Akbulut S., Byersdorfer CA., Larsen CP., Zimmer SL., Humphreys TD., Clarke BL. Expression of the melanocortin 5 receptor on rat lymphocytes.
Biochem Biophys Res. Commun. 2001; 281: 1086-1092.
Al-Barazanji KA., Arch JRS., Buckingham RE., Tadayyon M. Centeral exendin-4 infusion reduces body weight without altering plasma leptin in (fa/fa) Zucker rats. Obes Res. 2000; 8: 317-323.
Alvaro JD., Tatro JB., Duman RS. Minireview : melanocortins and opiate addiction. Life Sci. 1997; 61: 1- 9.
Argiolas A., Melis M.R., Murgia S., Schioth HB. ACTH and alpha-MSH- induced grooming, stretching, yawning and penile erection in male rats:
site of action in the brain and role of melanocortin receptors. Brain Res Bull. 2000; 51: 425-433.
Aziz A., Anderson GH. Exendin-4, a GLP-1 receptor agonist, interacts with proteins and their products of digestion to suppress food intake in rats. J Nutr. 2003; 133: 2326-2330.
Baggio L., Adatia F., Bock T., Brubaker PL., Drucker DJ. Sustained expression of exendin-4 does not perturb glucose homeostasis, ß-cell mass, or food intake in metallothionein-preproexendin transgenic mice.
Biol Chem. 2000; 275: -34471-34477.
Barragan JM., Rodriguez RE., Eng J., Blazquez E. Interaction of exendin-(9-39) with the effects of glucagons-like peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regul Pept. 1996; 67: 63-68.
Benoit SC., Air EL., Coolen LM., Strauss R., Jackman A., Clegg DJ., Seeley RJ., Eoods SC. The catabolic action of insulin in brain is mediated by melanocortins. Neuroscience. 2002; 22: 9048-9052.
Bernardis LL., Bellinger LL. The lateral hypothalamic area revisited：
Ingestive behavior. Neurosci Biobehav Rev. 1996; 20: 189-287.
Bonaz B, Tache Y. Induction of Fos immunoreactivity in the rat brain after cold-restraint induced gastric lesions and fecal excretion. Brain Res.
1994; 652: 56-64.
Bredt DS., Snyder SH. Nitric oxide as a neuronal messenger. Trends Pharmacol Sci. 1991; 12: 125-128.
Buffa B., Polak JM., Pearse AGE., Solcia E., Grimelius L., Capella C.
Identification of the intestinal cell storing gastric inhibitory polypeptide.
Histochemistry. 1975; 43: 249-255.
Butler AA., Kesterson RA., Khong K., Cullen MJ., Pelleymounter MA., Dekoning J., Baetscher M., Cone RD. A unique metabolic syndrome causes obesity in the melanocortin-3 receptordeficient mouse.
Endocrinology. 2000; 141: 3518-3521.
Butler, AA., Marks DL., Fan W., Kuhn CM., Bartolome M., Cone RD.
Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci. 2001; 4: 605- 611.
Chakraborty AK., Funasaka Y., Pawelek JM., Nagahama M., Ito A., Ichihashi M. J Invest Dermatol. 1999; 112: 853- 860.
Chen AS., Marsh DJ., Trumbauer ME., Frazier EG., Guan XM., Yu H., Rosenblum CI., Vongs A., Feng Y., Cao L., Metzger JM., Strack AM., Camacho RE., Mellin TN., Nunes CN., Min W., Fisher J., Gopal-Truter S., MacIntyre DE., Chen HY., Van der Ploeg LHT. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet. 2000; 26: 97- 102.
Chen W., Kelly MA., Opitz-Araya X., Thomas RE., Low MJ., Cone RD.
Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell. 1997; 91: 789-798.
Chhajlani V. Distribution of cDNA for melanocortin receptor subtypes in human tissues. Biochem Mol Biol Int. 1996; 38: 73-80.
Chhajlani V., Wikberg JE. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 1992;
309: 417- 420.
Choi YH., Furuse M., Okumura J., Denbow DM. Nitric oxide controls feeding behavior in the chicken. Brain Res. 1994; 654: 163-166.
Cone RD. The central melanocortin system and energy homeostasis.
