Exp Clin Endocrinol Diabetes 2001; 109(6): 307-319
DOI: 10.1055/s-2001-17297
Review

© Johann Ambrosius Barth

Rodent obesity models: An overview

Matthias Tschöp, Mark L. Heiman
  • Endocrine Division, Lilly Research Laboratories, Eli Lilly and Company Corporate Center, Indianapolis, Indiana, USA
Further Information

Publication History

Publication Date:
19 September 2001 (online)

Summary:

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

References

  • 1 Asnicar M, Smith D P, Yang D D, Heiman M L, Fox N, Chen Y F, Hsiung H M, Köster A. Absence of cocaine- and amphetamine-regulated transcript (Cart) results in obesity in mice fed a high caloric diet.  Endocrinology. (in press) 2001; 
  • 2 Begley C G, Lipkowitz S, Gobel V, Mahon K A, Bertness V, Green A R, Gough N M, Kirsch I R. 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 1992; 
  • 3 Bray G A, York D A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis.  Physiol Rev. 59 719-809 1979; 
  • 4 Bray G A, York D A. The MONA LISA hypothesis in the time of leptin.  Recent Prog Horm Res. 53 95-117 1998; 
  • 5 Bray G A, York D A, Fisler J S. Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system.  Vitam Horm. 45 1-125 1989; 
  • 6 Bruning J C, Gautam D, Burks D J, Gillette J, Schubert M, Orban P C, Klein R, Krone W, Muller-Wieland D, Kahn C R. Role of brain insulin receptor in control of body weight and reproduction.  Science. 289 2122-2125 2000; 
  • 7 Butler A A, Kesterson R A, Khong K, Cullen M J, Pelleymounter M A, Dekoning J, Baetscher M, Cone R D. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse.  Endocrinology. 141 3518-3521 2000; 
  • 8 Campfield L A, Smith F J, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.  Science. 269 546-549 1995; 
  • 9 Charlton H , Clark R G, Robinson I C, Goff A E, Cox B S, Bugnon C, Bloch B A. Growth hormone-deficient dwarfism in the rat: a new mutation.  J Endocrinol. 119 51-58 1988; 
  • 10 Chemelli R M, Willie J T, Sinton C M, Elmquist J K, Scammell T, Lee C, Richardson J A, Williams S C, Xiong Y, Kisanuki Y, Fitch T E, Nakazato M, Hammer R E, Saper C B, Yanagisawa M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.  Cell. 98 437-451 1999; 
  • 11 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, Van Der Ploeg L H. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.  Nat Genet. 26 97-102 2000; 
  • 12 Chen W, Kelly M A, Opitz-Araya X, Thomas R E, Low M J, Cone R D. Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides.  Cell. 91 789-798 1997; 
  • 13 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, Morgenstern J P. 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 1996; 
  • 14 Chua S C, Chung W K, Wu-Peng X S, Zhang Y, Liu S M, Tartaglia L, Leibel R L. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor.  Science. 271 994-996 1996; 
  • 15 Clark R G, Mortensen D L, Carlsson L M, Carlsson B, Carmignac D, Robinson I C. 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 1996; 
  • 16 Coleman D L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.  Diabetologia. 14 141-148 1978; 
  • 17 Coleman D L, Eicher E M. Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse.  J Hered. 81 424-427 1990; 
  • 18 Collier G R, McMillan J S, Windmill K, Walder K, Tenne-Brown J, de Silva A, Trevaskis J, Jones S, Morton G J, Lee S, Augert G, Civitarese A, Zimmet P Z. Beacon: a novel gene involved in the regulation of energy balance.  Diabetes. 49 1766-1771 2000; 
  • 19 Cool D R, Loh Y P. Carboxypeptidase E is a sorting receptor for prohormones: binding and kinetic studies.  Mol Cell Endocrinol. 139 7-13 1998; 
  • 20 Cool D R, Normant E, Shen F, Chen H C, Pannell L, Zhang Y, Loh Y P. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice.  Cell. 88 73-83 1997; 
