Overview of Rodent Models for Obesity Research

Matthias Tschöp1, Mark L. Heiman1

1 Lilly Research Laboratories, Indianapolis, Indiana
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.10
DOI:  10.1002/0471142301.ns0910s17
Online Posting Date:  February, 2002
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Abstract

Animal obesity models differ widely in type and extent of obesity. They are either based on environmental factors (e.g., high‐fat diet‐induced obesity), spontaneous mutants (i.e., ob/ob mice), genetically engineered animals (e.g., mice with melanocortin receptor subtype‐4 gene disruption (knock‐out), or mechanical intervention (e.g., chemical lesion of the ventromedial hypothalamus). This unit reviews available rodent models to study obesity and attempts to highlight the greatest utility for each model.

     
 
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Table of Contents

  • Study of Energy Homeostasis
  • Environmentally Induced Obesity
  • Spontaneous Mutants
  • Engineered Mutants: Models Based on Overexpression
  • Engineered Mutants: Models Based on Gene Disruption
  • Chemical or Surgical Manipulation
  • Conclusion
  • Literature Cited
  • Tables
     
 
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Materials

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Literature Cited

Literature Cited
   Begley, C.G., Lipkowitz, S., Gobel, V., Mahon, K.A., Bertness, V., Green, A.R., Gough, N.M., and Kirsch, I.R. 1992. Molecular characterization of NSCL, a gene encoding a helix‐loop‐helix protein expressed in the developing nervous system. Proc. Natl. Acad. Sci. U.S.A. 89:38‐42.
   Bray, G.A. and York, D.A. 1979. Hypothalamic and genetic obesity in experimental animals: An autonomic and endocrine hypothesis. Physiol. Rev. 59:719‐809.
   Bray, G.A. and York, D.A. 1998. The MONA LISA hypothesis in the time of leptin. Recent Prog. Horm. Res. 53:95‐118.
   Bray, G.A., York, D.A., and Fisler, J.S. 1989. Experimental obesity: A homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitam. Horm. 45:1‐125.
   Bruning, J.C., Gautam, D., Burks, D.J., Gillette, J., Schubert, M., Orban, P.C., Klein, R., Krone, W., Muller‐Wieland, D., and Kahn, C.R. 2000. Role of brain insulin receptor in control of body weight and reproduction. Science 289:2122‐2125.
   Butler, A.A., Kesterson, R.A., Khong, K., Cullen, M.J., Pelleymounter, M.A., Dekoning, J., Baetscher, M., and Cone, R.D. 2000. A unique metabolic syndrome causes obesity in the melanocortin‐3 receptor‐deficient mouse. Endocrinology 141:3518‐3521.
   Campfield, L.A., Smith, F.J., Guisez, Y., Devos, R., and Burn, P. 1995. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 269:546‐549.
   Charlton, H.M., Clark, R.G., Robinson, I.C., Goff, A.E., Cox, B.S., Bugnon, C., and Bloch, B.A. 1988. Growth hormone‐deficient dwarfism in the rat: A new mutation. J. Endocrinol. 119:51‐58.
   Chen, A.S., Marsh, D.J., Trumbauer, M.E., Frazier, E.G., Guan, X.M., Yu, H., Rosenblum, C.I., Vongs, A., Feng, Y., Cao, L., Metzger, J.M., Strack, A.M., Camacho, R.E., Mellin, T.N., Nunes, C.N., Min, W., Fisher, J., Gopal‐Truter, S., MacIntyre, D.E., Chen, H.Y., and Van Der Ploeg, L.H. 2000. Inactivation of the mouse melanocortin‐3 receptor results in increased fat mass and reduced lean body mass. Nature Genet. 26:97‐102.
