Abstract
Hypothalamic neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) influence feeding and levels of plasma glucose, insulin, free fatty acids, and triglycerides. Treatment of genetically obese, ob/ob mice, with dopamine receptor D1/D2 agonists normalizes hyperphagia, body weight gain, hyperglycemia, and hyperlipidemia. We therefore examined whether levels of NPY and CRH immunoreactivity in discrete hypothalamic nuclei are altered in ob/ob mice, and whether dopaminergic treatment reverses this alteration. Female ob/ob mice were treated daily at 1 h after light onset with the D1/D2 agonists, SKF-38393 (20 mg/kg) and bromocriptine (15 mg/kg), respectively or vehicle for 2 weeks. Such treatment, while normalizing body weight gain and hyperglycemia, also significantly reduced elevated NPY immunoreactivity in the suprachiasmatic (by 39%), intergeniculate (by 43%), paraventricular (PVN; by 31%), and arcuate (by 41%) nuclei in obese mice to levels observed in lean mice. This treatment also caused a 45–50% decline in levels of CRH in the PVN and dorsomedial hypothalamus compared to obese controls to levels observed in lean mice. Taken together, these findings suggest that dopaminergic D1/D2 receptor coactivation may improve hyperphagia, hyperglycemia, and obesity in the ob/ob mouse, in part, by normalizing elevated levels of both NPY and CRH.
References
1.
Cincotta AH, MacEachern TA, Meier AH: Bromocriptine redirects metabolism and prevents seasonal onset of obese hyperinsulinemic state in Syrian hamsters. Am J Physiol 1993;264:E285–E293.
2.
Cincotta AH, Meier AH: Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. Diabetes Care 1996;19:667–670.
3.
Cincotta AH, Meier AH: Reductions of body fat stores and total plasma cholesterol and triglyceride concentrations in several species by bromocriptine treatment. Life Sci 1989;45:2247–2254.
4.
Luo S, Liang Y, Cincotta AH: Intracerebroventricular administration of bromocriptine ameliorates the insulin-resistant/glucose-intolerant state in hamsters. Neuroendocrinology 1999;69:160–166.
5.
Meier AH, Cincotta AH: Circadian rhythms regulate the expression of the thrifty genotype/phenotype. Diabetes Rev 1996;4:464–487.
6.
Reaven GM, Lithell H, Landsberg L: Hypertension and associated metabolic abnormalities – The role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374–381.
7.
Cincotta A, Tozzo E, Scislowski PWD: Bromocriptine/SKF-38393 treatment ameliorates obesity and associated metabolic dysfunctions in obese (ob/ob) mice. Life Sci 1997;61:951–956.
8.
Scislowski PWD, Tozzo E, Zhang Y, Phaneuf S, Prevelige R, Cincotta AH: Biochemical mechanisms responsible for the attenuation of diabetic and obese condition in ob/ob mice treated with dopaminergic agonists. Int J Obes 1999;23:425–431.
9.
Zhang Y, Scislowski PWD, Prevelige R, Phaneuf S, Cincotta AH: Bromocriptine/SKF-38393 treatment ameliorates dyslipidemia in ob/ob mice. Metabolism 1999;48:1033–1040.
10.
Liang Y, Jetton TL, Lubkin M, Meier AH, Cincotta AH: Bromocriptine/SKF-38393 ameliorates islet dysfunction in the diabetic (db/db) mouse. Cell Mol Life Sci 1998;54:703–711.
11.
Jackson DM, Ross SB, Hashizume M: Further studies on the interaction between bromocriptine and SKF-38393 in reserpine and alpha-methyl-para-tyrosine-treated mice. Psychopharmacology 1988;94:321–327.
12.
Cooper SJ, Al-Naser HA: D1:D2 dopamine receptor interactions in relation to feeding responses and food intake; in Waddington J (ed): D1:D2 Dopamine Receptor Interactions. San Diego, Academic Press, 1993, pp 203–234.
13.
Oltmans GA: Norepinephrine and dopamine levels in hypothalamic nuclei of the genetically obese mouse (ob/ob). Brain Res 1983;273:369–373.
14.
Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P: Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546–549.
15.
Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, et al: The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995;377:530–532.
16.
Huang Q, Rivest R, Richard D: Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice. Endocrinology 1998;139:1524–1532.
17.
Walker HC, Romsos DR: Glucocorticoids in the CNS regulate BAT metabolism and plasma insulin in ob/ob mice. Am J Physiol 1992;262:E110–E117.
18.
Erickson JC, Hollopeter G, Palmiter RD: Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 1996;274:1704–1707.
19.
