Current Protocols in Pharmacology || Overview of Animal Models of Obesity

UNIT 5.61Overview of Animal Models of Obesity

Thomas A. Lutz1 and Stephen C. Woods2

1University of Zurich, Institute of Veterinary Physiology, Zurich Center of IntegrativeHuman Physiology, Zurich, Switzerland2Department of Psychiatry and Behavioral Neuroscience, College of Medicine, University ofCincinnati Obesity Research Center, Cincinnati, Ohio

ABSTRACT

The focus of this overview is on the animal models of obesity most commonly utilized inresearch. The models include monogenic models in the leptin pathway, polygenic diet-dependentmodels, and, in particular for their historical perspective, surgical and chemical models of obesity.However, there are far too many models to consider all of them comprehensively, especially thosecaused by selective molecular genetic approaches modifying one or more genes in specificpopulations of cells. Further, the generation and use of inducible transgenic animals (inducedknock-out or knock-in) is not covered, even though they often carry significant advantagescompared to traditional transgenic animals, e.g., influences of the genetic modification duringthe development of the animals can be minimized. The number of these animal models is simplytoo large to be covered in this unit. Curr. Protoc. Pharmacol. 58:5.61.1-5.61.18. C© 2012 by JohnWiley & Sons, Inc.

Keywords: monogenic models � polygenic models � genetic engineering � surgical model �

leptin � diabetes � hyperglycemia

INTRODUCTIONThe incidence of obesity continues to climb

worldwide, making it imperative that animalmodels sharing characteristics of human obe-sity and its co-morbidities be developed in thequest for novel preventions and/or treatments.While there is a clear and well-documented ge-netic component for the tendency to becomeobese, most instances of human obesity arenonetheless considered to be polygenic, result-ing from the integrated activity of numerousgenes, each of which carries only a small riskfactor. Animal models of obesity can thereforebe partitioned into different categories, the ma-jor ones being based on mutations or manipu-lations of one or a few individual genes versusthose in genetically intact animals exposed toobesigenic environments such as being main-tained on high-fat diets.

While it is beyond the scope of thisoverview to delve into the causes of obesity,many excellent reviews exist (Schwartz et al.,2003; Leibel, 2008; Woods, 2009; Kaiyalaand Schwartz, 2011). Considerable researchis based on the premise that a primary causalfactor lies in the interaction of the brain withperipheral tissues such as the gut, the liver, theendocrine pancreas, adipose tissue, and others.This is typically manifested as dysfunctional

eating, energy metabolism, and/or autonomicactivity. Note that this could occur via ab-normal signaling by peripheral organs to thebrain (e.g., indicating that insufficient fat ispresent, thus triggering increased food intakeand consequent increased body fat) and/or byabnormal signaling from the brain to other or-gans (e.g., reduced sympathetic and increasedparasympathetic activity to the endocrine pan-creas and liver after certain brain lesions).

Because food intake has high face valid-ity when considering possible factors influenc-ing body adiposity, most characterizations ofanimal models include assessments of intakeas well as of body fat, plasma leptin, insulin,and glucose, and other related parameters. Itis therefore important to understand the ba-sics of the control of food intake and how theymight relate to obesity. It is generally acceptedthat factors that influence food intake and con-sequently body fat can be conceptualized asthose that influence when individuals start eat-ing and those that influence when eating, oncebegun, will end: i.e., factors that stimulate ap-petite or eating per se and those that signalfullness or satiation. Except in rare circum-stances, eating is initiated by factors such ashabit, time of day, the social situation, foodavailability, and so on (Woods, 1991, 2009).

Current Protocols in Pharmacology 5.61.1-5.61.18, September 2012Published online September 2012 in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/0471141755.ph0561s58Copyright C© 2012 John Wiley & Sons, Inc.

Animal Modelsof Disease

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Supplement 58

Overview ofAnimal Models of

Obesity

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Supplement 58 Current Protocols in Pharmacology

The amount eaten (i.e., meal size), on the otherhand, is determined by satiation factors gener-ated by the gastrointestinal system interactingwith ingested food. The best known satiationfactor is the intestinal peptide cholecystokinin(CCK). Satiation factors interact in the brainwith signals emanating from adipose tissueand other organs indicating how lean or fatthe individual is. These adiposity signals, suchas leptin and insulin, interact with receptors inthe hypothalamus and have potent effects onfood intake, energy expenditure, and the levelof stored fat. The majority of animal mod-els commonly used to investigate causes andtreatments for obesity therefore have alteredactivity in brain circuits integrating satiationand adiposity signals (Woods, 1991, 2009).

ANIMAL MODELS OF OBESITYAdmittedly, reviews of animal models of

obesity are always somewhat subjective forthe choice of models included. The criteria forchoosing the animal models described in thisunit (Table 5.61.1) were:

• The model has been used frequently inobesity research.

• The model has a historic perspective, e.g.,it enabled identification of major areas in thebrain involved in the control of eating and bodyweight.

• The model has been influential for thesubsequent generation of more specific animalmodels, e.g., specific knockout or transgenic(potentially inducible) models based on thediscovery of the leptin pathway.

• The models cover the most important dif-ferent types of models such as genetic or non-genetic models.

• Within the genetic models, monogenicand polygenic models are represented.

• Within monogenic models, two main cat-egories are represented—monogenic modelslinked to the pathway of an adiposity signal(undoubtedly, the leptin pathway was the mostcritical to trigger an enormous research activ-ity in recent years) and of a satiation signallike CCK.

• The animal model shows a distinct phe-notype of obesity, hyperphagia, or change inenergy metabolism.

• The animal model may also show some ofthe most frequent comorbidities of obesity, likehyperglycemia, insulin resistance, or diabetes-like syndromes.

Because it is the best understood, the firstmodels discussed concern monogenic (single-gene) mutations involving the leptin pathway(Schwartz et al., 2000). Spontaneous muta-

tions leading to marked obesity had beendescribed long before the underlying causes(e.g., defects in the leptin gene or the leptinreceptor gene) had been discovered. Discov-eries in this pathway led to the subsequentgeneration of a large number of engineeredmutants. Another prominent animal model ofobesity that resulted from a spontaneous mu-tation is the Otsuka Long Evans TokushimaFatty (OLETF) rat, which lacks functional re-ceptors for the satiating hormone CCK. Diet-induced models of obesity (DIO) are oftenused to study polygenic causes of obesity. DIOanimals are believed to better mimic the stateof common obesity in humans than most ofthe genetically modified models, and may bethe best choice for testing prospective thera-peutics. Finally, models of surgically or chem-ically induced and seasonal models of obesityare summarized. Surgically induced obesityhas lost much of its importance since the in-troduction of genetically modified animals,which allow the more specific ablation of neu-rons in defined parts of the brain.