  • 21 Costet P, Legendre C, More J, Edgar A, Galtier P, Pineau T. Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis.  J Biol Chem. 273 29577-29585 1998; 
  • 22 Crouse J A, Elliott G E, Burgess T L, Chiu L, Bennett L, Nicolson M, Pacifici R E. Altered cell surface expression and signaling of leptin receptors containing the fatty mutation.  J Biol Chem. 273 18365-18373 1998; 
  • 23 da Silva B A, Bjorbaek C, Uotani S, Flier J S. Functional properties of leptin receptor isoforms containing the gln → pro extracellular domain mutation of the fatty rat.  Endocrinology. 139 3681-3690 1998; 
  • 24 Dong Z M, Gutierrez-Ramos J C, Coxon A, Mayadas T N, Wagner D D. A new class of obesity genes encodes leukocyte adhesion receptors.  Proc Natl Acad Sci U S A. 94 7526-7530 1997; 
  • 25 Even P C, Mokhtarian A, Pele A. Practical aspects of indirect calorimetry in laboratory animals.  Neurosci Biobehav Rev. 18 435-447 1994; 
  • 26 Friedman J E, Ishizuka T, Liu S, Farrell C J, Bedol D, Koletsky R J, Kaung H L, Ernsberger P. Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat.  Am J Physiol. 273 E1014-E1023 1997; 
  • 27 Friedman J M, Halaas J L. Leptin and the regulation of body weight in mammals.  Nature. 395 763-770 1998; 
  • 28 Friedman M I. Fuel partitioning and food intake.  Am J Clin Nutr. 67 513S-518S 1998; 
  • 29 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, Weinshank R L. A receptor subtype involved in neuropeptide-Y-induced food intake.  Nature. 382 168-171 1996; 
  • 30 Good D J, Porter F D, Mahon K A, Parlow A F, Westphal H, Kirsch I R. Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene.  Nat Genet. 15 397-401 1997; 
  • 31 Graham M, Shutter J R, Sarmiento U, Sarosi I, Stark K L. Overexpression of Agrt leads to obesity in transgenic mice.  Nat Genet. 17 273-274 1997; 
  • 32 Hagstrom S A, North M A, Nishina P L, Berson E L, Dryja T P. Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa.  Nat Genet. 18 174-176 1998; 
  • 33 Halaas J L, Gajiwala K S, Maffei M, Cohen S L, Chait B T, Rabinowitz D, Lallone R L, Burley S K, Friedman J M. Weight-reducing effects of the plasma protein encoded by the obese gene.  Science. 269 543-546 1995; 
  • 34 Hamann A, Benecke H, Le Marchand-Brustel Y, Susulic V S, Lowell B B, Flier J S. Characterization of insulin resistance and NIDDM in transgenic mice with reduced brown fat.  Diabetes. 44 1266-1273 1995; 
  • 35 Hani E H, Dupont S, Durand E, Dina C, Gallina S, Gantz I, Froguel P. Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians.  J Clin Endocrinol Metab. 86 2895-2898 2001; 
  • 36 Hara J, Beuckmann C T, Nambu T, Willie J T, Chemelli R M, Sinton C M, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity.  Neuron. 30 345-354 2001; 
  • 37 Hokfelt T, Broberger C, Diez M, Xu Z Q, Shi T, Kopp J, Zhang X, Holmberg K, Landry M, Koistinaho J. Galanin and NPY, two peptides with multiple putative roles in the nervous system.  Horm Metab Res. 31 330-334 1999; 
  • 38 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, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice.  Cell. 88 131-141 1997; 
  • 39 Kim K S, Larsen N, Short T, Plastow G, Rothschild M F. 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 2000; 
  • 40 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. Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family.  Cell. 85 281-290 1996; 
  • 41 Kristensen P, Judge M E, Thim L, Ribel U, Christjansen K N, Wulff B S, Clausen J T, Jensen P B, Madsen O D, Vrang N, Larsen P J, Hastrup S. Hypothalamic CART is a new anorectic peptide regulated by leptin.  Nature. 393 72-76 1998; 
  • 42 Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.  Nat Genet. 19 155-157 1998; 
  • 43 Kushi A, Sasai H, Koizumi H, Takeda N, Yokoyama M, Nakamura M. Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice.  Proc Natl Acad Sci U S A. 95 15659-15664 1998; 
