin is released from the human brain: influence of adiposity and gender. J Clin Endocrinol Metab 1999;84:2270–2274.
26.
Eikelis N, Esler M: The neurobiology of human obesity. Exp Physiol 2005;90:673–682.
27.
Bennett BD, Solar GP, Yuan JQ, Mathias J, Thomas GR, Matthews W: A role for leptin and its cognate receptor in hematopoiesis. Curr Biol 1996;6:1170–1180.
28.
Himms-Hagen J: Physiological roles of the leptin endocrine system: differences between mice and humans. Crit Rev Clin Lab Sci 1999;36:575–655.
29.
Arner P: Resistin: Yet another adipokine tells us that men are not mice. Diabetologia 2005;48:2203–2205.
30.
Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM: Leptin enters the brain by a saturable system independent of insulin. Peptides 1996;17:305–311.
31.
Banks WA: The blood-brain barrier as a regulatory interface in the gut-brain axes. Physiol Behav 2006;89:472–476.
32.
Zlokovic BV, Jovanovic S, Miao W, Samara S, Verma S, Farrell CL: Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier. Endocrinology 2000;141:1434–1441.
33.
Kurrimbux D, Gaffen Z, Farrell CL, Martin D, Thomas SA: The involvement of the blood-brain and the blood-cerebrospinal fluid barriers in the distribution of leptin into and out of the rat brain. Neuroscience 2004;123:527–536.
34.
Ahima RS: Central actions of adipocyte hormones. Trends Endocrinol Metab 2005;16:307–313.
35.
Rivest S: Does circulating leptin have the ability to cross the blood-brain barrier and target neurons directly? Endocrinology 2002;143:3211–3213.
36.
Banks WA, Clever CM, Farrell CL: Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice. Am J Physiol 2000;278:E1158–E1165.
37.
Hileman SM, Pierroz DD, Masuzaki H, Bjorbaek C, El-Haschimi K, Banks WA, Flier JS: Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. Endocrinology 2002;143:775–783.
38.
Kastin AJ, Pan W: Dynamic regulation of leptin entry into brain by the blood-brain barrier. Regul Pept 2000;92:37–43.
39.
Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF: Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest 1996;98:1277–1282.
40.
Zastrow O, Seidel B, Kiess W, Thiery J, Keller E, Bottner A, Kratzsch J: The soluble leptin receptor is crucial for leptin action: evidence from clinical and experimental data. Int J Obes Relat Metab Disord 2003;27:1472–1478.
41.
Wong ML, Licinio J, Yildiz BO, Mantzoros CS, Prolo P, Kling M, Gold PW: Simultaneous and continuous 24-hour plasma and cerebrospinal fluid leptin measurements: dissociation of concentrations in central and peripheral compartments. J Clin Endocrinol Metab 2004;89:258–265.
42.
Adam CL, Findlay PA, Miller DW: Blood-brain leptin transport and appetite and reproductive neuroendocrine responses to intracerebroventricular leptin injection in sheep: influence of photoperiod. Endocrinology 2006;147:4589–4598.
43.
Uotani S, Bjorbaek C, Tornoe J, Flier JS: Functional properties of leptin receptor isoforms: internalization and degradation of leptin and ligand-induced receptor downregulation. Diabetes 1999;48:279–286.
44.
Ahima RS, Qi Y, Singhal NS: Adipokines that link obesity and diabetes to the hypothalamus. Prog Brain Res 2006;153:155–174.
45.
Kelly JF, Elias CF, Lee CE, Ahima RS, Seeley RJ, Bjorbaek C, Oka T, Saper CB, Flier JS, Elmquist JK: Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain. Diabetes 2004;53:911–920.
46.
Hakansson ML, Meister B: Transcription factor STAT-3 in leptin target neurons of the rat hypothalamus. Neuroendocrinology 1998;68:420–427.
47.
Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM: Leptin activation of STAT-3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 1996;14:95–97.
48.
Hosoi T, Kawagishi T, Okuma Y, Tanaka J, Nomura Y: Brain stem is a direct target for leptin’s action in the central nervous system. Endocrinology 2002;143:3498–3504.
49.
Polizzotto MN, Bartlett PF, Turnley AM: Expression of ‘suppressor of cytokine signalling’ (SOCS) genes in the developing and adult mouse nervous system. J Comp Neurol 2000;423:348–358.