Most animal models of obesity are small ro-dents (rats or mice), but it should be mentionedthat most mammals, when maintained in smallenclosures with free food (as in many zoos inthe past), develop obesity. The most commonlyused animal models of obesity are probably theleptin-deficient ob/ob mouse, the leptin recep-tor deficient db/db mouse, its rat counterpartslike the Zucker rat, the MC4 receptor-deficientanimals and models of diet-induced obesity.

The choice of model for a particular ex-periment depends upon the goal of the study.For example, as described above, DIO animalsmay be the best choice for testing prospec-tive therapeutics. Transgenic models or mod-els with spontaneous mutations may be used inthe evaluation of a prospective therapeutic todetermine whether it engages a specific targetor pathway in vivo. The transgenic models andmodels with spontaneous mutations may alsobe used to explore the role of specific molec-ular targets and pathways in the physiology offood intake and their potential role in obesity.

MONOGENIC MODELS:MONOGENIC MUTATIONS IN THELEPTIN PATHWAY

Leptin and Its ReceptorAnimals with a defect in the leptin-

signaling pathway in the hypothalamus of thebrain develop a morbidly obese phenotype.The models include animals that lack leptinproduction and/or that are insensitive to leptin

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Current Protocols in Pharmacology Supplement 58

Table 5.61.1 Summary of Animal Models of Obesity Described in this Unita

Model name Mutation HyperphagiaDecreasedenergyexpenditure

HyperglycemiaInsulinresistance

Monogenic mutations in the leptin pathway

Leptin and its receptor

ob/ob mouse Lepob/Lepob (leptindeficiency)

X X X X

db/db mouse Lepdb/Lepdb (leptinreceptor)

X X X X

s/s mouse disrupted STAT3 signal ofleptin receptor

X X [X]

Zucker rat mutated leptin receptor(fa/fa)

X X X X

Koletsky rat mutated leptin receptor (nullmutation)

X X X X

ZDF rat mutated leptin receptor(fa/fa)

X X X X

Wistar Kyoto fatty rat Zucker /fa/fa xWistar-Kyoto

X X X X

Obesity models with a deficit downstream of the brain leptin receptor

POMC knockoutmouse

POMC deficiency X X X X

POMC/AgRP doubleknockout mice

POMC and AgRPdeficiency

X X X X

MC4R knockoutmouse

melanocortin 4 receptor X X X X

MC4R knockout rat melanocortin 4 receptor X X X X

MC3R knockoutmouse

melanocortin 3 receptor X X X [X]

MC4/MC3 receptordouble knockoutmouse

X X X X

Ectopic agoutiexpression

agouti overexpression X X X X

AgRP overexpression AgRP overexpression X X [X] X

Carboxypeptidase E(CPE) mutation

Disruption of prohormoneprocessing

X X [X] [X]

Other monogenic models

Otsuka Long EvansTokushima Fatty rat(OLETF)

CCK1 receptor knockout X X X X

Diet-induced models; polygenic models

Diet induced obese(DIO) rat

Polygenic X X [X] X

continued

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Table 5.61.1 Summary of Animal Models of Obesity Described in this Unita, continued



Cafeteria diet-inducedobesity

Polygenic X X [X] X

High-fat diet-inducedobesity

Polygenic X X X

New Zealand obesemouse

Polygenic X X X X

Age-related obesity inmice (LOO)

Polygenic [X] [X]

Age-related obesity inmacaques

Polygenic X X [X] [X]

Maternal overfeedingand exposure to highfat diets

Polygenic X [X] [X]

Early postnataloverfeeding inducedobesity; rearing insmall litters

Polygenic X X [X] [X]

Other genetically engineered mutants

CRF - Transgenicmouse

CRF-overexpression X [X] X

Glucose transportersubtype 4 transgenic

GLUT4 overexpression X X

Melaninconcentratinghormone (MCH)transgenic mouse

MCH overexpression X X [X]

Beta-3 adrenergicreceptor knockout

Beta-3 receptor X

Serotonin 5-HT-2creceptor knockout

5-HT-2c receptor X [X] [X]

Neuropeptide-Y 1receptor (NPY1R)knockout mouse

NPY1 receptor X

NPY2R knockoutmice

NPY2 receptor X

Bombesin 3 receptorknockout mice (BRS3ko)

BRS3 receptor X X X X

Neuronal insulinreceptor knockoutmice (NIRKO mice)

NIRKO X X X

11beta-HSD-1overexpression

11beta-HSD-1 X X X

continued


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Table 5.61.1 Summary of Animal Models of Obesity Described in this Unita, continued



Surgical or chemical models of obesity

Lesion of theventromedialhypothalamus (VMHlesion)

X X X X

Lesion of thehypothalamicparaventricularnucleus (PVN lesion)

X [X] [X]

Lesion of thehypothalamic arcuatenucleus (ARC lesion)

X X [X] [X]

Ovariectomy X X

Ablation of brownadipose tissue (BAT)

X

Seasonal models of obesity

Syrian hamster

Siberian hamster X

Other models of obesity and associated metabolic changes

Lipodystrophy X X X

GH-deficient dwarfrat

growth hormone deficiency

Tubbya“[ ]” indicates mild or late phenotype. See text for references and abbreviations.

due to leptin receptor mutations or extremeleptin resistance. Mutations are spontaneous(e.g., Lepob/Lepob mouse; Lepdb/Lepdb mouse)or genetically engineered. Animals with muta-tions that lie downstream of the leptin-sensingneurons in the hypothalamus are also included.

ob/ob mouse (Lepob/Lepob mouse, the‘obese’ mouse)

A spontaneous mutation leading to themarkedly obese phenotype in the Lepob/Lepob

mouse has been recognized since the 1950s(Mayer et al., 1951; Coleman, 1978). How-ever, it was not until the discovery in 1994of the underlying mechanisms and character-ization of the ob gene product, leptin, thatintensive research on the genetics of obesityincreased dramatically (Zhang et al., 1994).Today, the ob gene is one of the most stud-ied genes in obesity research. A single-basespontaneous mutation of the ob gene prevents

the secretion of bioactive leptin because leptinsynthesis is terminated prematurely. Leptin ismainly synthesized in white adipocytes, and itssecretion is directly proportional to the amountof stored triglyceride. Leptin deficiency hasalso been observed in rare cases of human obe-sity (O’Rahilly, 2009).