   Chen, H., Charlat, O., Tartaglia, L.A., Woolf, E.A., Weng, X., Ellis, S.J., Lakey, N.D., Culpepper, J., Moore, K.J., Breitbart, R.E., Duyk, G.M., Tepper, R.I., and Morgenstern, J.P. 1996. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491‐495.
   Chen, W., Kelly, M.A., Opitz‐Araya, X., Thomas, R.E., Low, ,M.J., and Cone, R.D. 1997. Exocrine gland dysfunction in MC5‐R‐deficient mice: Evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell 91:789‐798.
   Chua, S.C. Jr., Chung, W.K., Wu‐Peng, X.S., Zhang, Y., Liu, S.M., Tartaglia, L., and Leibel, R.L. 1996. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271:994‐996.
   Clark, R.G., Mortensen, D.L., Carlsson, L.M., Carlsson, B., Carmignac, D., and Robinson, I.C. 1996. The obese growth hormone (GH)‐deficient dwarf rat: Body fat responses to patterned delivery of GH and insulin‐like growth factor‐I. Endocrinology 137:1904‐1912.
   Coleman, D.L. 1978. Obese and diabetes: Two mutant genes causing diabetes‐obesity syndromes in mice. Diabetologia 14:141‐148.
   Coleman, D.L. and Eicher, E.M. 1990. Fat (fat) and tubby (tub): Two autosomal recessive mutations causing obesity syndromes in the mouse. J. Hered. 81:424‐427.
   Cool, D.R. and Loh, Y.P. 1998. Carboxypeptidase E is a sorting receptor for prohormones: Binding and kinetic studies. Mol. Cell. Endocrinol. 139:7‐13.
   Cool, D.R., Normant, E., Shen, F., Chen, H.C., Pannell, L., Zhang, Y., and Loh, Y.P. 1997. Carboxypeptidase E is a regulated secretory pathway sorting receptor: Genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88:73‐83.
   Costet, P., Legendre, C., More, J., Edgar, A., Galtier, P., and Pineau, T. 1998. Peroxisome proliferator‐activated receptor alpha‐isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J. Biol. Chem. 273:29577‐29585.
   Crouse, J.A., Elliott, G.E., Burgess, T.L., Chiu, L., Bennett, L., Moore, J., Nicolson, M., and Pacifici, R.E. 1998. Altered cell surface expression and signaling of leptin receptors containing the fatty mutation. J. Biol. Chem. 273:18365‐18373.
   da Silva, B.A., Bjorbaek, C., Uotani, S., and Flier, J.S. 1998. Functional properties of leptin receptor isoforms containing the gln→pro extracellular domain mutation of the fatty rat. Endocrinology 139:3681‐3690.
   Dong, Z.M., Gutierrez‐Ramos, , J.C., Coxon, A., Mayadas, T.N., and Wagner, D.D. 1997. A new class of obesity genes encodes leukocyte adhesion receptors. Proc. Natl. Acad. Sci. U.S.A. 94:7526‐7530.
   Even, P.C., Mokhtarian, A., and Pele, A. 1994. Practical aspects of indirect calorimetry in laboratory animals. Neurosci. Biobehav. Rev. 18:435‐447.
   Friedman, M.I. 1998. Fuel partitioning and food intake. Am. J. Clin. Nutr. 67:513S‐518S.
   Friedman, J.E., Ishizuka, T., Liu, S., Farrell, C.J., Bedol, D., Koletsky, R.J., Kaung, H.L., and Ernsberger, P. 1997. Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. Am. J. Physiol. 273:E1014‐E1023.
   Gerald, C., Walker, M.W., Criscione, L., Gustafson, E.L., Batzl‐Hartmann, , C., Smith, K.E., Vaysse, P., Durkin, M.M., Laz, T.M., Linemeyer, D.L., Schaffhauser, A.O., Whitebread, S., Hofbauer, K.G., Taber, R.I., Branchek, T.A., and Weinshank, R.L. 1996. A receptor subtype involved in neuropeptide‐Y‐induced food intake. Nature 382:168‐171.