50.
Stromberg H, Svensson SP, Hermanson O: Distribution of the transcription factor signal transducer and activator of transcription 3 in the rat central nervous system and dorsal root ganglia. Brain Res 2000;853:105–114.
51.
Pan W, Tu H, Kastin AJ: Differential BBB interactions of three ingestive peptides: obestatin, ghrelin, and adiponectin. Peptides 2006;27:911–916.
52.
Spranger J, Verma S, Gohring I, Bobbert T, Seifert J, Sindler AL, Pfeiffer A, Hileman SM, Tschop M, Banks WA: Adiponectin does not cross the blood-brain barrier but modifies cytokine expression of brain endothelial cells. Diabetes 2006;55:141–147.
53.
Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS: Adiponectin acts in the brain to decrease body weight. Nat Med 2004;10:524–529.
54.
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T: Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762–769.
55.
Maddineni S, Metzger S, Ocón O, Hendricks G 3rd, Ramachandran R: Adiponectin gene is expressed in multiple tissues in the chicken: food deprivation influences adiponectin messenger ribonucleic acid expression. Endocrinology 2005;146:4250–4256.
56.
Kastin AJ, Akerstrom V, Pan W: Validity of multiple-time regression analysis in measurement of tritiated and iodinated leptin crossing the blood-brain barrier: meaningful controls. Peptides 2001;22:2127–2136.
57.
Zelissen PM, Stenlof K, Lean ME, Fogteloo J, Keulen ET, Wilding J, Finer N, Rossner S, Lawrence E, Fletcher C, McCamish M: Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial. Diabetes Obes Metab 2005;7:755–761.
58.
Bell-Anderson KS, Bryson JM: Leptin as a potential treatment for obesity: progress to date. Treat Endocrinol 2004;3:11–18.
59.
Farooqi IS, O’Rahilly S: Monogenic obesity in humans. Annu Rev Med 2005;56:443–458.
60.
Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O’Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004;101:4531–4536.
61.
Pan W, Yu Y, Cain CM, Nyberg F, Couraud PO, Kastin AJ: Permeation of growth hormone across the blood-brain barrier. Endocrinology 2005;146:4898–4904.
62.
Donahue CP, Kosik KS, Shors TJ: Growth hormone is produced within the hippocampus where it responds to age, sex, and stress. Proc Natl Acad Sci USA 2006;103:6031–6036.
63.
Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T: Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 2002;113:607–615.
64.
Harvey J, Solovyova N, Irving A: Leptin and its role in hippocampal synaptic plasticity. Prog Lipid Res 2006;45:369–378.
65.
Farr SA, Banks WA, Morley JE: Effects of leptin on memory processing. Peptides 2006;27:1420–1425.
66.
Oomura Y, Hori N, Shiraishi T, Fukunaga K, Takeda H, Tsuji M, Matsumiya T, Ishibashi M, Aou S, Li XL, Kohno D, Uramura K, Sougawa H, Yada T, Wayner MJ, Sasaki K: Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats. Peptides 2006;27:2738–2749.
67.
Elias MF, Elias PK, Sullivan LM, Wolf PA, D’Agostino RB: Obesity, diabetes and cognitive deficit: The Framingham Heart Study. Neurobiol Aging 2005;26(suppl 1):11–16.
68.
Steppan CM, Lazar MA: The current biology of resistin. J Intern Med 2004;255:439–447.
69.
Sahu A: Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol 2003;24:225–253.
70.
Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B: Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci 1998;18:559–572.
71.
Patz S, Wahle P: Developmental changes of neurotrophin mRNA expression in the layers of rat visual cortex. Eur J Neurosci 2006;24:2453–2460.
72.
Ur E, Wilkinson DA, Morash BA, Wilkinson M: Leptin immunoreactivity is localized to neurons in rat brain. Neuroendocrinology 2002;75:264–272.
73.
Wilkinson M, Wilkinson D, Wiesner G, Morash B, Ur E: Hypothalamic resistin immunoreactivity is reduced by obesity in the mouse: co-localization with α-melanostimulating hormone. Neuroendocrinology 2005;81:19–30.
74.