Phenotypically, the lack of leptin leadsto marked, early-onset obesity characterizedby hyperphagia, reduced energy expenditure,and hypothermia; further defects are hyper-corticosteronemia, insulin resistance associ-ated with hyperglycemia and hyperinsuline-mia, hypothyroidism, and growth hormonedeficiency leading to a decrease in lineargrowth. Lepob/Lepob mice are infertile. Obe-sity in Lepob/Lepob mice is one of the fewforms of obesity that can be treated effec-tively by the administration of exogenous lep-tin. Leptin normalizes all known phenotypicdefects in Lepob/Lepob mice including obesity,


Obesity

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symptoms of the metabolic syndrome, and re-productive function (Coleman, 1978; Bray andYork, 1979; Zhang et al., 1994; Campfieldet al., 1995; Halaas et al., 1995; Pelleymounteret al., 1995; Friedman, 1998).

db/db mouse (the ‘diabetic’ mouse)The leptin receptor-deficient “db/db”

mouse, also called the Lepdb/Lepdb mouse,is phenotypically similar to the Lepob/Lepob

mouse and was so named because there is moremarked hyperglycemia on some backgroundstrains than occurs in the Lepob/Lepob mouse.Lepob/Lepob mice are also characterized byhyperphagia and reduced energy expenditure,leading to marked early-onset obesity; theyare hypothermic, have decreased linear growthdue to growth hormone deficiency, and are in-fertile (Coleman, 1978; Halaas et al., 1995;Chua et al., 1996). The major difference fromthe Lepob/Lepob mouse is the marked re-sistance to leptin due to the fact that theLepdb/Lepdb mouse has a (spontaneously) mu-tated leptin receptor. These mice also sufferfrom morbid obesity, but their leptin levels aremarkedly elevated. Lepdb/Lepdb mice are in-sulin resistant and develop diabetes. They haveoften been used to study type II diabetes-likesyndromes, but these animals do not developthe full phenotype of type II diabetes. Amongother differences, they lack pancreatic amy-loid deposition. Analogous to the ob gene mu-tation, the mutation of the leptin receptor geneis also found in some human families; how-ever, the mutation is very rare.

s/s mouseThe s/s mouse is a more specific, genet-

ically engineered animal model of leptin re-ceptor deficiency (Bates et al., 2003, 2005).In contrast to the defect in the Lepdb/Lepdb

mouse, which leads to generalized leptin re-ceptor dysfunction, the s/s mouse carries a mu-tation that specifically disrupts the transcrip-tion factor STAT3, which is a key componentof the signaling pathway of the long form of theleptin receptor and mediates leptin’s effects onenergy homeostasis. The amino acid tyrosineat position Tyr 1138 is crucial for the acti-vation of this pathway by leptin. The specificreplacement of the gene encoding the leptin re-ceptor in mice with an allele coding for a serineresidue (Ser 1138 instead of Tyr 1138) disruptsthe STAT3 signal. Homozygous (s/s) mice arehyperphagic and obese, but they are fertile,have normal body length, and are less hyper-glycemic compared to the Lepdb/Lepdb mouse.

STAT3 mediates leptin’s effects on body en-ergy homeostasis via melanocortin signaling,whereas other signaling pathways are neces-sary for the control of fertility, body growth,and glucose homeostasis. Eventually, how-ever, s/s mice develop severe insulin resistancesimilar to that in Lepdb/Lepdb mice, particu-larly in the liver.

Leptin receptor-deficient rats: Zuckerrat, ZDF rat, Koletsky rat

Analogous to the Lepdb/Lepdb mouse, sev-eral rat models of leptin-resistant obesity havemutations in the leptin receptor. The obeseZucker (fa/fa or ‘fatty’ rat) and the Koletskyrat carry mutated forms of the extracellulardomain of the leptin receptor. They develop asimilar phenotype of hyperphagia and reducedenergy expenditure, leading to morbid obe-sity (Bray, 1977; Bray and York, 1979). Theserats have impaired glucose tolerance, a growthdeficit possibly related to a lower activity of theGH/IGF-1 axis, and hypothyroidism. Fertilityis reduced. Koletsky rats have a nonsense andnull mutation that leads to undetectable levelsof leptin-receptor mRNA expression (Chua etal., 1996; Takaya et al., 1996; Friedman, 1997;Wu-Peng et al., 1997; Crouse et al., 1998; daSilva et al., 1998). In contrast, the fa/fa mu-tation of Zucker fatty rats is associated with aprocessing defect of the leptin receptor; the re-ceptor is generated but retained intracellularly,leading to reduced numbers of leptin receptorson the cell surface. This is associated with de-creased leptin binding and signal transduction.Koletsky rats are more hypertensive and havea more severe phenotype of insulin resistancethan Zucker fatty rats.

Zucker Diabetic Fatty (ZDF) rats were de-rived from a substrain of obese Zucker fattyrats that displayed early dysregulation of glu-cose metabolism. ZDF rats develop early di-abetes when presented with a high-fat diet,and part of their propensity to develop earlydiabetes may be related to altered expressionof the glucose transporter GLUT4 in skeletalmuscle (Zierath et al., 1998).

Wistar Kyoto fatty rat (WDF rat)A related rat model was created by crossing

Zucker (fa/fa) rats with Wistar-Kyoto (WKY)rats. Similar to the Zucker (fa/fa) rat, the Wis-tar Kyoto fatty (WDF) rat develops obesity andco-morbidities like insulin resistance, hyperin-sulinemia and hyperlipidemia. Male WDF ratsdevelop early hyperglycemia and glucosuria.Insulin resistance is associated with reduced


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insulin binding in the brain and peripheral or-gans (liver) (Ikeda et al., 1981; Figlewicz et al.,1986).

Obesity Models with a DeficitDownstream of the Brain LeptinReceptorPOMC knockout mouse

Proopiomelanocortin- (POMC-) express-ing neurons in the hypothalamic arcuate nu-cleus are direct targets of leptin. POMC is theprecursor of several biologically active pep-tides including α-melanocyte-stimulating hor-mone (αMSH). In the brain, αMSH is a potentanorexigenic neuropeptide that reduces eatingand increases energy expenditure by activat-ing melanocortin (MC) 3 and 4 receptors inthe paraventricular nucleus of the hypothala-mus and elsewhere.