   Good, D.J., Porter, F.D., Mahon, K.A., Parlow, A.F., Westphal, H., and Kirsch, I.R. 1997. Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene. Nature Genet. 15:397‐401.
   Graham, M., Shutter, J.R., Sarmiento, U., Sarosi, I., and Stark, K.L. 1997. Overexpression of Agrt leads to obesity in transgenic mice. Nature Genet. 17:273‐274.
   Hagstrom, S.A., North, M.A., Nishina, P.L., Berson, E.L., and Dryja, T.P. 1998. Recessive mutations in the gene encoding the tubby‐like protein TULP1 in patients with retinitis pigmentosa. Nature Genet. 18:174‐176.
   Halaas, J.L., Gajiwala, K.S., Maffei, M., Cohen, S.L., Chait, B.T., Rabinowitz, D., Lallone, R.L., Burley, S.K., and Friedman, J.M. 1995. Weight‐reducing effects of the plasma protein encoded by the obese gene. Science 269:543‐546.
   Hamann, A., Benecke, H., Le Marchand‐Brustel, Y., Susulic, V.S., Lowell, B.B., and Flier, J.S. 1995. Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat. Diabetes 44:1266‐1273.
   Hokfelt, T., Broberger, C., Diez, M., Xu, Z.Q., Shi, T., Kopp, J., Zhang, X., Holmberg, K., Landry, M., and Koistinaho, J. 1999. Galanin and NPY, two peptides with multiple putative roles in the nervous system. Horm. Metab. Res. 31:330‐334.
   Huszar, D., Lynch, C.A., Fairchild‐Huntress, V., Dunmore, J.H., Fang, Q., Berkemeier, L.R., Gu, W., Kesterson, R.A., Boston, B.A., Cone, R.D., Smith, F.J., Campfield, L.A., Burn, P., and Lee, F. 1997. Targeted disruption of the melanocortin‐4 receptor results in obesity in mice. Cell 88:131‐141.
   Kim, K.S., Larsen, N., Short, T., Plastow, G., and Rothschild, M.F. 2000. A missense variant of the porcine melanocortin‐4 receptor (MC4R) gene is associated with fatness, growth, and feed intake traits. Mamm. Genome 11:131‐135.
   Kleyn, P.W., Fan, W., Kovats, S.G., Lee, J.J., Pulido, J.C., Wu, Y., Berkemeier, L.R., Misumi, D.J., Holmgren, L., Charlat, O., Woolf, E.A., Tayber, O., Brody, T., Shu, P., Hawkins, F., Kennedy, B., Baldini, L., Ebeling, C., Alperin, G.D., Deeds, J., Lakey, N.D., Culpepper, , J., Chen, H., Glucksmann‐Kuis, M.A., Moore, K.J., et al. 1996. Identification and characterization of the mouse obesity gene tubby: A member of a novel gene family. Cell 85:281‐290.
   Kushi, A., Sasai, H., Koizumi, H., Takeda, N., Yokoyama, M., and Nakamura, M. 1998. Obesity and mild hyperinsulinemia found in neuropeptide Y‐Y1 receptor‐deficient mice. Proc. Natl. Acad. Sci. U.S.A. 95:15659‐15664.
   Lauterio, T.J., Davies, M.J., DeAngelo, M., Peyser, M., and Lee, J. 1999. Neuropeptide Y expression and endogenous leptin concentrations in a dietary model of obesity. Obes. Res. 7:498‐505.
   Le Tissier, P.R., Bains, R.K., Wells, S.E., Flavell, D.M., Stoye, J.P., Bennett, P.A., and Robinson, I.C.A.F. 2000. Characterization of the transgene insert in SLOB rats showing severe late‐onset obesity. Abstract, 11th International Congress of Endocrinology (ICE), Sydney, Australia.
   Lin, X., Braymer, H.D., Bray, G.A., and York, D.A. 1998. Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet‐induced obesity. Life Sci. 63:145‐153.