Morash B, Wilkinson D, Murphy P, Ur E, Wilkinson M: Developmental regulation of leptin gene expression in rat brain and pituitary. Mol Cell Endocrinol 2001;185:151–159.
75.
Morash BA, Ur E, Wilkinson M: Pituitary leptin gene expression is reduced by neonatal androgenization of female rats. Pituitary 2001;4:63–70.
76.
Thompson HJ, Lifshitz J, Marklund N, Grady MS, Graham DI, Hovda DA, McIntosh TK: Lateral fluid percussion brain injury: a 15-year review and evaluation. J Neurotrauma 2005;22:42–75.
77.
Wilkinson M, Brown R, Thompson H, Imran A, Ur E, Lebold DG: Expression of brain-derived leptin and fasting-induced adipose factor following traumatic brain injury. Front Neuroendocrinol 2006;27:93.
78.
Morash B, Johnstone J, Leopold C, Li A, Murphy P, Ur E, Wilkinson M: The regulation of leptin gene expression in the C6 glioblastoma cell line. Mol Cell Endocrinol 2000;165:97–105.
79.
Li AW, Morash B, Hollenberg AN, Ur E, Wilkinson M, Murphy PR: Transcriptional regulation of the leptin gene promoter in rat GH3 pituitary and C6 glioma cells. Mol Cell Endocrinol 2001;176:57–65.
80.
Slieker LJ, Sloop KW, Surface PL, Kriauciunas A, LaQuier F, Manetta J, Bue-Valleskey J, Stephens TW: Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 1996;271:5301–5304.
81.
Miller VM, Paulson HL, Gonzalez-Alegre P: RNA interference in neuroscience: progress and challenges. Cell Mol Neurobiol 2005;25:1195–1207.
82.
Makimura H, Mizuno TM, Mastaitis JW, Agami R, Mobbs CV: Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake. BMC Neurosci 2002;3:18.
83.
Brown R, Morash B, Ur E, Wilkinson M: RNAi-mediated silencing of leptin gene expression increases cell death in C6 glioblastoma cells. Brain Res Mol Brain Res 2005;139:357–360.
84.
Russo VC, Metaxas S, Kobayashi K, Harris M, Werther GA: Antiapoptotic effects of leptin in human neuroblastoma cells. Endocrinology 2004;145:4103–4112.
85.
Knerr I, Schuster S, Nomikos P, Buchfelder M, Dotsch J, Schoof E, Fahlbusch R, Rascher W: Gene expression of adrenomedullin, leptin, their receptors and neuropeptide Y in hormone-secreting and non-functioning pituitary adenomas, meningiomas and malignant intracranial tumours in humans. Neuropathol Appl Neurobiol 2001;27:215–222.
86.
Eikelis N, Esler M, Barton D, Dawood T, Wiesner G, Lambert G: Reduced brain leptin in patients with major depressive disorder and in suicide victims. Mol Psychiatry 2006;11:800–801.
87.
Eikelis N, Lambert G, Wiesner G, Kaye D, Schlaich M, Morris M, Hastings J, Socratous F, Esler M: Extra-adipocyte leptin release in human obesity and its relation to sympathoadrenal function. Am J Physiol 2004;286:E744–E752.
88.
Esler M, Vaz M, Collier G, Nestel P, Jennings G, Kaye D, Seals D, Lambert G: Leptin in human plasma is derived in part from the brain, and cleared by the kidneys. Lancet 1998;351:879.
89.
Reichlin S: Is leptin a secretion of the brain? J Clin Endocrinol Metab 1999;84:2267–2269.
90.
Korbonits M, Chitnis MM, Gueorguiev M, Norman D, Rosenfelder N, Suliman M, Jones TH, Noonan K, Fabbri A, Besser GM, Burrin JM, Grossman AB: The release of leptin and its effect on hormone release from human pituitary adenomas. Clin Endocrinol (Oxf) 2001;54:781–789.
91.
Smith EL, Hainsworth AH: Acute effects of interleukin-1β on noradrenaline release from the human neuroblastoma cell line SH-SY5Y. Neurosci Lett 1998;251:89–92.
92.
Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA: Activation of SOCS-3 by resistin. Mol Cell Biol 2005;25:1569–1575.
93.
Jung HS, Park KH, Cho YM, Chung SS, Cho HJ, Cho SY, Kim SJ, Kim SY, Lee HK, Park KS: Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc Res 2006;69:76–85.
