The effects of Z56822977 on biosynthesis of serotonin in the brain of rats in the conditions of MSG-induced obesity
Abstract
Wstęp: Badanie przeprowadzono w celu wyjaśnienia wpływu Z56822977 na biosyntezę serotoniny w mózgu szczurów z otyłością wywołaną podawaniem glutaminianu sodu (monosodium glutamate, MSG).
Materiał i metody: W badaniu wykorzystano 18 samców szczura. Zwierzęta podzielono na trzy grupy: 1 — grupa kontrolna, 2 — grupa MSG, 3 — grupa MSG + Z56822977. Szczurzym oseskom w grupie 2 i 3 podawano podskórnie MSG rozpuszczony w soli fizjologicznej w dawce 4 mg/g masy ciała w objętości 8 μl/g w 2., 4., 6., 8. i 10. dniu życia. Grupie 3 podawano doustnie wodny roztwór Z56822977 w dawce 25 mg/kg w objętości 1 ml/kg. Pierwszą dawkę Z56822977 podawano po ukończeniu 4 tygodni życia, a następnie kontynuowano podawanie badanej substancji cyklicznie wedlug schematu tydzień podawania substancji badanej/3 tygodnie przerwy. Zwierzętom z grupy MSG podawano odpowiednio 1 ml/kg wody doustnie. Przez pierwsze 4 miesiące życia szczury otrzymywały standardową karmę. Zmierzono zawartość serotoniny, tryptofanu i 5-hydroksytryptofanu (5-HTr) oraz aktywność hydroksylazy tryptofanowej (tryptophan hydroxylase, TRH), dekarboksylazy aminokwasów (amino acid decarboxylase, AADC) i monoaminooksydazy (MAO) w tkance mózgowej.
Wyniki: Wykazano, że podawanie Z56822977 ma pozytywny wpływ na główne wskaźniki otyłości, co odzwierciedlają zmiany podstawowych parametrów fizjologicznych i biochemicznych [zmniejszenie masy ciała o 13% vs. MSG (p < 0,05); zmniejszenie wskaźnika masy ciała (body mass index, BMI), wskaźnika Lee oraz masy tkanki tłuszczowej trzewnej odpowiednio o 18%, 7% i 55%, (p < 0,05) w porównaniu z grupą MSG]. Zawartość tryptofanu i serotoniny była istotnie niższa (p < 0,05) u szczurów z otyłością wywołaną przez MSG. W badaniach wykazano, że u otyłych szczurów aktywność MAO zwiększa się o 97% (p < 0,05), a aktywność TRH i AADC odpowiednio o 44% i 53% (p < 0,05). Podawanie Z56822977 powodowało zwiększenie zawartości serotoniny i tryptofanu w mózgach szczurów i przywracało poziom aktywności enzymów (MAO, TRH, AADC) do wartości mierzonych u zwierząt kontrolnych.
Wnioski: Wiadomo, że otyłość wiąże się z zaburzeniem syntezy serotoniny w mózgu szczurów. Jednak podawanie Z56822977 prowadzi do normalizacji stężenia serotoniny i tryptofanu oraz przywrócenia prawidłowej aktywności enzymów uczestniczących w biosyntezie i degradacji serotoniny. Podawanie Z56822977, cząsteczki wpływającej na układ serotoninergiczny, może powodować korzystne efekty w leczeniu otyłości wywołanej przez MSG u szczurów. Można rozważać zastosowanie cząsteczki Z56822977 jako nowego leku stosowanego w otyłości, jednak konieczne są dalsze badania w celu potwierdzenia jej działania.
Keywords: serotoninaZ56822977glutaminian sodumózgreceptor wolnych kwasów tłuszczowych GPR40
References
- Broberger C. Brain regulation of food intake and appetite: molecules and networks. J Intern Med. 2005; 258(4): 301–327.
- Galbraith JK. The New Industrial State. Houghton Mifflin, Boston, MA 1967.
- World Health Organization. Obesity: Preventing and Managing the Global Epidemic. World Health Organization, Geneva 2000.