Trends Endocrinol Metab. 1999; 10: 211-216.
Cowley MA., Pronchuk N., Fan W., Dinulescu DM., Colmers WF.,Cone RD. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron. 1999; 24: 155-163.
Curran T., Morgan JI. Memories of fos. Bioessays. 1987; 7: 225-228.
Doyle ME., Theodorakis MJ., Holloway HW., Bernier M., Greig NH., Egan JM. The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity.
Regul Pept. 2003; 114: 153-158.
Drucker DJ. Glucagon-like peptides. Diabetes. 1998; 47: 159-69.
Edwards CMB.,Abott CR., Sunter D., Kim MS., Dakin CL., Murphy KG., Abusnana S., Taheri S., Rossi M., Rossi M., Bloom SR. Cocaine-and amphetamine-regulated transcript, glucagons-like peptide-1 and corticotrophin releasing factor inhibit feeding via agouti-related protein independent pathways in the rat. Brain Res. 2000; 866: 128-134.
Eissele R., Goke R., Willemer S., Harthus HP., Vermeer H., Arnold R., Goke B. Glucagon-like peptide-1 cell in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest. 1992; 22: 283-291.
Eng J., Kleinman WA., Singh L., Singh G., Raufman JP. Isolation and characterization of exendin -4, an exendin-3 analogue from Heloderma suspectum venom. J Biol Chem. 1992; 267: 7402-7405.
Fan W., Boston BA., Kesterson RA., Hruby VJ., Cone RD. Role of melanocortinergic neurons in feeding and the Agouti obesity syndrome.
Nature. 1997; 385: 165-168.
Fathi Z., Iben LG., Parker EM. Cloning, expression, and tissue distribution of a fifth melanocortin receptor subtype. Neurochem Res.
1995; 20: 107-113.
Flint A., Raben A., Astrup A., Holst JJ. Glucagon like peptide-1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998; 101:
515-520.
Gantz I., Konda Y., Tashiro T., Shimoto Y., Miwa H., Munzert G.,Watson SJ., DelValle J., Yamada T. Molecular cloning of a novel melanocortin receptor. J Biol Chem. 1993; 268: 8246-8250.
Giraudo SQ., Billington CJ., Levine AS. Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain Res. 1998; 809:
302-306.
Glod RM. Hypothalamus obesity：The myth of the ventromedial nucleus.
Science. 1973; 182: 488-490.
Goke R., Fehmarm HC., Lirm T., Schmidt H., Krause M., Eng J., Goke B.
Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide receptor of insulin-secreting ß-cells. J Biol Chem. 1993; 268:
19650-19655.
Grill HJ., Ginsberg AB., Seeley RJ., Kaplan JM. Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. Neurosci. 1998; 18: 10128-10135.
Gutzwiller JP., Goke B., Drewe J., Hildebrand P., Ketterer S., Handschin D., Winterhalder R., Conen D., Beglinger C. Glucagon like peptide-1: a potent regulator of food intake in humans. Gut. 1999; 44: 81-86.
Jodka C., Gedulin B., Young A. Exendin-4 potently regulates gastric emptying in rats. Diabetes. 1998; 47: 403A. (Abstract)
Kask A., Rgo L., Phkla R., Wikber JES., Schioth HB. Selective antagonist for the melanocortin 4 receptor (HS014) increase food intake in free-feeding rats. Biochem Biophys Res Commun. 1998; 245: 90-93.
Kieffer TJ., McIntosh CH., Pederson RA. Degradation of glucose-
dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;
136: 3585-3596.
Kim MS., Rossi M., Abusnana S., Sunter D., Morgan DG., Small CJ., Edwards CM., Heath MM., Stanley SA., Seal LJ., Bhatti JR., Smith DM., Ghatei MA., Bloom SR. Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone.
Diabetes. 2000; 49: 177-182.
Koegler FH., Grove KL., Schiffmacher A., Smith MS., Cameron JL.
Central melanocortin receptors mediate changes in food intake in the rhesus macaque. Endocrinology. 2001; 142: 2586-2592.
Kolterman OG., Buse JB., Fineman MS., Gaines E., Heintz S., Bicsak TA.