94.
Yang RZ, Huang Q, Xu A, McLenithan JC, Eisen JA, Shuldiner AR, Alkan S, Gong DW: Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun 2003;310:927–935.
95.
Lappas M, Yee K, Permezel M, Rice GE: Release and regulation of leptin, resistin and adiponectin from human placenta, fetal membranes, and maternal adipose tissue and skeletal muscle from normal and gestational diabetes mellitus-complicated pregnancies. J Endocrinol 2005;186:457–465.
96.
Minn AH, Patterson NB, Pack S, Hoffmann SC, Gavrilova O, Vinson C, Harlan DM, Shalev A: Resistin is expressed in pancreatic islets. Biochem Biophys Res Commun 2003;310:641–645.
97.
Nogueiras R, Gallego R, Gualillo O, Caminos JE, Garcia-Caballero T, Casanueva FF, Dieguez C: Resistin is expressed in different rat tissues and is regulated in a tissue- and gender-specific manner. FEBS Lett 2003;548:21–27.
98.
Tsukamoto H: Adipogenic phenotype of hepatic stellate cells. Alcohol Clin Exp Res 2005;29:132S–133S.
99.
McTernan PG, Kusminski CM, Kumar S: Resistin. Curr Opin Lipidol 2006;17:170–175.
100.
Morash BA, Ur E, Wiesner G, Roy J, Wilkinson M: Pituitary resistin gene expression: effects of age, gender and obesity. Neuroendocrinology 2004;79:149–156.
101.
Morash BA, Wilkinson D, Ur E, Wilkinson M: Resistin expression and regulation in mouse pituitary. FEBS Lett 2002;526:26–30.
102.
Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O’Rahilly S: Resistin/fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-γ action in humans. Diabetes 2001;50:2199–2202.
103.
Tovar S, Nogueiras R, Tung LY, Castaneda TR, Vazquez MJ, Morris A, Williams LM, Dickson SL, Dieguez C: Central administration of resistin promotes short-term satiety in rats. Eur J Endocrinol 2005;153:R1–R5.
104.
Ort T, Arjona AA, MacDougall JR, Nelson PJ, Rothenberg ME, Wu F, Eisen A, Halvorsen YD: Recombinant human fizz3/resistin stimulates lipolysis in cultured human adipocytes, mouse adipose explants, and normal mice. Endocrinology 2005;146:2200–2209.
105.
Bouret SG, Simerly RB: Leptin and development of hypothalamic feeding circuits. Endocrinology 2004;145:2621–2626.
106.
Bouret SG, Draper SJ, Simerly RB: Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 2004;24:2797–2805.
107.
Bouret SG, Draper SJ, Simerly RB: Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108–110.
108.
Flier JS: Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004;116:337–350.
109.
Liu F, Guo XR, Gong HX, Ni YH, Fei L, Pan XQ, Guo M, Chen RH: A resistin binding peptide selected by phage display inhibits 3T3-L1 preadipocyte differentiation. Chin Med J (Engl) 2006;119:496–503.
110.
Brunetti L, Orlando G, Recinella L, Michelotto B, Ferrante C, Vacca M: Resistin, but not adiponectin, inhibits dopamine and norepinephrine release in the hypothalamus. Eur J Pharmacol 2004;493:41–44.
111.
Belsham DD, Cai F, Cui H, Smukler SR, Salapatek AM, Shkreta L: Generation of a phenotypic array of hypothalamic neuronal cell models to study complex neuroendocrine disorders. Endocrinology 2004;145:393–400.
112.
Brown R, Imran S, Belsham DD, Ur E, Wilkinson M: Valproic acid reduces resistin, but increases SOCS-3, expression in a novel hypothalamic cell line. Front Neuroendocrinol 2006;27:93.
113.
Brown R, Imran S, Belsham DD, Ur E, Wilkinson M: Adipokine gene expression in a novel hypothalamic neuronal cell line: resistin-dependent regulation of fasting-induced adipose factor and SOCS-3. Neuroendocrinology 2007;85:232–241.
114.
Brown RE, Imran A, Belsham DD, Ur E, Wilkinson M: Regulation of brain-derived resistin and FIAF in a novel hypothalamic neuronal cell line. 8th European Congress of Endocrinology, Glasgow 2006.