Transgenic mice lacking POMC (POMC-/-)and consequently all POMC-derived peptidesovereat and develop marked obesity that is ex-aggerated on a high-fat diet (Yaswen et al.,1999; Challis et al., 2004). Heterozygous mu-tants develop an intermediate phenotype, im-plying that both copies of a functional POMCgene are necessary to maintain normal energyhomeostasis. Although treatment with leptin isineffective, the obesity in POMC-/- mice can bemarkedly reduced when these mice are treatedwith αMSH or other agonists of the MC4 re-ceptor, such as MT II. POMC deficiency hasalso been reported in rare cases of human obe-sity (O’Rahilly, 2009).

POMC/AgRP knockout miceAgouti-related protein (AgRP) is co-

expressed with neuropeptide Y (NPY) in adifferent population of arcuate nucleus neu-rons than those that express POMC. AgRP in-creases eating by acting as an antagonist at theMC4 receptor. Recently, mice with a doubleknockout for POMC and AgRP were created(Corander et al., 2011). Phenotypically and interms of their hyperphagia and development ofobesity, they were similar to the homozygousPOMC-/- knockout mouse. Because αMSH butnot AgRP restored the defects in the controlof eating and body weight, AgRP on its ownseemed to be ineffective. AgRP is thereforeconsidered as an antagonist, but not an inverseagonist, at the critical melanocortin receptorsat physiological concentrations.

MC4R knockout modelsαMSH and AgRP influence energy home-

ostasis via MC receptors. The MC4 receptorsubtype in particular is involved in the con-

trol of food intake. Specific inactivation of theMC4 receptor by a targeted knockout produceshyperphagia and morbid obesity (Huszar et al.,1997). MC4-/- mice are also hyperinsulinemic,hyperglycemic, and hyperleptinemic. In con-trast to many other obesity models, MC4-/-

mice do not have elevated circulating corti-costerone levels. MC4-/- mice do not respondto leptin, AgRP, or αMSH. Similar mutationsof the MC4 receptor are often stated to be themost frequent genetic cause of obesity in hu-mans (O’Rahilly, 2009).

An MC4 knockout rat has recently been de-scribed (Mul et al., 2011). While it has manycharacteristics in common with MC4 KO mice(such as increased body weight, food intakeand body length, and lower spontaneous ac-tivity), there are some noteworthy differences.In particular, while the MC4-/- mouse has in-creased expression of NPY but not of POMCin parts of the hypothalamus, the adult MC4knockout rat has unchanged NPY levels butincreased POMC expression.

MC3R knockout mouseTargeted inactivation of another MC re-

ceptor subtype, the MC3 receptor, also pro-duces an obese phenotype (Butler et al., 2000).This syndrome is characterized by a compara-bly mild increase in total body weight but amarked, late increase in fat accumulation; i.e.,MC3 knockout mice have relative adiposity.Fat oxidation in these mice is reduced, es-pecially on a high-fat diet. The mice exhibithyperleptinemia and relatively mild hyperin-sulinemia. Physical activity in cages equippedwith running wheels is reduced.

MC4/MC3 receptor knockout mouseA double knockout of the MC3 and MC4 re-

ceptors results in mice that are heavier than thesingle knockouts (Chen et al., 2000). The MCagonist MTII decreases eating much less inMC3 or MC4 receptor knockout mice than inwild-type controls, but only the double knock-outs are completely unresponsive to MTII.These findings suggest that at least in respectto eating, MC4- and MC3-receptor mediatedactions are complementary.

Ectopic agouti expression in miceThe agouti gene was cloned in 1992 and

was the first obesity gene to be characterizedat the molecular level. In wild-type mice, thegene is transiently expressed in hair follicles,where it leads to the production of red oryellow pigments and inhibits the productionof black or brown pigments in melanocytesby antagonizing MC1 receptors. Mice with a


Obesity

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spontaneous ectopic agouti gene mutation areyellow (‘yellow mice’).

Several agouti mutations have been de-scribed (Michaud et al., 1994). The lethalyellow (Ay) mutation is one of five dominantagouti mutations leading to ectopic agouti ex-pression. Homozygous expression of the spon-taneous mutation is lethal, and mice typicallydie before implantation. Heterozygotes areviable and, in addition to having yellow haircolor, they usually develop obesity within thefirst few months of life. Obesity results fromthe ectopic expression of the agouti gene prod-uct, especially in the hypothalamus, where,like AgRP, it functionally antagonizes α-MSHat MC3 and MC4 receptors. Lean body massis slightly increased, and adipose tissue massis increased due to fat cell hypertrophy. In as-sociation with the obesity, the mice are proneto developing type II diabetes and are hyper-leptinemic. The mice are infertile. Engineeredtransgenic mice that ubiquitously expressagouti have a similar phenotype, arguing for acausal effect of the ectopic agouti expression.

The viable agouti Avy/- mouse also has amottled yellow pigmentation of the hair. Avy/-

mice are obese and slightly larger than theirrespective controls. The mice are hyperinsu-linemic, hyperleptinemic, and hyperglycemic,as well as insulin resistant and leptin resistant(Yen et al., 1994; Klebig et al., 1995). Inter-estingly, both homozygous (Avy/Avy) and het-erozygous (Avy/A and Avy/a) mice vary con-siderably in appearance: i.e., in the extent ofthe yellow fur color. The degree of obesity iscorrelated with the extent of the yellow furcoloration. In addition to the strong influenceby the agouti-locus genotype and the geneticbackground of the dam, epigenetics provides alikely explanation for these differences (Wolffet al., 1998; Morgan et al., 1999).

AgRP overexpressionAgrt (also known as Art or the Agrp gene)

shares sequence homology with the agoutigene. Its gene product, agouti-related proteinor AgRP, is considered the natural antagonistto α-MSH at MC3 and MC4 receptors in thehypothalamus. Similar to the mice with ec-topic agouti expression, transgenic mice over-expressing AgRP are obese and develop hy-perinsulinemia with late-onset hyperglycemia(Graham et al., 1997). This eventually resultsin hyperplastic pancreatic islets.