- National Task Force on the Prevention and Treatment of Obesity. Overweight, obesity, and health risk. Arch Intern Med. 2000; 160(7): 898–904.
- World Health Organization. Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser. 2003; 916: i–viii, 1–149, backcover.
- Lazar MA. How obesity causes diabetes: not a tall tale. Science. 2005; 307(5708): 373–375.
- Wоlіn K, Cаrsоn K, Cоldіtz G. Оbеsіty аnd Cаncеr. Thе Оncоlоgіst. 2009; 6: 556–565.
- Drenick EJ, Johnson D, Johnson D, et al. Therapeutic fasting in morbid obesity. Arch Intern Med. 1977; 137(10): 1381–1382.
- Mitchel JS, Keesey RE. Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: evidence from a restriction-refeeding regimen. Physiol Behav. 1977; 18(6): 1121–1125.
- Farrigan C, Pang K. Obesity market overview. Nat Rev Drug Discov. 2002; 1(4): 257–258.
- Aschner B. Über die Funktion der Hypophyse. Pflüger's Archiv für die Gesammte Physiologie des Menschen und der Tiere. 1912; 146(1-3): 1–146.
- Hetherington AW, Ranson SW. Hypothalamic lesions and adiposity in the rat. The Anatomical Record. 1940; 78(2): 149–172.
- Anand BK, Brobeck JR. Hypothalamic control of food intake in rats and cats. Yale J Biol Med. 1951; 24(2): 123–140.
- Anand BK, Brobeck JR. Localization of a "feeding center" in the hypothalamus of the rat. Proc Soc Exp Biol Med. 1951; 77(2): 323–324.
- Grill HJ, Norgren R. Chronically decerebrate rats demonstrate satiation but not bait shyness. Science. 1978; 201(4352): 267–269.
- 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(901): 578–596.
- Maclagan NF. The role of appetite in the control of body weight. J Physiol. 1937; 90(4): 385–394.
- de Jong A, Strubbe JH, Steffens AB. Hypothalamic influence on insulin and glucagon release in the rat. Am J Physiol. 1977; 233(5): E380–E388.
- Blundell JE. Serotonin and appetite. Neuropharmacology. 1984; 23(12B): 1537–1551.
- Garattini S, Samanin R. D-Fenfluramine and salbutamol: Two drugs causing anorexia through different neurochemical mechanisms. Int J Obesity. 1984; 8(Suppl. 1): 151–157.
- Leibowitz SF, Weiss GF, Yee F, et al. Noradrenergic innervation of the paraventricular nucleus: specific role in control of carbohydrate ingestion. Brain Res Bull. 1985; 14(6): 561–567.
- Konopelnyuk VV, Karpovets TP, Kot LI, et al. Biosynthesis of serotonin in the brain of rats under conditions of obesity induced by compatible consumption of high calorie diet and 10% fructose solution as a possible target for obesity prevention. Int J Health Sci Res. 2015; 5: 496–506.
- Routh VH, Stern JS, Horwitz BA. Serotonergic activity is depressed in the ventromedial hypothalamic nucleus of 12-day-old obese Zucker rats. Am J Physiol. 1994; 267(3 Pt 2): R712–R719.
- Karpovets TP, Konopelnyuk VV, Galenova TI, et al. High-calorie diet as a factor of prediabetes development in rats. Bull Exp Biol Med. 2014; 156(5): 639–641.
- Karpovets TP, Konopelnyuk VV, Savchuk OM, et al. Food behavior of rats under development of obesity. Res J Pharm Biol Chem Sci. 2014; 5: 253–259.
- Ashley DV, Fleury MO, Golay A, et al. Evidence for diminished brain 5-hydroxytryptamine biosynthesis in obese diabetic and non-diabetic humans. Am J Clin Nutr. 1985; 42(6): 1240–1245.
- De Fanti BA, Hamilton JS, Horwitz BA. Meal-induced changes in extracellular 5-HT in medial hypothalamus of lean (Fa/Fa) and obese (fa/fa) Zucker rats. Brain Res. 2001; 902(2): 164–170.