115.
Kim S, Moustaid-Moussa N: Secretory, endocrine and autocrine/paracrine function of the adipocyte. J Nutr 2000;130:3110S–3115S.
116.
Kim I, Moon SO, Koh KN, Kim H, Uhm CS, Kwak HJ, Kim NG, Koh GY: Molecular cloning, expression, and characterization of angiopoietin-related protein. Angiopoietin-related protein induces endothelial cell sprouting. J Biol Chem 1999;274:26523–26528.
117.
Wiesner G, Morash BA, Ur E, Wilkinson M: Food restriction regulates adipose-specific cytokines in pituitary gland but not in hypothalamus. J Endocrinol 2004;180:R1–R6.
118.
Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J, Philippe J, Sibony M, Gasc JM, Corvol P, Germain S: Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol 2003;162:1521–1528.
119.
Lal A, Peters H, St Croix B, Haroon ZA, Dewhirst MW, Strausberg RL, Kaanders JH, van der Kogel AJ, Riggins GJ: Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 2001;93:1337–1343.
120.
Kim I, Kim HG, Kim H, Kim HH, Park SK, Uhm CS, Lee ZH, Koh GY: Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis. Biochem J 2000;346:603–610.
121.
Belanger AJ, Lu H, Date T, Liu LX, Vincent KA, Akita GY, Cheng SH, Gregory RJ, Jiang C: Hypoxia up-regulates expression of peroxisome proliferator-activated receptor-γ angiopoietin-related gene in cardiomyocytes: role of hypoxia inducible factor 1α. J Mol Cell Cardiol 2002;34:765–774.
122.
Wiesner G, Brown RE, Robertson GS, Imran SA, Ur E, Wilkinson M: Increased expression of the adipokine genes resistin and fasting-induced adipose factor in hypoxic/ischaemic mouse brain. Neuroreport 2006;17:1195–1198.
123.
Hayashi T, Noshita N, Sugawara T, Chan PH: Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 2003;23:166–180.
124.
Nag S: The blood-brain barrier and cerebral angiogenesis: lessons from the cold-injury model. Trends Mol Med 2002;8:38–44.
125.
Trayhurn P, Wood IS: Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 2004;92:347–355.
126.
Xu A, Lam MC, Chan KW, Wang Y, Zhang J, Hoo RL, Xu JY, Chen B, Chow WS, Tso AW, Lam KS: Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci USA 2005;102:6086–6091.
127.
Mobbs CV, Isoda F, Makimura H, Mastaitis J, Mizuno T, Shu IW, Yen K, Yang XJ: Impaired glucose signaling as a cause of obesity and the metabolic syndrome: the glucoadipostatic hypothesis. Physiol Behav 2005;85:3–23.
128.
Jin L, Zhang S, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV: Leptin and leptin receptor expression in rat and mouse pituitary cells. Endocrinology 2000;141:333–339.
129.
Korbonits M, Chitnis MM, Gueorguiev M, Jordan S, Norman D, Kaltsas G, Burrin JM, Grossman AB: Leptin in pituitary adenomas – a novel paracrine regulatory system. Pituitary 2001;4:49–55.
130.
Smolinska N, Przala J, Kaminski T, Siawrys G, Gajewska A, Kochman K, Okrasa S: Leptin gene expression in the hypothalamus and pituitary of pregnant pigs. Neuro Endocrinol Lett 2004;25:191–195.
131.
Yonekura S, Senoo T, Kobayashi Y, Yonezawa T, Katoh K, Obara Y: Effects of acetate and butyrate on the expression of leptin and short-form leptin receptor in bovine and rat anterior pituitary cells. Gen Comp Endocrinol 2003;133:165–172.
132.
Crespi EJ, Denver RJ: Leptin (ob gene) of the South African clawed frog Xenopus laevis. Proc Natl Acad Sci USA 2006;103:10092–10097.
133.
Sone M, Nagata H, Takekoshi S, Osamura RY: Expression and localization of leptin receptor in the normal rat pituitary gland. Cell Tissue Res 2001;305:351–356.
134.
Morash BA, Imran A, Wilkinson D, Ur E, Wilkinson M: Leptin receptors are developmentally regulated in rat pituitary and hypothalamus. Mol Cell Endocrinol 2003;210:1–8.