Carboxypeptidase E (CPE) mutationCPE is an enzyme involved in the post-

translational processing of many prohormones

into active neuropeptides. For example, in theperiphery, CPE helps convert pro-insulin toinsulin, and in the central nervous system,CPE helps cleave the POMC molecule. Spe-cific point mutations lead to the inactivationof CPE [Cpe(fat)] and a disruption of process-ing and secretion of POMC and its products,including α-MSH. The latter is most likely re-sponsible for the development of obesity inanimals with disrupted CPE due to a shiftedbalance between α-MSH and AgRP activity atMC3 and MC4 receptors. Homozygous micedevelop late-onset marked obesity and are in-fertile (Naggert et al., 1995; Bures et al., 2001).

OTHER MONOGENIC MODELS

Otsuka Long Evans Tokushima FattyRat (OLETF)

Otsuka Long Evans Tokushima Fatty(OLETF) rats are a model of mild obesity(Kawano et al., 1992; Moran and Bi, 2006;Moran, 2008). The name is derived from acolony of Long Evans rats that was selectivelybred at the Tokushima Research Institute ofOtsuka Pharmaceutical in Japan. The underly-ing pathology of OLETF rats is that of a CCK-1 receptor knockout; hence, OLETF rats andtheir lean counterparts (LETO; Long-EvansTokushima Otsuka) have been used to studyphysiological CCK functions. Because CCKplays an important role in satiation, and be-cause this effect is mediated by CCK-1 recep-tors, OLETF rats are a valuable animal modelto study dysregulated control of meals, eating,and obesity. The obesity phenotype is rela-tively mild.

The hyperphagia and ensuing obesity ofOLETF rats relates to a significant increasein the size of meals. This increase resultsfrom the lack of the CCK feedback signal thatprimarily projects to the nucleus of the soli-tary tract (NTS) in the hindbrain, but whichmay also result from the increased expres-sion of neuropeptide Y (NPY) in the dorsome-dial hypothalamic nucleus (DMH). The lattermay also explain some apparent species dif-ferences between the OLETF rat, which be-comes obese on a normal diet, and the CCK1receptor knockout mouse, which does not (Loet al., 2010). Interestingly, overeating and anincrease in meal size in OLETF rats can beobserved in rat pups 2 days of age. In con-trast, obesity models with defective hypotha-lamic signaling systems often develop overeat-ing and obesity later in life. This difference inthe onset of overeating may relate to the mat-uration of the hindbrain system of satiation, a


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process which normally occurs much earlierthan that of the hypothalamus; hence, defectsin the hindbrain systems, which mainly controlmeal size, become obvious at a much earlierage. Consistent with this idea, the overexpres-sion of NPY in the DMH only occurs in thethird week of life of the OLETF rats. Hence,at least at this young age, the lack of the in-coming CCK signal seems to be sufficient todrive overeating in OLETF rats.

As a result of obesity, OLETF rats developdiabetes; they are hyperglycemic from about4 to 5 months of age and develop polyuriaand polydipsia. Further, due to the lack offunctional CCK1 receptors in the exocrinepancreas, OLETF rats respond less to CCK-induced stimulation of pancreatic secretions.While these rats seem unable to compensatefor their large meals, they can prevent obesityfrom occurring if they have access to a runningwheel.

DIET-INDUCED MODELS;POLYGENIC MODELS

Diet-Induced Obese (DIO) andDiet-Resistant (DR) Rats

Outbred Sprague-Dawley rats have beenused as a polygenic model of obesity thatpresumably shares many characteristics withthe common form of human obesity. Whenexposed to a high-energy (HE) diet, manySprague-Dawley rats become obese (DIO),whereas others have a body weight trajec-tory similar to that of control rats on a low-energy diet. The latter are therefore called diet-resistant (DR) (Levin et al., 1986, 1997; Levinand Dunn-Meynell, 2000, 2002).

DIO and DR rats have been bred selectivelyover several generations (Levin et al., 1997;Michel et al., 2004). This has led to a moredistinct obese phenotype in DIO compared toDR rats on HE diets. Some strains of DIO ratsare now becoming obese without the necessityof being exposed to a HE diet, an effect thatis more pronounced in males than in females.Interestingly, the selectively bred DIO rats areless sensitive to the hypophagic action of leptinby 4 to 5 weeks of age, at a time when they arestill lean and before the body weights of DIOand DR rats start to diverge. Lean DIO rats alsohave a reduced leptin-induced response in sev-eral hypothalamic nuclei as assessed by the ex-pression of phosphorylated signal transducerand activator of transcription 3 (the pSTAT3response). The reduced response to peripheralleptin is not due to a defect at the level of theblood-brain barrier transport system. The lat-

ter system only becomes defective once theDIO rats have developed overt obesity on alow-energy diet or when exposed to a HE diet.Collectively, the data indicate that the hypotha-lamic leptin signaling system is defective inselectively bred DIO rats before they becomeovertly obese.

Interestingly, selectively bred DIO rats canbe protected from becoming obese by rearingthem in large litters (Patterson et al., 2010),effectively limiting the pups’ nutrient supplyduring the suckling period, and consequentlyreducing circulating leptin levels and hypotha-lamic leptin resistance. This reduced bodyweight persists into adulthood and is associ-ated with a higher sensitivity to leptin in thearcuate nucleus, and to the anorectic effect ofleptin.

Cafeteria diet-induced obesityRats become obese when offered a var-

ied and palatable diet which mimics the so-called Western diet of humans (cafeteria diet)(Rothwell and Stock, 1979; Rogers and Blun-dell, 1984; Perez et al., 1999). Cafeteria diet–induced obesity mainly results from hyperpha-gia that is partly compensated by increasedenergy expenditure, in particular diet-inducedthermogenesis (DIT) due to sympathetic ac-tivation of brown fat. Overeating of cafeteriadiets is due to increased average meal size aswell as increased meal frequency. This con-trasts with overeating of palatable diets withno choice of foods, which mainly influencesmeal size.

High-fat diet-induced obesityEven though the contribution of high-fat

(HF) diets to human adiposity is disputed (Wil-lett and Leibel, 2002), it is clear that the ex-posure of animals to HF diets often resultsin the development of obesity. As discussedabove, some strains of rats prone to developDIO exhibit reductions in insulin and leptinsensitivity, but HF diets have similar effects inlean and in DR rats. While the caloric densityof HF diets and the ensuing higher intake oftotal energy contribute to this effect, HF di-ets rapidly and specifically reduce the centralactions of insulin and leptin, most likely dueto a post-receptor effect (Banks et al., 2004;Woods et al., 2004; Benoit et al., 2009; Haririand Thibault, 2010; Clegg et al., 2011). Thiseffect is rapid, occurring after a few days ofHF exposure. HF diets seem to directly affectthe respective intracellular signaling pathwaysin hypothalamic target neurons, with resultingchanges in neuropeptide expression (e.g., lack


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of an insulin effect on POMC expression), butpossibly also in other brain areas. Fat compo-sition seems to have a major role in this effectbecause saturated fat (e.g., palmitic acid) ismore deleterious than unsaturated fat.