  • 44 Lauterio T J, Davies M J, DeAngelo M, Peyser M, Lee J. Neuropeptide Y expression and endogenous leptin concentrations in a dietary model of obesity.  Obes Res. 7 498-505 1999; 
  • 45 Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong P J, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.  Cell. 98 365-376 1999; 
  • 46 Lin X, Braymer H D, Bray G A, York D A. Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity.  Life Sci. 63 145-153 1998; 
  • 47 Lowell B B, Hamann A, Lawitts J A, Himms-Hagen J, Boyer B B, Kozak L P, Flier J S. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue.  Nature. 366 740-742 1993; 
  • 48 Le Tissier P R, Bains R K, Wells S E, Flavell D M, Stoye J P, Bennett P A, Robinson I CAF. Characterization of the transgene insert in SLOB rats showing severe late-onset obesity. Abstract, 11th International Congress of Endocrinology (ICE) Sidney, Australia : 2000
  • 49 Ludwig D S, Tritos N A, Mastaitis J W, Kulkarni R, Kokkotou E, Elmquist J, Lowell B, Flier J S, Maratos-Flier E. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance.  J Clin Invest. 107 379-386 2001; 
  • 50 Luketich J D, Michel K E, Curcillo P G, Rigberg D A, Weiss M E, Feurer I D, Mullen J L. Automated, eight-cage indirect calorimetry in rats.  Nutrition. 14 672-677 1998; 
  • 51 MacKay S J, Loiseau A, Poivre R, Huot A. Calibration method for small animal indirect calorimeters.  Am J Physiol. 261 E661-E664 1991; 
  • 52 Matarese L E. Indirect calorimetry: technical aspects.  J Am Diet Assoc. 97 S154-S160 1997; 
  • 53 Moussa N M, Claycombe K J. The yellow mouse obesity syndrome and mechanisms of agouti-induced obesity.  Obes Res. 7 506-514 1999; 
  • 54 Naggert J K, Fricker L D, Varlamov O, Nishina P M, Rouille Y, Steiner D F, Carroll R J, Paigen B J, Leiter E H. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity.  Nat Genet. 10 135-142 1995; 
  • 55 Naveilhan P, Hassani H, Canals J M, Ekstrand A J, Larefalk A, Chhajlani V, Arenas E, Gedda K, Svensson L, Thoren P, Ernfors P. Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor.  Nat Med. 5 1188-1193 1999; 
  • 56 Nemeroff C B, Lipton M A, Kizer J S. Models of neuroendocrine regulation: use of monosodium glutamate as an investigational tool.  Dev Neurosci. 1 102-109 1978; 
  • 57 Nishina P M, North M A, Ikeda A, Yan Y, Naggert J K. Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans.  Genomics. 54 215-220 1998; 
  • 58 Oberbauer A M, Stern J S, Johnson P R, Horwitz B A, German J B, Phinney S D, Beermann D H, Pomp D, Murray J D. Body composition of inactivated growth hormone (oMt1a-oGH) transgenic mice: generation of an obese phenotype.  Growth Dev Aging. 61 169-179 1997; 
  • 59 Ohki-Hamazaki H, Watase K, Yamamoto K, Ogura H, Yamano M, Yamada K, Maeno H, Imaki J, Kikuyama S, Wada E, Wada K. Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity.  Nature. 390 165-169 1997; 
  • 60 Ollmann M M, Wilson B D, Yang Y K, Kerns J A, Chen Y, Gantz I, Barsh G S. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.  Science. 278 135-138 1997; 
  • 61 Pelleymounter M A, Cullen M J, Baker M B, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice.  Science. 269 540-543 1995; 
  • 62 Pickavance L C, Tadayyon M, Widdowson P S, Buckingham R E, Wilding J P. Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution.  Br J Pharmacol. 128 1570-1576 1999; 
  • 63 Pomp D, Oberbauer A M, Murray J D. Development of obesity following inactivation of a growth hormone transgene in mice.  Transgenic Res. 5 13-23 1996; 
  • 64 Reizes O, Lincecum J, Wang Z, Goldberger O, Huang L, Kaksonen M, Ahima R, Hinkes M T, Barsh G S, Rauvala H, Bernfield M. Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3.  Cell. 106 105-116 2001; 