- Lambert GW, Vaz M, Cox HS, et al. Human obesity is associated with a chronic elevation in brain 5-hydroxytryptamine turnover. Clin Sci (Lond). 1999; 96(2): 191–197.
- Mori RC, Guimarães RB, Nascimento CM, et al. Lateral hypothalamic serotonergic responsiveness to food intake in rat obesity as measured by microdialysis. Can J Physiol Pharmacol. 1999; 77(4): 286–292.
- Briscoe CP, Tadayyon M, Andrews JL, et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003; 278(13): 11303–11311.
- Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003; 422(6928): 173–176.
- Kotarsky K, Nilsson NE, Flodgren E, et al. A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun. 2003; 301(2): 406–410.
- Prentki M, Vischer S, Glennon MC, et al. Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrientinduced insulin secretion. J Biol Chem. 1992; 267(9): 5802–5810.
- Sargsyan E, Bergsten P. Lipotoxicity is glucose-dependent in INS-1E cells but not in human islets and MIN6 cells. Lipids Health Dis. 2011; 10: 115.
- Prentki M, Madiraju SR. Glycerolipid metabolism and signaling in health and disease. Endocr Rev. 2008; 29(6): 647–676.
- Briscoe CP, Tadayyon M, Andrews JL, et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003; 278(13): 11303–11311.
- Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature. 2003; 422(6928): 173–176.
- Fujiwara K, Maekawa F, Yada T. Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am J Physiol Endocrinol Metab. 2005; 289(4): E670–E677.
- Shapiro H, Shachar S, Sekler I, et al. Role of GPR40 in fatty acid action on the beta cell line INS-1E. Biochem Biophys Res Commun. 2005; 335(1): 97–104.
- Araki T, Hirayama M, Hiroi S, et al. GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes. Diabetes Obes Metab. 2012; 14(3): 271–278.
- Burant C, Viswanathan P, Marcinak J, et al. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. The Lancet. 2012; 379(9824): 1403–1411.
- Leifke E, Naik H, Wu J, et al. A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes. Clin Pharmacol Ther. 2012; 92(1): 29–39.
- Naik H, Vakilynejad M, Wu J, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of the GPR40 agonist TAK-875: results from a double-blind, placebo-controlled single oral dose rising study in healthy volunteers. J Clin Pharmacol. 2012; 52(7): 1007–1016.
- Hann M. Molecular obesity, potency and other addictions in drug discovery. MedChemComm. 2011; 2(5): 349.
- Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov. 2010; 5(3): 235–248.
- Gleeson MP. Generation of a set of simple, interpretable ADMET rules of thumb. J Med Chem. 2008; 51(4): 817–834.
- Walters WP, Green J, Weiss JR, et al. What do medicinal chemists actually make? A 50-year retrospective. J Med Chem. 2011; 54(19): 6405–6416.
- Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017; 15(1): 45.
- Dowman JK, Armstrong MJ, Tomlinson JW, et al. Pathogenesis of non-alcoholic fatty liver disease. QJM. 2010; 103(2): 71–83.
- Hassan K, Bhalla V, El Regal ME, et al. Nonalcoholic fatty liver disease: a comprehensive review of a growing epidemic. World J Gastroenterol. 2014; 20(34): 12082–12101.
- Lu J, Byrne N, Wang J, et al. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol. 2017; 24(7): 570–577.
- Kobyliak N, Falalyeyeva T, Bodnar P, et al. Probiotics Supplemented with Omega-3 Fatty Acids are More Effective for Hepatic Steatosis Reduction in an Animal Model of Obesity. Probiotics Antimicrob Proteins. 2017; 9(2): 123–130.
- Kobyliak N, Falalyeyeva T, Virchenko O, et al. Comparative experimental investigation on the efficacy of mono- and multiprobiotic strains in non-alcoholic fatty liver disease prevention. BMC Gastroenterol. 2016; 16: 34.
- Kobyliak N, Abenavoli L, Falalyeyeva T, et al. Efficacy of Probiotics and Smectite in Rats with Non-Alcoholic Fatty Liver Disease. Ann Hepatol. 2018; 17(1): 153–161.