   Lowell, B.B., S.‐Susulic, V., Hamann, A., Lawitts, J.A., Himms‐Hagen, , J., Boyer, B.B., Kozak, L.P., and Flier, J.S. 1993. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366:740‐742.
   Luketich, J.D., Michel, K.E., Curcillo, P.G. II, Rigberg, D.A., Weiss, M.E., Feurer, I.D., and Mullen, J.L. 1998. Automated, eight‐cage indirect calorimetry in rats. Nutrition. 14:672‐677.
   MacKay, S.J., Loiseau, A., Poivre, R., and Huot, A. 1991. Calibration method for small animal indirect calorimeters. Am. J. Physiol. 261:E661‐E664.
   Matarese, L.E. 1997. Indirect calorimetry: Technical aspects. J. Am. Diet. Assoc. 97:S154‐S160.
   Moussa, N.M. and Claycombe, K.J. 1999. The yellow mouse obesity syndrome and mechanisms of agouti‐induced obesity. Obes. Res. 7:506‐514.
   Naggert, J.K., Fricker, L.D., Varlamov, O., Nishina, P.M., Rouille, Y., Steiner, D.F., Carroll, R.J., Paigen, B.J., and Leiter, E.H. 1995. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet. 10:135‐142.
   Naveilhan, P., Hassani, H., Canals, J.M., Ekstrand, A.J., Larefalk, A., Chhajlani, V., Arenas, E., Gedda, K., Svensson, L., Thoren, P., and Ernfors, P. 1999. Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor. Nature Med. 5:1188‐1193.
   Nemeroff, C.B., Lipton, M.A., and Kizer, J.S. 1978. Models of neuroendocrine regulation: Use of monosodium glutamate as an investigational tool. Dev. Neurosci 1:102‐109.
   Nishina, P.M., North, M.A., Ikeda, A., Yan, Y., and Naggert, J.K. 1998. Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans. Genomics 54:215‐220.
   Oberbauer, A.M., Stern, J.S., Johnson, P.R., Horwitz, B.A., German, J.B., Phinney, S.D., Beermann, D.H., Pomp, D., and Murray, J.D. 1997. Body composition of inactivated growth hormone (oMt1a‐oGH) transgenic mice: Generation of an obese phenotype. Growth Dev. Aging 61:169‐179.
   Ohki‐Hamazaki, H., Watase, K., Yamamoto, K., Ogura, H., Yamano, M., Yamada, K., Maeno, H., Imaki, J., Kikuyama, S., Wada, E., and Wada, K. 1997. Mice lacking bombesin receptor subtype‐3 develop metabolic defects and obesity. Nature 390:165‐169.
   Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., and Barsh, G.S. 1997. Antagonism of central melanocortin receptors in vitro and in vivo by agouti‐related protein (published erratum appears in Science 281:1615). Science 278:135‐138.
   Pelleymounter, M.A., Cullen, M.J., Baker, M.B., Hecht, R., Winters, D., Boone, T., and Collins, F. 1995. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540‐543.
   Pickavance, L.C., Tadayyon, M., Widdowson, P.S., Buckingham, R.E., and Wilding, J.P. 1999. Therapeutic index for rosiglitazone in dietary obese rats: Separation of efficacy and haemodilution. Br. J. Pharmacol. 128:1570‐1576.
   Pomp, D., Oberbauer, A.M., and Murray, J.D. 1996. Development of obesity following inactivation of a growth hormone transgene in mice. Transgenic Res. 5:13‐23.
   Shepherd, P.R. and Kahn, B.B. 1999. Glucose transporters and insulin action: Implications for insulin resistance and diabetes mellitus. N. Engl. J. Med. 341:248‐257.
   Shepherd, P.R., Gnudi, L., Tozzo, E., Yang, H., Leach, F., and Kahn, B.B. 1993. Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. J. Biol. Chem. 268:22243‐22246.
