Hostname: page-component-586b7cd67f-t7fkt Total loading time: 0 Render date: 2024-11-22T13:55:30.418Z Has data issue: false hasContentIssue false
  • English
  • Français

Mouse Genetic Approaches to Feeding Regulation: Serotonin 5-HT2C Receptor Mutant Mice

Published online by Cambridge University Press:  07 November 2014

Laurence H. Tecott  and
Luna Abdallah
Get access Rights & Permissions [Opens in a new window]

Abstract

Neural mechanisms underlying the regulation of ingestive behavior and energy balance are well conserved among mammals. Many neural pathways, each reflecting the function of many genes, interact to regulate these processes. Systematic genetic perturbations are not feasible in humans—the examination of gene functions relevant to feeding regulation must be performed in other species. Many advances in this field have been made through molecular genetic studies of mice, the most genetically tractable of mammalian species. The relevance of mouse ingestive behavior to the mechanisms underlying the regulation of feeding in humans is discussed. Approaches for evaluating the contribution of genes to the regulation of energy balance and to the actions of anorectic drugs are described in the context of studies focused on a line of mice lacking the serotonin 5-HT2C receptor subtype. These animals display reduced responsiveness to serotonergic anorexic drugs and a late-onset obesity syndrome associated with features reminiscent of common forms of human obesity. Developmental studies of energy balance uncovered a novel age-dependent physiological process that may contribute generally to the predisposition of humans and other mammals to accumulate fat stores during “middle-age.” These findings are presented to illustrate considerations in the use of mouse molecular genetic technologies to investigate genetic influences on ingestive behavior and energy balance.

Type
Review Article
Information
CNS Spectrums , Volume 8 , Issue 8: Genetically Altered Mice in the Study of Neuropsychiatrty , August 2003 , pp. 578 - 588
Copyright
Copyright © Cambridge University Press 2003