King BM, Banta AR, Tharel GN, Bruce BK, Frohman LA: Hypothalamic hyperinsulinemia and obesity: Role of adrenal glucocorticoids. Am J Physiol 1983;245:E194–E199.
20.
Ohshima K, Shargill NS, Chan TM, Bray GA: Adrenalectomy reverses insulin resistance in muscle from obese (ob/ob) mice. Am J Physiol 1984;246:E193–E197.
21.
Shimomura Y, Bray GA, Lee M: Adrenalectomy and steroid treatment in obese (ob/ob) and diabetic (db/db) mice. Horm Metab Res 1987;19:295–299.
22.
Levine AS, Morley JE: Neuropeptide Y: A potent inducer of consummatory behavior in rats. Peptides 1984;5:1025–1029.
23.
Stanley BG, Leibowitz SF: Neuropeptide Y injected in the paraventricular hypothalamus: A powerful stimulant of feeding behavior. Proc Natl Acad Sci USA 1985;82:3940–3943.
24.
Stanley BG, Magdalin W, Seirafi A, Thomas WJ, Leibowitz SF: The perifornical area: The major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res 1993;604:304–317.
25.
Billington CJ, Briggs JE, Grace M, Levine AS: Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. Am J Physiol 1991;260:R321–R327.
26.
Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF: Neuropeptide Y chronically injected into the hypothalamus: A powerful neurochemical inducer of hyperphagia and obesity. Peptides 1986;7:1189–1192.
27.
Zarjevski N, Cusin I, Vettor R, Rohner-Jeanrenaud F, Jeanrenaud B: Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 1993;133:1753–1758.
28.
Marks JL, Waite K, Davies L: Intracerebroventricular neuropeptide Y produces hyperinsulinemia in the presence and absence of food. Physiol Behav 1996;60:685–692.
29.
Sainsbury A, Rohner-Jeanrenaud F, Cusin I, Zakrzewska KE, Halban PA, Gaillard RC, Jeanrenaud B: Chronic central neuropeptide Y infusion in normal rats: Status of the hypothalamo-pituitary-adrenal axis, and vagal mediation of hyperinsulinaemia. Diabetologia 1997;40:1269–1277.
30.
Bai FL, Yamano M, Shiotani Y, Emson PC, Smith AD, Powell JF, Tohyama M: An arcuato-paraventricular and -dorsomedial hypothalamic neuropeptide Y-containing system which lacks noradrenaline in the rat. Brain Res 1985;331:172–175.
31.
Card JP, Moore RY: Ventral lateral geniculate nucleus efferents to the rat suprachiasmatic nucleus exhibit avian pancreatic polypeptide-like immunoreactivity. J Comp Neurol 1982;206:390–396.
32.
Harrington ME, Nance DM, Rusak B: Neuropeptide Y immunoreactivity in the hamster geniculo-suprachiasmatic tract. Brain Res Bull 1985;15:465–472.
33.
Saito M, Bray GA: Diurnal rhythm for corticosterone in obese (ob/ob) diabetes (db/db) and gold-thioglucose-induced obesity in mice. Endocrinology 1983;113:2181–2185.
34.
Niimi M, Takahara J, Hashimoto K, Kawanishi K: Immunohistochemical identification of corticotropin-releasing factor-containing neurons projecting to the stalk-median eminence of the rat. Peptides 1988;9:589–593.
35.
Brown MR, Fisher LA, Spiess J, Rivier C, Rivier J, Vale W: Corticotropin-releasing factor: Actions on the sympathetic nervous system and metabolism. Endocrinology 1982;111:928–931.
36.
Gunion MW, Rosenthal MJ, Tache Y, Miller S, Butler B, Zib B: Intrahypothalamic microinfusion of corticotropin-releasing factor elevates blood glucose and free fatty acids in rats. J Auton Nerv Syst 1988;24:87–95.
37.
Jeanrenaud B: Central nervous system and peripheral abnormalities: Clues to the understanding of obesity and NIDDM. Diabetologia 1994;37:S169–S178.
38.
Rohner-Jeanrenaud F, Jeanrenaud B: Beneficial effect of intravenous bolus of corticotropin-releasing factor on glucose intolerance of genetically obese (fa/fa) rats. Diabetes 1992;41:493–498.
39.
Rohner-Jeanrenaud F, Walker CD, Greco-Perotto R, Jeanrenaud B: Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (fa/fa) rats. Endocrinology 1989;124:733–739.
40.