135.
McDuffie IA, Akhter N, Childs GV: Regulation of leptin mRNA and protein expression in pituitary somatotropes. J Histochem Cytochem 2004;52:263–273.
136.
Sone M, Osamura RY: Leptin and the pituitary. Pituitary 2001;4:15–23.
137.
Fauquier T, Lacampagne A, Travo P, Bauer K, Mollard P: Hidden face of the anterior pituitary. Trends Endocrinol Metab 2002;13:304–309.
138.
Jin L, Tsumanuma I, Ruebel KH, Bayliss JM, Lloyd RV: Analysis of homogeneous populations of anterior pituitary folliculostellate cells by laser capture microdissection and reverse transcription-polymerase chain reaction. Endocrinology 2001;142:1703–1709.
139.
Lloyd RV, Jin L, Ruebel KH, Bayliss JM: Analysis of folliculostellate cells by laser capture microdissection and reverse transcription-polymerase chain reaction. Methods Enzymol 2002;356:248–255.
140.
Lloyd RV, Jin L, Tsumanuma I, Vidal S, Kovacs K, Horvath E, Scheithauer BW, Couce ME, Burguera B: Leptin and leptin receptor in anterior pituitary function. Pituitary 2001;4:33–47.
141.
Vidal S, Cohen SM, Horvath E, Kovacs K, Scheithauer BW, Burguera BG, Lloyd RV: Subcellular localization of leptin in non-tumorous and adenomatous human pituitaries: an immuno-ultrastructural study. J Histochem Cytochem 2000;48:1147–1152.
142.
Cammisotto PG, Bukowiecki LJ: Role of calcium in the secretion of leptin from white adipocytes. Am J Physiol 2004;287:R1380–R1386.
143.
Bjorbaek C, Kahn BB: Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 2004;59:305–331.
144.
Horsch D, Kahn CR: Region-specific mRNA expression of phosphatidylinositol 3-kinase regulatory isoforms in the central nervous system of C57BL/6J mice. J Comp Neurol 1999;415:105–120.
145.
Tsumanuma I, Jin L, Zhang S, Bayliss JM, Scheithauer BW, Lloyd RV: Leptin signal transduction in the HP75 human pituitary cell line. Pituitary 2000;3:211–220.
146.
Gautron L, Lafon P, Chaigniau M, Tramu G, Laye S: Spatiotemporal analysis of signal transducer and activator of transcription 3 activation in rat brain astrocytes and pituitary following peripheral immune challenge. Neuroscience 2002;112:717–729.
147.
Bousquet C, Zatelli MC, Melmed S: Direct regulation of pituitary proopiomelanocortin by STAT-3 provides a novel mechanism for immuno-neuroendocrine interfacing. J Clin Invest 2000;106:1417–1425.
148.
Glavaski-Joksimovic A, Rowe EW, Jeftinija K, Scanes CG, Anderson LL, Jeftinija S: Effects of leptin on intracellular calcium concentrations in isolated porcine somatotropes. Neuroendocrinology 2004;80:73–82.
149.
Casanueva FF, Dieguez C: Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol 1999;20:317–363.
150.
Ahima RS, Saper CB, Flier JS, Elmquist JK: Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 2000;21:263–307.
151.
Kaminski T, Smolinska N, Gajewska A, Siawrys G, Okrasa S, Kochman K, Przala J: Leptin and long form of leptin receptor genes expression in the hypothalamus and pituitary during the luteal phase and early pregnancy in pigs. J Physiol Pharmacol 2006;57:95–108.
152.
Szczepankiewicz D, Wojciechowicz T, Kaczmarek P, Nowak KW: Leptin and its receptors in the course of pregnancy in the rat. Int J Mol Med 2006;17:95–99.
153.
Bennett PA, Lindell K, Karlsson C, Robinson IC, Carlsson LM, Carlsson B: Differential expression and regulation of leptin receptor isoforms in the rat brain: effects of fasting and oestrogen. Neuroendocrinology 1998;67:29–36.
154.
Meli R, Pacilio M, Raso GM, Esposito E, Coppola A, Nasti A, Di Carlo C, Nappi C, Di Carlo R: Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats. Endocrinology 2004;145:3115–3121.