New Zealand obese mouseThe New Zealand obese (NZO) mouse is

obese and has severe type-2 diabetes (Joost,2010). A number of genetic susceptibility locithat favor the development of adiposity andhyperglycemia have been identified in NZOmice. In addition to the leptin receptor gene,several genes of transcription factors wereidentified as potential candidate genes. Someof them are involved in substrate utilizationin skeletal muscle and triglyceride storage inadipocytes. Interestingly, orthologs of at leastsome of these genes have been linked to thehuman metabolic syndrome.

Age-related obesity in mice (LOO)Single-housed C57B6 mice develop late-

onset obesity (LOO) even when fed a standardchow diet (Becskei et al., 2009, 2010). Themodel resembles common human obesity be-cause it is characterized by a slow, gradual fataccumulation over the individual’s life span.LOO mice develop elevated fasting glucoselevels as well as fasting hyperleptinemia andhyperinsulinemia. They are also resistant to theanorectic effect of leptin and the hypoglycemicaction of insulin.

Age-related obesity in macaquesLate-onset obesity also occurs in other

species, including rhesus macaque monkeys(Macaca mulatta; Schwartz et al., 1993;Hansen et al., 1995). Obesity develops overa period of about 10 to 15 years, mainly asa result of (relative) overeating. Maintenanceof stable adult body weight requires a 30%to 40% reduction of daily energy intake com-pared to a free-feeding diet. Macaque obesityis associated with metabolic changes similarto the human metabolic syndrome, such as in-creased intra-abdominal fat, elevated basal in-sulin, impaired glucose tolerance, and elevatedserum triglycerides and cholesterol.

Maternal overfeeding and exposure tohigh fat diets

The intrauterine and perinatal environmentplays an important role in the life-long controlof energy balance. Considerable evidence in-dicates that early programming can influencemetabolism and various aspects of the con-trol of energy intake and expenditure. Feed-

ing pregnant dams a high-fat (HF) diet has amarked effect on their offspring (West et al.,1982; Levin and Govek, 1998; Tamashiroet al., 2009; Sullivan et al., 2010a,b). Offspringof DIO dams are heavier and more obese thanoffspring of DR animals, and the effect isgreater in DIO dams exposed to a HF diet.The obesity in the offspring of DIO dams ex-tends into adult life. Similarly, maternal HFfeeding in humans leads to offspring that havea markedly increased risk of obesity in adultlife; this is paralleled by hyperphagia and ahigher preference for fatty and sweet foods.The effect of maternal exposure to HF feedingon energy expenditure is less clear. Overall,maternal obesity is associated with increasedobesity in genetically predisposed individuals,and this effect is intensified by dietary factors.

Early postnatal overfeeding–inducedobesity: rearing in small litters

Manipulation of the litter size has been usedas a model of early postnatal overnutrition inrats and mice (Faust et al., 1980; Schmidtet al., 2001; Morris et al., 2005). Due to thelimited total supply of the dams’ milk, ad-justment of litter size leads to two levels ofearly nutrition, with pups reared in small lit-ters ingesting more than pups reared in largelitters. Early overfeeding leads to adult animalswith a significantly higher body weight, andis associated with increased adiposity, earlyleptin resistance, hyperinsulinemia, and glu-cose intolerance. The effect in the offspringcan be potentiated when offered a HF diet af-ter weaning. Importantly, overfeeding rat pupsindependently of the dam (to eliminate dif-ferential maternal behavior as an interactingfactor) also leads to increased susceptibility tobecome obese as adults (West et al., 1987).

OTHER GENETICALLYENGINEERED MUTANTS

CRF: Transgenic CRF-OverexpressingAnimals

Corticotrophin releasing factor (CRF),which is synthesized in the hypothalamic para-ventricular nucleus, is the primary driver of thehypothalamic-pituitary-adrenal axis (HPAA).Activation of CRF neurons results in ele-vated plasma levels of adrenocorticotropichormone (ACTH) and corticosterone (GCC).CRF transgenic mice display truncal obesitycombined with muscle wasting, thin skin,and hair loss. Hence, the mice are a modelfor the obesity associated with states of


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hyperadrenocorticism such as Cushing’s syn-drome (Stenzel-Poore et al., 1992).

Glucose transporter subtype 4 (GLUT4)The GLUT4 glucose transporter is the ma-

jor transporter for insulin-stimulated glucosetransport in adipose tissue, skeletal muscle,and other tissues. Obesity is often associ-ated with enhanced expression of GLUT4 inadipose tissue, suggesting an involvement ofGLUT4 in the pathophysiology of obesity.Transgenic mice overexpressing GLUT4 inwhite or brown adipose tissue develop early-onset obesity, probably because of increasedinsulin-stimulated glucose transport and hencean increased nutrient substrate for adipogene-sis. These mice have a marked increase in thenumber but not size of fat cells, and thereforehave been used to study fat-cell replication anddifferentiation during the development of obe-sity (Shepherd et al., 1993).

Perhaps analogously, rats that transgeni-cally overexpress the gluconeogenic en-zyme, phosphoenolpyruvate carboxykinase(PEPCK), generate increased glucose andhence increased substrate for synthesizingtriglycerides. These animals become hyper-triglyceridemic and obese, even on a low-fatdiet (Thorburn et al., 1999).

Melanin-concentrating hormone(MCH)

While the physiological role of MCH in thecontrol of eating and body weight is not clear,central administration of MCH increases eat-ing in rats and mice. Transgenic mice overex-pressing MCH are hyperphagic and developobesity late in life when exposed to a HF diet(Ludwig et al., 2001). The ensuing obesity isassociated with hyperinsulinemia and insulinresistance.