Heinrichs SC, Lapsansky J, Behan DP, Chan RKW, Sawchenko PE, Lorang M, Ling N, Vale WW, De Souza EB: Corticotropin-releasing factor-binding protein ligand inhibitor blunts excessive weight gain in genetically obese Zucker rats and rats during nicotine withdrawal. Proc Natl Acad Sci USA 1996;93:15475–15480.
41.
Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, De Souza EB, Oltersdorf T: Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain [published erratum appears in Proc Natl Acad Sci USA 1995;92:5759]. Proc Natl Acad Sci USA 1995;92:836–840.
42.
Nishiyama M, Makino S, Asaba K, Hashimoto K: Leptin effects on the expression of type-2 CRH receptor mRNA in the ventromedial hypothalamus in the rat. J Neuroendocrinol 1999;11:307–314.
43.
Bestetti GE, Abramo F, Guillaume-Gentil C, Rohner-Jeanrenaud F, Jeanrenaud B, Rossi GL: Changes in the hypothalamo-pituitary-adrenal axis of genetically obese fa/fa rats: A structural, immunocytochemical, and morphometrical study. Endocrinology 1990;126:1880–1886.
44.
Tang-Christensen M, Kristensen P, Stidsen CE, Brand CL, Larsen PJ: Central administration of Y5 receptor antisense decreases spontaneous food intake and attenuates feeding in response to exogenous neuropeptide Y. J Endocrinol 1998;159:307–312.
45.
Schaffhauser AO, Sricker-Krongard A, Brunner L, Cumin F, Gerald C, Whitebread S, Criscione L, Hofbauer KG: Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. Diabetes 1997;46:1792–1798.
46.
Davies L, Marks JL: Role of hypothalamic neuropeptide Y gene expression in body weight regulation. Am J Physiol 1994;266:R1687–R1691.
47.
Jakubowski M, Blum M, Roberts JL: Postnatal development of gonadotropin-releasing hormone and cyclophilin gene expression in the female and male rat brain. Endocrinology 1991;128:2702–2708.
48.
Akabayashi A, Levin N, Paez X, Alexander JT, Leibowitz SF: Hypothalamic neuropeptide Y and its gene expression: Relation to light/dark cycle and circulating corticosterone. Mol Cell Neurosci 1994;5:210–218.
49.
Wilding JP, Gilbey SG, Bailey CJ, Batt RA, Williams G, Ghatei MA, Bloom SR: Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse. Endocrinology 1993;132:1939–1944.
50.
Tozzo E, Scislowski P, Phaneuf S, Prevelige R: Bromocriptine/SKF-38393 ameliorates circadian metabolic abnormalities in ob/ob mice. Diabetes 1997;46(suppl 1):231A.
51.
Hollopeter G, Erickson JC, Palmiter RD: Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice. Int J Obes 1998;22:506–512.
52.
Albers HE, Ferris CF, Leeman SE, Goldman BD: Avian pancreatic polypeptide phase shifts hamster circadian rhythms when microinjected into the suprachiasmatic region. Science 1984;223:833–835.
53.
Janik D, Mikkelsen JD, Mrosovsky N: Cellular colocalization of Fos and neuropeptide Y in the intergeniculate leaflet after nonphotic phase-shifting events. Brain Res 1995;698:137–145.
54.
Golombek DA, Biello SM, Rendon RA, Harrington ME: Neuropeptide Y phase shifts the circadian clock in vitro via a Y2 receptor. Neuroreport 1996;7:1315–1319.
55.
Harrington ME, Rusak B: Lesions of the thalamic intergeniculate leaflet alter hamster circadian rhythms. J Biol Rhythms 1986;1:309–325.
56.
Nagai K, Nakagawa H: The role of the SCN in regulation of energy metabolism; in Nagai K, Nakagawa H (eds): Central Regulation of Energy Metabolism with Special Reference to Circadian Rhythm. Boca Raton, CRC Press, 1992, pp 103–144.
57.
Luo S, Luo J, Cincotta AH: Suprachiasmatic monoamine metabolism of glucose tolerant versus intolerant hamsters. Neuroreport 1999;10:2073–2077.
58.
Luo S, Luo J, Meier AH, Cincotta AH: Dopaminergic neurotoxin administration to the area of the suprachiasmatic nuclei induces insulin resistance. Neuroreport 1997;8:3495–3499.
59.
Beck B, Burlet A, Bazin R, Nicolas JP, Burlet C: Early modification of neuropeptide Y but not of neurotension in the suprachiasmatic nucleus of the obese Zucker rat. Neurosci Lett 1992;136:185–188.
60.
Midgley LP, Bush LG, Gibb JW, Hanson GR: Differential regulation of neuropeptide Y systems in limbic structures of the rat. J Pharmacol Exp Ther 1993;267:707–713.