155.
Ramachandran R, Ocón-Grove OM, Metzger SL: Molecular cloning and tissue expression of chicken AdipoR1 and AdipoR2 complementary deoxyribonucleic acids. Domest Anim Endocrinol 2007;33:19–31.
156.
Malagon MM, Rodriguez-Pacheco F, Martinez-Fuentes AJ, Tovar S, Pinilla L, Tena-Sempere M, Dieguez C, Castano JP: Regulation of pituitary cell function by the adipokine adiponectin. Front Neuroendocrinol 2006;27:35.
157.
Lu M, Tang Q, Olefsky JM, Webster NJG, Mellon PL: Adiponectin activates AMPK and increases luteinizing hormone secretion in LbT2 gonadotropes. Endocrine Society. Abstracts 2006, P1–381.
158.
Brown R, Wiesner G, Ur E, Wilkinson M: Pituitary resistin gene expression is upregulated in vitro and in vivo by dexamethasone but is unaffected by rosiglitazone. Neuroendocrinology 2005;81:41–48.
159.
Unger JW, Betz M: Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: a review on morphological findings and functional implications. Histol Histopathol 1998;13:1215–1224.
160.
Kawamata Y, Habata Y, Fukusumi S, Hosoya M, Fujii R, Hinuma S, Nishizawa N, Kitada C, Onda H, Nishimura O, Fujino M: Molecular properties of apelin: tissue distribution and receptor binding. Biochim Biophys Acta 2001;1538:162–171.
161.
Platt KA, Min HY, Ross SR, Spiegelman BM: Obesity-linked regulation of the adipsin gene promoter in transgenic mice. Proc Natl Acad Sci USA 1989;86:7490–7494.
162.
Zhang HT, Li LY, Zou XL, Song XB, Hu YL, Feng ZT, Wang TT: The immunohistochemical distribution of NGF, BDNF, NT-3, NT-4 in the brains of adult rhesus monkeys. J Histochem Cytochem 2007;55:1–19.
163.
Peeraully MR, Jenkins JR, Trayhurn P: NGF gene expression and secretion in white adipose tissue: regulation in 3T3-L1 adipocytes by hormones and inflammatory cytokines. Am J Physiol 2004;287:E331–E339.
164.
Gomez-Ambrosi J, Catalan V, Diez-Caballero A, Martinez-Cruz LA, Gil MJ, Garcia-Foncillas J, Cienfuegos JA, Salvador J, Mato JM, Fruhbeck G: Gene expression profile of omental adipose tissue in human obesity. FASEB J 2004;18:215–217.
165.
Guan H, Arany E, van Beek JP, Chamson-Reig A, Thyssen S, Hill DJ, Yang K: Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats. Am J Physiol 2005;288:E663–E673.
166.
Friedberg M, Zoumakis E, Hiroi N, Bader T, Chrousos GP, Hochberg Z: Modulation of 11β-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. J Clin Endocrinol Metab 2003;88:385–393.
167.
Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA, Ehrhart-Bornstein M: Corticotropin-releasing hormone system in human adipose tissue. J Clin Endocrinol Metab 2004;89:965–970.
168.
McIntosh TK, Vink R, Noble L, Yamakami I, Fernyak S, Soares H, Faden AL: Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience 1989;28:233–244.
169.
Beretta E, Dube MG, Kalra PS, Kalra SP: Long-term suppression of weight gain, adiposity, and serum insulin by central leptin gene therapy in prepubertal rats: effects on serum ghrelin and appetite-regulating genes. Pediatr Res 2002;52:189–198.
170.
Ehrhardt RA, Bell AW, Boisclair YR: Spatial and developmental regulation of leptin in fetal sheep. Am J Physiol 2002;282:R1628–R1635.
171.
Boswell T, Dunn IC, Wilson PW, Joseph N, Burt DW, Sharp PJ: Identification of a non-mammalian leptin-like gene: characterization and expression in the tiger Salamander (Ambystoma tigrinum). Gen Comp Endocrinol 2006;146:157–166.
172.
Buono S, Putti R: Leptin, leptin receptors and ACTH immunoreactivities are present in the gastrointestinal tract and the neural tube of tadpoles of the newt Triturus. J Mol Histol 2004;35:103–109.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.