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1.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.CrossRefGoogle ScholarPubMed
2.Friedman, JM, Halaas, JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763–770.CrossRefGoogle ScholarPubMed
3.Tartaglia, LA, Dembski, M, Weng, X, et al.Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–1271.CrossRefGoogle ScholarPubMed
4.Tecott, LH. The genes and brains of mice and men. Am J Psychiatry. 2003;160:646–656.CrossRefGoogle ScholarPubMed
5.Waterston, RH, Lindblad-Toh, K, Birney, E, et al.Initial sequencing and comparative analysis of the mouse genome. Nature. 2002;420:520–562.Google ScholarPubMed
6.Sarnat, HB, Netsky, MG. Evolution of the Nervous System. 2d ed. New York, NY: Oxford University Press; 1981.Google Scholar
7.Tecott, LH. The genes and brains of mice and men. Am J Psychiatry. In press.Google Scholar
8.Montague, CT, Farooql, IS, Whitehead, JP, et al.Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–906.CrossRefGoogle ScholarPubMed
9.Clement, K, Boutin, P, Froguel, P. Genetics of obesity. Am J Pharmacogenomics. 2002;2:177–187.CrossRefGoogle ScholarPubMed
10.Rowland, NE, Carlton, J. Neurobiology of an anorectic drug: fenfluramine. Prog Neurobiol. 1986;27:13–62.CrossRefGoogle ScholarPubMed
11.Rogers, PJ, Blundell, JE. Effect of anorexic drugs on food intake and the micro-structure of eating in human subjects. Psychopharmacology. 1979;66:159–165.CrossRefGoogle ScholarPubMed
12.Foltin, RW, Moran, TH. Food intake in baboons: effects of a long-acting cholecystokinin analog. Appetite. 1989;12:145–152.CrossRefGoogle ScholarPubMed
13.McGuirk, J, Goodall, E, Silverstone, T, Willner, P. Differential effects of d-fenfluramine and d-amphetamine on the microstructure of human eating behavior. Behav Pharmacol. 1991;2:113–119.CrossRefGoogle Scholar
14.Simansky, KJ. Serotonergic control of the organization of feeding and satiety. Behav Brain Res. 1996;73:37–42.CrossRefGoogle ScholarPubMed
15.Saller, CF, Stricker, EM. Hyperphagia and increased growth in rats after intraventricular injection of 5, 7-dihydroxytryptamine. Science. 1976;192:385–387.CrossRefGoogle ScholarPubMed
16.Geyer, MA, Puerto, A, Menkes, DB, Segal, DS, Mandell, AJ. Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways. Brain Res. 1976;106:257–270.CrossRefGoogle ScholarPubMed
17.Ghosh, MN, Parvathy, S. The effect of cyproheptadine on water and food intake and on body weight in the fasted adult and weanling rats. Br J Pharmacol. 1973;48:328P–329P.Google ScholarPubMed
18.Blundell, JE, Leshem, MB. Central action of anorexic agents: effects of amphetamine and fenfluramine in rats with lateral hypothalamic lesions. Eur J Pharmacol. 1974;28:81–88.CrossRefGoogle ScholarPubMed
19.Hoyer, D, Clarke, DE, Fozard, JR, et al.International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev. 1994;46:157–203.Google ScholarPubMed
20.Hoyer, D. Functional correlates of serotonin 5-HT1 recognition sites. Receptor Res. 1988;8:59–63.CrossRefGoogle ScholarPubMed
21.Kennett, GA, Curzon, G. Potencies of antagonists indicate that 5-HTlc receptors mediate 1-3(chlorophenyl) piperazine-induced hypophagia. Br J Pharmacol. 1991;103:2016–2020.CrossRefGoogle Scholar
22.Middlemiss, DN, Tricklebank, MD. Centrally active 5-HT receptor agonists and antagonists. Neurosci Biobehav Rev. 1992;16:75–82.CrossRefGoogle ScholarPubMed
23.Kennett, GA, Wood, MD, Bright, F, et al.SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology. 1997;36:609–620.CrossRefGoogle ScholarPubMed
24.Walsh, AE, Smith, KA, Oldman, AD, Williams, C, Goodall, EM, Cowen, PJ. m-Chlorophenylpiperazine decreases food intake in a test meal. Psychopharmacology. 1994;116:120–122.CrossRefGoogle Scholar
25.Sargent, PA, Sharpley, AL, Williams, C, Goodall, EM, others a. 5-HT2C receptor activation decreases appetite and body weight in obese subjects. Psychopharmacology. 1997;133:309–312.CrossRefGoogle ScholarPubMed
26.Zimmermann, U, Kraus, T, Himmerich, H, Schuld, A, Pollmacher, T. Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients. J Psychiatr Res. 2003;37:193–220.CrossRefGoogle ScholarPubMed
27.Kennedy, AJ, Gibson, EL, O'Connell, MT, Curzon, G. Effects of housing, restraint and chronic treatments with mCPP and sertraline on behavioural responses to mCPP. Psychopharmacology (Berl). 1993;113:262–268.CrossRefGoogle ScholarPubMed
28.Kennett, GA, Lightowler, S, de Biasi, V, et al.Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function. Neuropharmacology. 1994;33:1581–1588.CrossRefGoogle ScholarPubMed
29.Roth, BL, Ciaranello, RD, Meltzer, HY. Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors. J Pharmacol Exp Ther. 1992;260:1361–1365.Google ScholarPubMed