61.
Obuchowicz E: Long-term treatment with chlorpromazine and haloperidol but not with sulpiride and clozapine markedly elevates neuropeptide Y-like immunoreactivity in the rat hypothalamus. Neuropeptides 1996;30:471–478.
62.
Strack AM, Sawyer WB, Hughes JH, Platt KB, Loewy AD: A general pattern of CNS innervation of the sympathetic outflow demonstrated by transneuronal pseudorabies viral infections. Brain Res 1989;491:156–162.
63.
Valentino RJ, Foote SL, Aston-Jones G: Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Brain Res 1983;270:363–367.
64.
Bernardis LL, Bellinger LL: The dorsomedial hypothalamic nucleus revisited: 1998 update. Proc Soc Exp Biol Med 1998;218:284–306.
65.
Brown M: Corticotropin-releasing factor: Central nervous system sites of action. Brain Res 1986;399:10–14.
66.
Brown MR, Fisher LA, Webb V, Vale WW, Rivier JE: Corticotropin-releasing factor: A physiologic regulator of adrenal epinephrine secretion. Life Sci 1985;36:1197–1203.
67.
Bina KG, Phaneuf S, Hodge S: Stress-induced increases in blood glucose in ob/ob mice are modified by corticotropin-releasing factor, independent of the hypothalamo-pituitary-adrenal axis. Diabetes 1998;47(suppl 1):A289.
68.
Bjorntorp P, Holm G, Rosmond R: Hypothalamic arousal, insulin resistance and type 2 diabetes mellitus. Diabet Med 1999;16:373–383.
69.
Young JB, Landsberg L: Diminished sympathetic nervous system activity in genetically obese (ob/ob) mouse. Am J Physiol 1983;245:E148–E154.
70.
Chen HL, Romsos DR: Dexamethasone rapidly increases hypothalamic neuropeptide Y secretion in adrenalectomized ob/ob mice. Am J Physiol 1996;271:E151–E158.
71.
Tempel DL, Leibowitz SF: Adrenal steroid receptors: Interactions with brain neuropeptide systems in relation to nutrient intake and metabolism. J Neuroendocrinol 1994;6:479–501.
72.
Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, Prunkard DE, Porte D Jr, Woods SC, Seeley RJ, Weigle DS: Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 1996;45:531–535.
73.
Ceccatelli S, Cortes R, Hokfelt T: Effect of reserpine and colchicine on neuropeptide mRNA levels in the rat hypothalamic paraventricular nucleus. Brain Res Mol Brain Res 1991;9:57–69.
74.
Edwardson JA, Hough CA: The pituitary-adrenal system of the genetically obese (ob/ob) mouse. Endocrinology 1975;97:265–274.
75.
Timofeeva E, Richard D: Functional activation of CRH neurons and expression of the genes encoding CRH and its receptors in food-deprived lean (Fa/?) and obese (fa/fa) Zucker rats. Neuroendocrinology 1997;66:327–340.
76.
Plotsky PM, Thrivikraman KV, Watts AG, Hauger RL: Hypothalamic-pituitary-adrenal axis function in the Zucker obese rat. Endocrinology 1992;130:1931–1941.
77.
Guillaume V, Conte-Devolx B, Szafarczyk A, Malaval F, Pares-Herbute N, Grino M, Alonso G, Assenmacher I, Oliver C: The corticotropin-releasing factor release in rat hypophysial portal blood is mediated by brain catecholamines. J Clin Endocrinol Metab 1987;65:262–267.
78.
Haas DA, George SR: Neuropeptide Y administration acutely increases hypothalamic corticotropin-releasing factor immunoreactivity: Lack of effect in other rat brain regions. Life Sci 1987;41:2725–2731.
79.
Plotsky PM: Facilitation of immunoreactive corticotropin-releasing factor secretion into the hypophysial-portal circulation after activation of catecholaminergic pathways or central norepinephrine injection. Endocrinology 1987;121:924–930.
80.
McKibbin PE, Cotton SJ, McCarthy HD, Williams G: The effect of dexamethasone on neuropeptide Y concentrations in specific hypothalamic regions. Life Sci 1992;51:1301–1307.
81.
Rohner-Jeanrenaud F: A neuroendocrine reappraisal of the dual-centre hypothesis: Its implications for obesity and insulin resistance. Int J Obes 1995;19:517–534.
82.
Tsai HJ, Romsos DR: Glucocorticoid and mineralocorticoid receptor-binding characteristics in obese (ob/ob) mice. Am J Physiol 1991;261:E495–E499.
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2000
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