   Shimada, M., Tritos, N.A., Lowell, B.B., Flier, J.S., and Maratos‐Flier, E. 1998. Mice lacking melanin‐concentrating hormone are hypophagic and lean. Nature 396:670‐674.
   Shutter, J.R., Graham, M., Kinsey, A.C., Scully, S., Luthy, R., and Stark, K.L. 1997. Hypothalamic expression of ART, a novel gene related to agouti, is up‐regulated in obese and diabetic mutant mice. Genes Dev. 11:593‐602.
   Stenzel‐Poore, M.P., Cameron, V.A., Vaughan, J., Sawchenko, P.E., and Vale, W. 1992. Development of Cushing's syndrome in corticotropin‐releasing factor transgenic mice. Endocrinology 130:3378‐3386.
   Stenzel‐Poore, M.P., Heinrichs, S.C., Rivest, S., Koob, G.F., and Vale, W.W. 1994. Overproduction of corticotropin‐releasing factor in transgenic mice: A genetic model of anxiogenic behavior. J. Neurosci. 14:2579‐2584.
   Susulic, V.S., Frederich, R.C., Lawitts, J., Tozzo, E., Kahn, B.B., Harper, M.E., Himms‐Hagen, , J., Flier, J.S., and Lowell, B.B. 1995. Targeted disruption of the beta 3‐adrenergic receptor gene. J. Biol. Chem. 270:29483‐29492.
   Takaya, K., Ogawa, Y., Hiraoka, J., Hosoda, K., Yamori, Y., Nakao, K., and Koletsky, R.J. 1996. Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nature Genet. 14:130‐131.
   Tecott, L.H., Sun, L.M., Akana, S.F., Strack, A.M., Lowenstein, D.H., Dallman, M.F., and Julius, D. 1995. Eating disorder and epilepsy in mice lacking 5‐HT2c serotonin receptors. Nature 374:542‐546.
   Tokunaga, K., Fukushima, M., Lupien, J.R., Bray, G.A., Kemnitz, J.W., and Schemmel, R. 1989. Effects of food restriction and adrenalectomy in rats with VMH or PVH lesions. Physiol. Behav. 45:1131‐1137.
   Tolkamp, B.J., Day, J.E., and Kyriazakis, I. 1998. Measuring food intake in farm and laboratory animals. Proc. Nutr. Soc. 57:313‐319.
   West, D.B. and York, B. 1998. Dietary fat, genetic predisposition, and obesity: Lessons from animal models. Am. J. Clin. Nutr. 67:505S‐512S.
   Westerterp, K.R. 1999. Body composition, water turnover and energy turnover assessment with labelled water. Proc. Nutr. Soc. 58:945‐951.
   Wilde, D.W., Massey, K.D., Walker, G.K., Vollmer, A., and Grekin, R.J. 2000. High‐fat diet elevates blood pressure and cerebrovascular muscle Ca(2+) current. Hypertension 35:832‐837.
   Woods, S.C., Schwartz, M.W., Baskin, D.G., and Seeley, R.J. 2000. Food intake and the regulation of body weight. Annu. Rev. Psychol. 51:255‐277.
   Wu‐Peng, X.S., Chua, S.C. Jr., Okada, N., Liu, S.M., Nicolson, M., and Leibel, R.L. 1997. Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): Evidence for deficient plasma‐to‐CSF transport of leptin in both the Zucker and Koletsky obese rat. Diabetes 46:513‐518.
   Yamashita, T., Murakami, T., Iida, M., Kuwajima, M., and Shima, K. 1997. Leptin receptor of Zucker fatty rat performs reduced signal transduction. Diabetes 46:1077‐1080.
   Yen, T.T., Gill, A.M., Frigeri, L.G., Barsh, G.S., and Wolff, G.L. 1994. Obesity, diabetes, and neoplasia in yellow A(vy)/– mice: Ectopic expression of the agouti gene. FASEB J. 8:479‐488.
   Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M. 1994. Positional cloning of the mouse obese gene and its human homologue (published erratum appears in Nature 374:479). Nature 372:425‐432.
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