30.Jenck, F, Moreau, JL, Mutel, V, Martin, JR. Brain 5-HT1C receptors and antidepressants. Progress Neuro-Psychopharmacol. Biol Psych. 1994;18:563–574.Google Scholar
31.Reynolds, GP, Zhang, Z, Zhang, X. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight Gain. Am J Psychiatry. 2003;160:677–679.CrossRefGoogle Scholar
32.Shor-Posner, G, Grinker, JA, Marinescu, C, Brown, O, Leibowitz, SF. Hypothalamic serotonin in the control of meal patterns and macronutrient selection. Brain Res Bull. 1986;17:663–671.CrossRefGoogle ScholarPubMed
33.Hutson, PH, Donohoe, TP, Curzon, G. Infusion of the 5-hydroxytryptamine agonists RU24969 and TFMPP into the paraventricular nucleus of the hypothalamus causes hypophagia. Psychopharmacology. 1988;95:550–552.CrossRefGoogle ScholarPubMed
34.Schwartz, D, Hernandez, L, Hoebel, BG. Fenfluramine administered systemically or locally increases extracellular serotonin in the lateral hypothalamus as measured by microdialysis. Brain Res. 1989;482:261–270.CrossRefGoogle ScholarPubMed
35.Leibowitz, SF, Weiss, GF, Shor-Posner, G. Hypothalamic serotonin: pharmacological, biochemical, and behavioral analyses of its feeding-suppressive action. Clin Neuropharmacol. 1988;11:S51–S71.Google ScholarPubMed
36.Hoffman, BJ, Mezey, E. Distribution of serotonin 5-HT1C receptor mRNA in adult rat brain. FEBS Lett. 1989;247:453–462.CrossRefGoogle Scholar
37.Wright, DE, Seroogy, KB, Lundgren, KH, Davis, BM, Jennes, L. Comparative localization of serotonin 1A, 1C, and 2 receptor subtype mRNAs in rat brain. J Comp Neurol. 1995;351:357–373.CrossRefGoogle ScholarPubMed
38.Tecott, LH, Shtrom, S, Julius, D. Expression of a serotonin-gated ion channel in embryonic neural and non-neural tissues. Mol Cell Neurosci. 1995;6:43–55.CrossRefGoogle Scholar
39.Nonogaki, K, Strack, A, Dallman, M, Tecott, LH. Leptin-insensitive hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. 1998;4:1152–1156.CrossRefGoogle Scholar
40.Maffei, M. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1:1155–1161.CrossRefGoogle ScholarPubMed
41.Frederich, RC, Hamann, A, Anderson, S, Lollmann, B, Lowell, BB, Flier, JS. Leptin levels reflect body lipid content in mice: Evidence for diet-induced resistance to leptin action. Nat Med. 1995;1:1311–1314.CrossRefGoogle ScholarPubMed
42.Bray, GA, York, DA. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol Rev. 1979;59:719–809.CrossRefGoogle ScholarPubMed
43.Yen, TT, Gill, AM, Friger, LG, Barsh, GS, Wolff, GL. Obesity, diabetes, and neoplasia in yellow Avy/- mice: ectopic expression of the agouti gene. FASEB. 1994;8:479–488.CrossRefGoogle ScholarPubMed
44.Huszar, D, Lynch, CA, Fairchild-Huntress, V, et al.Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88:131–141.CrossRefGoogle ScholarPubMed
45.Nonogaki, K, Abdallah, L, Goulding, EH, Bonasera, SJ, Tecott, LH. Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT(2C) receptor nutant mice. Diabetes. 2003;52:315–320.CrossRefGoogle Scholar
46.Kotz, CM, Billington, CJ, Levine, AS. Obesity and aging. Clin Geriatr Med. 1999;15:391–412.CrossRefGoogle ScholarPubMed
47.Flegal, KM. Trends in body weight and overweight in the U.S. population. Nutr Rev. 1996;54:S97–100.CrossRefGoogle ScholarPubMed
48.Seidell, JC, Flegal, KM. Assessing obesity: classification and epidemiology. Brit Med Bull. 1997;53:238–252.CrossRefGoogle ScholarPubMed
49.Vickers, SP, Clifton, PG, Dourish, CT, Tecott, LH. Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology. 1999;143:309–314.CrossRefGoogle Scholar
50.Levine, JA, Eberhardt, NL, Jensen, MD. Role of nonexercise activity thermogenesis in resistance to fat gain in humans [see comments]. Science. 1999;283:212–214.CrossRefGoogle ScholarPubMed
51.Blundell, J. Pharmacological approaches to appetite suppression. Trends Pharm Sci. 1991;12:147–157.CrossRefGoogle ScholarPubMed
52.Smith, GP. The direct and indirect controls of meal size. Neurosci Biobehav Rev. 1996;20:41–46.CrossRefGoogle ScholarPubMed
53.Rocha, BA, Goulding, EH, O'Dell, LE, et al.Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutant mice. J Neurosci. 2002;22:10039–10045.CrossRefGoogle ScholarPubMed
54.Yeo, GS, Farooqi, IS, Aminian, S, Halsall, DJ, Stanhope, RG, O'Rahilly, S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 1998;20:111–112.CrossRefGoogle ScholarPubMed
55.Vaisse, C, Clement, K, Guy-Grand, B, Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet. 1998;20:113–114.CrossRefGoogle ScholarPubMed
56.Vaisse, C, Clement, K, Durand, E, Hercberg, S, Guy-Grand, B, Froguel, P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest. 2000;106:253–262.CrossRefGoogle ScholarPubMed
57.Heisler, LK, Cowley, MA, Tecott, LH, et al.Activation of central melanocortin pathways by fenfluramine. Science. 2002;297:609–611.CrossRefGoogle ScholarPubMed