Synthetic exendin-4 (AC2993) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003; 88: 3082- 3089.
Kreymann B., Ghatei MA., Burnet P., Williams G., Kanse S., Diani AR., Bloom SR. Characterization of glucagonlike peptide-1- (7–36)amide in the hypothalamus. Brain Res. 1989; 502: 325-331.
Labbe O., Desarnaud F., Eggerickx D., Vassart G., Parmentier M.
Molecular cloning of a mouse melanocortin 5 receptor gene widely expressed in peripheral tissues. Biochemistry. 1994; 33: 4543-4549.
Lambert PD., Wilding JPH., Ghatei MA., Bloom SR. Arole for GLP-1(7-36) NH2 in the central control of feeding behavior. Digestion.
1993; 54: 360-361.
Larsen PJ., Tang-Christensen M., Holst JJ., Orskov C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience. 1997; 77: 257-270.
Low MJ., Simerly R., Cone RD. Receptors for the melanocortin peptides in the central nervous system. Current Opinion in Endocrinol Diab. 1994;
1: 79-88.
MacNeil DJ., Howard AD., Guan X., Fong TM., Nargund RP., Bednarek MA., Goulet MT., Weinberg DH., Strack AM., Marsh DJ et al. The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. Eur J Pharmacol. 2002; 440: 141-157.
Mentlein R., Gallwitz B., Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993; 214: 829-835.
Mistry AM., Helferich W., Romsos DR. Elevated neuronal c-Fos-like immunoreactivity and messenger ribonucleic acid (mRNA) in genetically obese (ob/ob) mice. Brain res. 1994; 666: 53-60.
Monda M., Viggiano A., Sullo A., De Luca V. Nitric oxide reduces hypophagia induced by threonine free diet in the rat. Brain Res. 1998;
808: 129-133.
Montrose-Rafizadeh C., Yang H., Pritchette LA., Eng J. Distinct activation of GLP-1 receptor by exendin-4 and GLP-1. Diabetes. 1998;
47: 192A. (Abstract)
Morley JE., Flood JF. Evidence that nitric oxide modulates food intake in mice. Life Sci. 1991; 49: 707-711.
Mountjoy KG., Mortrud MT., Low MJ., Simerly RB., Cone RD.
Localization of the melanocortin -4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol. 1994; 8:
1298-1308.
Mountjoy KG., Wild JM. Melanocortin-4 receptor mRNA expression in the developing autonomic and central nervous systems. Dev Brain Res.
1998; 107: 309-314.
Mountjoy KG., Wong J. Obesity, diabetes and functions for
proopiomelanocortin-derived peptides. Mol Cell Endocrinol. 1997; 128:
171- 177.
Ollmann MM., Wilson BD., Yang YK., Kerns JA., Chen Y., Gantz I.,et al.
Antagonism of central melanocortin receptors in vitro and in vivo by Agouti-related protein. Science. 1997; 178:135-138.
Owji AA., Khoshdel Z., Sanea F., Panjehshahin MR., Shojaee Fard M., Smith DM., Coppock HA., Ghatei MA., Bloom SR. Effect of intracerebroventricular injection of glucagon like peptide-1 and its related peptide on sertonin metabolism and on levels of amino acids in the rat hypothalamus. Brain Res. 2002; 929: 70-75.
Parkes D., Jodka C., Smith P., Nayak S., Rinehart L., Gingerich R., Chen K., Young A. Pharmacokinetic actions of exendin -4 in the rat:comparison with glucagon-like peptide-1. Drug Dev Res. 2001; 53: 260-267.
Parkes DG., Pittner R., Jodka C., Smith P., Young A. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro.
Metabolism. 2001; 50: 583- 589.
Perfetti R., Merkel P. Glucagon-like peptide-1: a major regulator of pancreatic beta-cell function. Eur J Endocrinol. 2000; 143: 717-725.
Racotta R., Soto-Mora LM., Pinon-Lopez MJ., Quevedo L. Effect of intraperitoneal nitroprusside and adrenergic agonists on food and water intake. Physiol Behav. 1998; 63: 455-461.
Paxinos G., Watson C. The rat brain in stereotaxic coordinates. 2nd Ed.
Academic press Inc; 1986.