Beta-3 adrenergic receptor knockoutβ3 receptors are mainly expressed in white

and brown adipose tissue. Mice deficient in β3receptors are moderately obese (Susulic et al.,1995), and the phenotype is stronger in femalethan in male mice. Obesity in β3-receptor-deficient mice results mainly from decreasedactivity of the sympathetic nervous system, be-cause food intake is similar to that in wild-type mice. Total energy expenditure is alsounchanged, but activation of brown adiposetissue is reduced.

Serotonin 5-HT-2c receptor knockout5-hydroxytryptamine (5-HT, serotonin) is a

transmitter involved in the control of many es-

sential functions, including eating. Mice thatlack functional 5-HT2C receptors develop hy-perphagia (Tecott et al., 1995; Heisler andTecott, 1999) that is obvious from the timeof weaning and which results in marked bodyweight gain and adiposity. Energy expenditureis unchanged. Changes in glucose metabolismand insulin sensitivity only occur after the on-set of obesity.

Neuropeptide-Y 1 receptor (NPY1R)knockout mouse

Neuropeptide Y (NPY) is an important hy-pothalamic neuropeptide that stimulates eat-ing via several receptor subtypes, includingthe NPY1R. Paradoxically, NPY1R-deficientmice develop obesity that occurs indepen-dently of an increase in eating and seems tobe caused mainly by decreased energy expen-diture (Kushi et al., 1998). The latter is associ-ated with a reduced expression of the uncou-pling protein type 2 (UCP2) in white fat tissue.These mice allow the study of obesity in theabsence of overeating. The effect appears tobe more prevalent in females than in males.

NPY2R knockout miceSimilar to the NPY1R knockout mice,

NPY2R-deficient mice also develop paradox-ical obesity (Naveilhan et al., 1999). Affectedmice are mildly hyperphagic and develop obe-sity. On normal chow diets, the mice do notdevelop metabolic abnormalities of glucose orfat metabolism.

Bombesin 3 receptor knockout mice(BRS3 ko)

Bombesin-like peptides include the am-phibian peptide bombesin (BBS), its mam-malian analog gastrin-releasing peptide(GRP), and other peptides including neu-romedin B (NMB). All are considered to besatiation factors, reducing the size of ongoingmeals much as CCK does. Mice hemizygousfor the BRS3 receptor develop late-onset obe-sity due to an increase in eating and a decreasein the metabolic rate (Ohki-Hamazaki et al.,1997). Obesity is associated with disturbedglucose metabolism such as elevated baselineglucose levels, hyperinsulinemia, and insulinresistance.

Neuronal insulin receptor knockoutmice (NIRKO mice)

Insulin receptors are widely distributedthroughout the brain, and the role of cen-tral nervous system insulin receptors has been


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extensively studied in recent years. The physi-ological role of these receptors has been stud-ied with the use of neuron-specific insulinreceptor knockout mice (NIRKO mice). Incontrast to systemic insulin receptor knock-out mice, NIRKO mice are viable. Consistentwith the role of insulin as a negative feed-back adiposity signal (Schwartz et al., 2000),NIRKO mice have a moderate increase in foodintake and a resulting increase in body weightand adiposity (Bruning et al., 2000). The ef-fect is more pronounced in mice exposed to aHF diet. On a chow diet, only female NIRKOmice develop obesity. Obesity is paralleled byhypertriglyceridemia. Even though only cen-tral insulin receptors are deficient, systemicplasma insulin levels are elevated in NIRKOmice.

11beta-HSD-1 overexpressionThe inactive 11-keto form of glucocortico-

steroids (cortisone) can be transformed locallyin adipose tissue to the bioactive forms cortisolor corticosterone through the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD-1). Excessive glucocorticosteroids areassociated with visceral obesity and diabeteseven though circulating glucocorticosteroidlevels are often normal. Overexpression of11beta HSD-1 selectively in adipose tissue re-sults in increased adipose tissue levels of corti-costerone and visceral obesity including mostfeatures of the metabolic syndrome (Patersonet al., 2004; Man et al., 2011). The effect ismore pronounced when mice are exposed to anHF diet. Fat-specific 11beta HSD-1 transgenicmice eat more than wild-type controls, areinsulin-resistant, and develop diabetes. Trans-genic mice expressing increased 11beta-HSD1activity selectively in the liver do not increasetheir adipose tissue mass but develop mild in-sulin resistance and dyslipidemia.

SURGICAL OR CHEMICALMODELS OF OBESITY

Lesion of the VentromedialHypothalamus (VMH Lesion)

One of the earliest models of induced obe-sity in rodents used rats with surgical le-sions of the ventromedial/arcuate region ofthe mediobasal hypothalamus (VMH lesions)that resulted in hyperphagia, increased bodyweight, and adiposity. While the precise causesof VMH-lesion-induced obesity are still un-clear, a change in the tone of the sympathetic(decrease) and parasympathetic (increase) ner-vous systems contributes to the syndrome.

These changes are associated with reduced en-ergy expenditure, which may in part be due toreduced ambulatory activity and a disruptionof the circadian rhythm in activity. Hyperpha-gia is probably due to the destruction of POMCneurons and possibly of neurons producingbrain-derived neurotrophic factor (BDNF) inthe hypothalamic arcuate nucleus (Penicaudet al., 1983; King, 1991, 2006).

VMH rats also have elevated circulatinginsulin and reduced glucagon. Both baselineand nutrient-stimulated insulin secretion arehigher in VMH-lesioned rats. These hormonalchanges are most likely due to a shift in auto-nomic tone that favors parasympathetic activ-ity, since removing the parasympathetic inputto the pancreas where insulin is secreted keepsthe VMH-lesioned animals from developingobesity (Cox and Powley, 1981).

Lesion of the HypothalamicParaventricular Nucleus (PVN Lesion)

Similar to VMH lesions, extensive lesionsof the PVN also induce obesity. Obesity ismainly due to increased eating. Energy ex-penditure and ambulatory activity are not af-fected by PVN lesions, indicating that themechanisms of the obesity phenotype of PVN-lesioned rats differ from that of VMH lesions.Obesity in PVN-lesioned rats eventually re-sults in insulin resistance and hyperinsuline-mia (Bray and York, 1979; Sims and Lorden,1986; Tokunaga et al., 1991).