- Kobyliak N, Abenavoli L, Falalyeyeva T, et al. Prevention of NAFLD development in rats with obesity via the improvement of pro/antioxidant state by cerium dioxide nanoparticles. Clujul Med. 2016; 89(2): 229–235.
- Bernardis LL, Patterson BD. Correlation between 'Lee index' and carcass fat content in weanling and adult female rats with hypothalamic lesions. J Endocrinol. 1968; 40(4): 527–528.
- Maximenko Е, Savchenko V. The level of tryptophan and serotonin in terms of seizure activity in the brain. Journal of V. N. Karazin Kharkiv National University Medicine. 2000; 494(1): 40–43.
- Kalninya IE, Bloom RКA. A fluorimetric determination of 5-hydroxytryptophan in the blood. Medecine. 1991; 1: 29–39.
- Kuhn DM, O'Callaghan JP, Juskevich J, et al. Activation of brain tryptophan hydroxylase by ATP-MG2+: dependence on calmodulin. Proc Natl Acad Sci U S A. 1980; 77(8): 4688–4691.
- Sangwan RS, Mishra S, Kumar S. Direct fluorometry of phase-extracted tryptamine-based fast quantitative assay of L-tryptophan decarboxylase from Catharanthus roseus leaf. Anal Biochem. 1998; 255(1): 39–46.
- Ali BH, Bartlet AL. Inhibition of monoamine oxidase by furazolidone in the chicken and the influence of the alimentary flora thereon. Br J Pharmacol. 1980; 71(1): 219–224.
- Nemeroff CB, Grant LD, Bissette G, et al. Growth, endocrinological and behavioral deficits after monosodium L-glutamate in the neonatal rat: possible involvement of arcuate dopamine neuron damage. Psychoneuroendocrinology. 1977; 2(2): 179–196.
- Nemeroff CB, Konkol RJ, Bissette G, et al. Analysis of the disruption in hypothalamic-pituitary regulation in rats treated neonatally with monosodium L-glutamate (MSG): evidence for the involvement of tuberoinfundibular cholinergic and dopaminergic systems in neuroendocrine regulation. Endocrinology. 1977; 101(2): 613–622.
- Oida K, Nakai T, Hayashi T, et al. Plasma lipoproteins of monosodium glutamate-induced obese rats. Int J Obes. 1984; 8(5): 385–391.
- Nakagawa T, Ukai K, Ohyama T, et al. Effects of Chronic Administration of Sibutramine on Body Weight, Food Intake and Motor Activity in Neonatally Monosodium Glutamate-Treated Obese Female Rats: Relationship of Antiobesity Effect with Monoamines. Experimental Animals. 2000; 49(4): 239–249.
- Cancello R, Clément K. Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue. BJOG. 2006; 113(10): 1141–1147.
- Castanon N, Lasselin J, Capuron L. Neuropsychiatric comorbidity in obesity: role of inflammatory processes. Front Endocrinol (Lausanne). 2014; 5: 74.
- Belemets N, Kobyliak N, Virchenko O, et al. Effects of polyphenol compounds melanin on NAFLD/NASH prevention. Biomed Pharmacother. 2017; 88: 267–276.
- Sanal MG. The blind men 'see' the elephant-the many faces of fatty liver disease. World J Gastroenterol. 2008; 14(6): 831–844.
- Capuron L, Gumnick JF, Musselman DL, et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002; 26(5): 643–652.
- Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011; 130(2): 226–238.
- Capuron L, Schroecksnadel S, Féart C, et al. Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: role in neuropsychiatric symptoms. Biol Psychiatry. 2011; 70(2): 175–182.
- Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001; 344(13): 961–966.
- Maes M, Jacobs MP, Suy E, et al. Effects of dexamethasone on the availability of L-tryptophan and on the insulin and FFA concentrations in unipolar depressed patients. Biol Psychiatry. 1990; 27(8): 854–862.
- Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998; 3(4): 271–280.
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)