Rodriquez de Fonseca F., Navarro M., Alvarez E., Roncero I., Chowen JA., Maestre O., Gomez R., Munoz RM., Eng J., Blazquez E. Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism. 2000; 49:
709-717.
Roselli-Rehfuss L., Mountjoy KG., Robbins LS., Mortrud MT., Low MJ., Tatro JB., Entwistle ML., Simerly RB., Cone RD. Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci USA.
1993; 90; 8856-8860.
Sarkar S., Fekete C., Legradi G., Lechan RM. Glucagon like peptide-1(7-36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing homone neurons in the hypothalamic paraventricular nucleus. Brain Res. 2003; 985: 163-168.
Schaffer JV., Bolognia JL. The melanocortin-1 receptor: red hair and beyond. Arch. Dermatology. 2001; 137: 1477- 1485.
Schick RR., Zimmermann JP., Vorm Walde T., Schusdziarra V., Classen M. Glucagon-like peptide (GLP)-1-(7-36)-amide: A central suppressor of food intake in fasted rats. Gastroenterology. 2002; 102: 756A. (Abstract)
Schioth HB., Mutulis F., Muceniece R., Prusis P., Wikberg JE. Discovery of novel melanocortin 4 receptor selective MSH analogues. Br J Pharmacol. 1998; 124: 75- 82.
Schmidt HH., Nau H., Wittfoht W., Gerlach J., Prescher KE., Klein MM., Niroomand F., Bohme E. Arginine is a physiological precursor of endothelium-derived nitric oxide. Eur J Pharmacol. 1988; 154: 213-216.
Schwartz MW., Figlewicz DP., Baskin DG., Woods SC., Porte Jr D.
Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev.
1992; 13: 387-414.
Sebastien GB., Shin JD., Richard BS. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hupothalamic regions implicated in the neural control of feeding behavior in mice.
Neuroscience. 2004; 24: 2797-2805.
Seeley RJ., Yagaloff KA., Fisher SL., Burn P., Thiele TE., Van Dijk G., Baskin DG., Schwartz MW. Melanocotin receptor in leptin effects.
Nature. 1997; 390: 349.
Shimizu I., Hirota M., Ohboshi C., Shima K. Identification and localization of glucagon like peptide-1 and its receptor in rat brain.
Endocrinology. 1987; 121:1076-7082.
Squadrito F., Calapai G., Cucinotta D., Altavilla D., Zingarelli B., Ioculano M., Urna G., Sardella A., Campo GM., Caputi AP. Anorectic activity of NG-nitro-L-arginine, an inhibitor of brain nitric oxide synthase, in obese Zucker rats. Eur. J. Pharmacol. 1993; 230: 125-128.
Starowicz K., Przewlocka B. The role of melanocortins and their receptor in inflammatory processes, nerve regeneration and nociception. Life Sci.
2003; 73: 823-847.
Szayna M., Doyle ME., Betkey JA., Holloway HW., Spencer RGS., Greig NH., Egan JM. Exendin -4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology. 2000; 141: 1936-1941.
Turton MD., O’Shea D., Gunn, I., Beak SA., Edwards CM., Meeran K., Choi SJ., Taylor GM., Heath MM., Lambert PD., Wilding JP., Smith DM., Ghatei MA., Herbert J., Bloom SR. A role for glucagon-like peptide-1 in the central regulation of feeding . Nature. 1996; 379: 69-72.
Vergoni AV., Bertolini A. Role of melanocortin in the central control of feeding. Eur J Pharmacol. 2000; 405: 25-32.
Watson SJ., Akil H., Richard III CW., Barchas JD. Evidence for two separate opiate peptide neuronal systems. Nature. 1978; 275: 226-228.
Wikberg JES. Melanocortin receptors: perspectives for novel drugs. Eur J Pharmacol. 1999; 375: 295-310.
Wikberg JES., Muceniece R., Mandrika I., Prusis P., Lindblom J., Post C., Skottner A. New aspects on the melanocortins and their receptors.
Pharmacol Res. 2000; 42: 393-420.
Williams DL., Kaplan JM., Grill HJ. The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Endocrinology. 2000; 141: 1332- 1337.