Lesion of the Arcuate Nucleus (ARCLesion)

A selective surgical lesion of the ARC isdifficult to perform due to the ARC’s anatomi-cal shape and location. Most lesions performedso far encompassed the entire mediobasal hy-pothalamus, including the ventromedial area.As an alternative, the repeated administrationof monosodium glutamate (MSG) to neona-tal rats within the first 10 postnatal days hasbeen used, which leads to the relatively se-lective destruction of ARC neurons projectingto the VMH and PVN. MSG-lesioned rats arehyperphagic and develop obesity with ensuinginsulin resistance and hyperinsulinemia (Ne-meroff et al., 1978). It is important to note thatsystemic MSG treatment also lesions neuronsin the circumventricular organs due to theiropen blood-brain barrier. MSG lesions aretherefore not restricted to the ARC, and inter-pretation of results must take this into account.

ARC neurons can also be destroyed bylocal administration of gold thioglucose,


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resulting in a similar obesity phenotype(Bergen et al., 1998; Young, 1992; Young etal., 1994). A more selective lesion can also beobtained by the local administration of NPY-saporin (NPY-SAP; Li et al., 2008). Due tothe neurotoxin SAP, microinjection of NPY–SAP causes a loss of NPY receptor-carryingneurons such as NPY and POMC/CART neu-rons. These lesions also produce hyperpha-gia and obesity, but the origin of these phe-notypic changes is still unclear. Hyperpha-gia seems unrelated to the overexpression oforexigenic hypothalamic neuropeptides suchas NPY, AgRP, MCH, or the orexins.

OvariectomyGonadectomy in females leads to an in-

crease in body weight associated with an in-crease in eating. Ovariectomy (OVX) in fe-male rats and mice has therefore been used asa model for the increased female obesity thatoccurs at menopause. Due to the lack of estra-diol, OVX rats and mice do not exhibit thecyclic decrease in eating in estrus. This cycliceffect can be restored by estradiol replacementin OVX animals. Further, eating is also in-creased in OVX rats on other days of the cycle,indicating a tonic disinhibition due to the lackof estradiol. The mechanisms underlying thetonic increase in eating after OVX are not clear,while the cyclic effect is probably caused bythe (lack of) effect of estradiol on meal con-trollers such as CCK, GLP-1, glucagon, andothers (Asarian and Geary, 2002, 2006, 2007;Thammacharoen et al., 2008).

Interestingly, total adipose tissue mass isincreased in OVX rats and in menopausalwomen. However, OVX causes a preferen-tial deposition as subcutaneous fat, whereasmenopause leads to an increase in intra-abdominal fat. Further, lean body mass isincreased in OVX rats but decreased inmenopause (Gloy et al., 2011). Importantly,OVX leads to an immediate transition from anormally cycling female to a non-cycling an-imal, while the transition is more gradual inmenopause.

Ablation of Brown Adipose Tissue(BAT)

Brown adipose tissue (BAT) plays an im-portant role in the control of energy ex-penditure. BAT expresses uncoupling pro-tein 1 (UCP-1), which dissipates energy asheat. Transgenic mice with BAT ablation are

markedly obese and have decreased energy ex-penditure (Hamann et al., 1996; Klaus et al.,1998). Ablation of BAT in these mice isachieved by expressing the diphtheria toxinA in UCP-1-expressing cells, leading to abla-tion of approximately 70% of BAT. The obesephenotype is enhanced in mice on an HF diet.With developing obesity, mice also becomeinsulin-resistant and eventually develop type2-like diabetes mellitus.

SEASONAL MODELS OF OBESITY

Syrian and Siberian HamstersLike other seasonal mammals, the body

weight and body adiposity differ markedlyacross a yearly cycle in Syrian and Siberianhamsters (Bartness and Wade, 1985; Mer-cer and Tups, 2003; Tups, 2009; Leitner andBartness, 2011). The ultimate trigger of thesechanges is the change in the photoperiodand consequently day length, and a result-ing change in melatonin release. Even thoughboth cases are dependent on melatonin, theseasonal rhythmicity reveals interesting differ-ences between the species because melatoninproduces opposite effects on body weight inthe two hamster species. The reproductive ca-pacity decreases in both types of hamsters inshort photoperiods; however, Syrian hamstersgain weight and Siberian hamsters lose weightunder short-day conditions. The evolutionarystrategy thus differs between the two species.The body weight changes are largely indepen-dent of altered energy intake in Syrian andin Siberian hamsters. In preparation for win-ter, Syrian hamsters store more energy as fat.Siberian hamsters, in contrast, reduce over-all metabolism by reducing their metabolicallyactive body mass; hence, total energy expen-diture is reduced.

At least some of these changes may be dueto the altered sensitivity of hypothalamic cir-cuits to leptin; however, it is unclear whetheraltered transport into the brain or altered sig-naling at the receptor or post-receptor levelplays the primary role.

Many other animals exhibit seasonal fluc-tuations in body fat and associated metabolicparameters in anticipation of storing suffi-cient energy to last through the winter or tomake a long migration. For examples, mar-mots overeat and become quite obese in prepa-ration for the winter, and they have associatedchanges in plasma hormones and insulin sen-sitivity (Florant and Healy, 2011).


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OTHER MODELS OF OBESITYAND ASSOCIATED METABOLICCHANGES

LipodystrophyObesity is strongly associated with insulin

resistance, which itself is a major risk factor forthe development of type 2 diabetes. Interest-ingly, the complete lack of fat tissue (lipodys-trophy) leads to similar metabolic changes asseen in severe obesity, and it is associated withinsulin resistance. The common link seems tobe the accumulation of excess fat in ectopicsites such as the liver and skeletal muscle; fataccumulation in the latter organs is associatedwith insulin resistance, type 2 diabetes, anddyslipidemia.

Genetically modified mice with a lack ofadipose tissue are characterized by hyperpha-gia, hepatic steatosis, hypertriglyceridemia,insulin resistance, and type 2 diabetes. Dueto the lack of functional adipose tissue, thesemice are leptin deficient. Interestingly, leptinreplacement at least partly restores the dys-regulated metabolism in these mice (Savage,2009; Huang-Doran et al., 2010).

GH-Deficient Dwarf RatThe dwarf rat (dw/dw) results from a spon-

taneous mutation resulting in deficient growthhormone (GH) synthesis and secretion. Therats are smaller but accumulate excessiveamounts of body fat. This is most likely dueto the lack of GH’s effect as a major lipolytichormone (Davies et al., 2007).

TubbyThe function of the tubby gene is only

partly understood. Homozygous mutation ofthe tubby gene (tub) results in late-onset obe-sity but mice typically do not develop diabetes(Coleman and Eicher, 1990; Guan et al., 1998).

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