  • 65 Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli R M, Tanaka H, Williams S C, Richardson J A, Kozlowski G P, Wilson S, Arch J R, Buckingham R E, Haynes A C, Carr S A, Annan R S, McNulty D E, Liu W S, Terrett J A, Elshourbagy N A, Bergsma D J, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.  Cell. 92 573-585 1998; 
  • 66 Shepherd P R, Gnudi L, Tozzo E, Yang H, Leach F, Kahn B B. Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue.  J Biol Chem. 268 22243-22246 1993; 
  • 67 Shepherd P R, Kahn B B. Glucose transporters and insulin action-implications for insulin resistance and diabetes mellitus.  N Engl J Med. 341 248-257 1999; 
  • 68 Shimada M, Tritos N A, Lowell B B, Flier J S, Maratos-Flier E. Mice lacking melanin-concentrating hormone are hypophagic and lean.  Nature. 396 670-674 1998; 
  • 69 Shutter J R, Graham M, Kinsey A C, Scully S, Luthy R, Stark K L. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.  Genes Dev. 11 593-602 1997; 
  • 70 Smith A I, Funder J W. Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues.  Endocr Rev. 9 159-179 1988; 
  • 71 Stenzel-Poore M P, Cameron V A, Vaughan J, Sawchenko P E, Vale W. Development of Cushing's syndrome in corticotropin-releasing factor transgenic mice.  Endocrinology. 130 3378-3386 1992; 
  • 72 Stenzel-Poore M P, Heinrichs S C, Rivest S, Koob G F, Vale W W. Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior.  J Neurosci. 14 2579-2584 1994; 
  • 73 Susulic V S, Frederich R C, Lawitts J, Tozzo E, Kahn B B, Harper M E, Himms-Hagen J, Flier J S, Lowell B B. Targeted disruption of the beta 3-adrenergic receptor gene.  J Biol Chem. 270 29483-29492 1995; 
  • 74 Takaya K, Ogawa Y, Hiraoka J, Hosoda K, Yamori Y, Nakao K, Koletsky R J. Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat.  Nat Genet. 14 130-131 1996; 
  • 75 Tecott L H, Sun L M, Akana S F, Strack A M, Lowenstein D , Dallman M F, Julius D. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.  Nature. 374 542-546 1995; 
  • 76 Tokunaga K, Fukushima M, Lupien J R, Bray G A, Kemnitz J W, Schemmel R. Effects of food restriction and adrenalectomy in rats with VMH or PVH lesions.  Physiol Behav. 45 1131-1137 1989; 
  • 77 Tolkamp B J, Day J E, Kyriazakis I. Measuring food intake in farm and laboratory animals.  Proc Nutr Soc. 57 313-319 1998; 
  • 78 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. 106 253-262 2000; 
  • 79 Vrang N, Larsen P J, Clausen J T, Kristensen P. Neurochemical characterization of hypothalamic cocaine- amphetamine-regulated transcript neurons.  J Neurosci. 19 RC5 1999; 
  • 80 West D B, York B. Dietary fat, genetic predisposition, and obesity: lessons from animal models.  Am J Clin Nutr. 67 505S-512S 1998; 
  • 81 Westerterp K R. Body composition, water turnover and energy turnover assessment with labelled water (In Process Citation).  Proc Nutr Soc. 58 945-951 1999; 
  • 82 Wilde D W, Massey K D, Walker G K, Vollmer A, Grekin R J. High-fat diet elevates blood pressure and cerebrovascular muscle Ca(2+) current.  Hypertension. 35 832-837 2000; 
  • 83 Woods S C, Schwartz M W, Baskin D G, Seeley R J. Food intake and the regulation of body weight.  Annu Rev Psychol. 51 255-277 2000; 
  • 84 Wu-Peng X S, Chua S C, Okada N, Liu S M, Nicolson M, Leibel R L. 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 1997; 
  • 85 Yamashita T, Murakami T, Iida M, Kuwajima M, Shima K. Leptin receptor of Zucker fatty rat performs reduced signal transduction.  Diabetes. 46 1077-1080 1997; 
  • 86 Yaswen L, Diehl N, Brennan M B, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.  Nat Med. 5 1066-1070 1999; 
  • 87 Yen T T, Gill A M, Frigeri L G, Barsh G S, Wolff G L. Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene.  Faseb J. 8 479-488 1994; 
  • 88 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 372 425-432 1994; 

Matthias H. TschoepM.D. 

Endocrine Research

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