Xia Y., Wikberg JE. Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal gland. Cell Tissue Res. 1996; 286: 63- 68.
Xu G., Stoffers DA., Habener JF., Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999; 48:
2270- 2276.
Yasuda N., Nagakura T., Yamazaki K., Inoue T., Tanaka I. Improvement of high fat-diet-induced insulin resistance in dipeptidly peptidase IV-deficient Fischer rats. Life Sci. 2002; 71: 227-238.
Young AA., Gedulin BR., Bhavsar S., Bodkin N., Jodka C., Hansen B.,et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes. 1999; 48:
1026-1034.
圖一、腹腔注射exendin-4或一氧化氮提供劑nitroprusside引起降低大白鼠攝食行為作用的影響之流程圖。
圖三、腦部冠狀切面圖顯示弓狀核(Arc)之解剖位置。3V：第三腦室；
ME：median eminence，中突處。方框處為分析部位。
A. B.
1 hr cumulated food intake (g)
NS+NS
2 hr cumulated food intake (g)
**
4 hr cumulated food intake (g)
**
6 hr cumulated food intake (g)
**
**
#
圖四、給予低劑量的 nitroprusside 對 exendin-4 降低攝食效果之 影響( n = 4~5 )。同時以腹腔注射 nitroprusside ( 500
A. B.
1 hr cumulated food intake (g)
NS+NS
2 hr cumulated food intake (g)
**
4 hr cumulated food intake (g)
** **
6 hr cumulated food intake (g)
**
**
#
圖五、給予高劑量的 nitroprusside 對 exendin-4 降低攝食效果之 影 響 ( n = 4~5)。 同 時 以 腹 腔 注 射 nitroprusside ( 2 mg/ml/Kg )與 exendin-4 ( 0.5 µg/ml/Kg )，對於大白鼠攝食 量之影響。各組以 mean ± SEM 表示，**p < 0.01 v.s NS + NS；# p < 0.05 v.s NS + NP。A 圖為累積 1 小時之攝食量；
B 圖為累積 2 小時之攝食量；C 圖為累積 4 小時之攝食量；
D 圖 為 累 積 6 小 時 之 攝 食 量 。 ( NS： saline； NP：
nitroprusside；E-4：exendin-4 )
A. B.
1hr cumulated food intake (g)
Saline+ Saline
SHU9119 + Saline
HS014 (1.5μg) + Saline
HS014 (5μg) + Saline
Saline + E-4
2 hr cumulated food intake (g)
*
3 hr cumulated food intake (g)
*
4 hr cumulated food intake (g)
* exendin-4 ( 0.5 µg/ml/Kg )，對於大白鼠攝食量之影響。各組以 mean ± SEM 表示，# p < 0.05 v.s NS + E-4；* p < 0.01 v.s NS + NS。A 圖為累積 1 小時之攝食量；B 圖為累積 2 小時之攝食 量；C 圖為累積 3 小時之攝食量；D 圖為累積 4 小時之攝食量。
( E-4：exendin-4 )。
Exendin-4 Control
圖七、下視丘弓狀核 cFos 對於腹腔注射 exendin-4 之反應。左圖：頸 靜脈注射 exendin-4 ( 0.5 µg/ml/Kg )；右圖：頸靜脈注射 saline( 1 ml/Kg )。黑色橫線( )相當於 80 µm。
0 50 100 150 200
Total neuronal numbers
Saline exendin-4
*
0 10 20 30 40 50 60
Neurons / section
Saline exendin-4
*
圖八、腹腔注射 exendin-4 對於下視丘弓狀核 cFos 表現量的影 響。上圖：全部弓狀核 cFos 的含量；下圖：平均每片組 織上弓狀核 cFos 的含量( *p < 0.01 v.s saline )。
A.
B.
C.
圖九、弓狀核中 cFos (藍色細胞核)與 a-MSH 細胞(褐色細胞核) 的表現。A 圖：對照組；B 圖：注射 exendin-4；C 圖：A 圖方框部份放大。黑色橫線( )相當於 80 µm (A、B 圖) 或 20 µm (C 圖)。
A.
Total alpha-MSH neuronal numbers
Saline
% of alpha-MSH neuron double-labeled with cFos
Saline