obesity has reached epidemic proportions globally , and the world health organization estimates that there are more than 1 billion overweight adults , of which at least 300 million are obese .
societal changes and the worldwide nutrition transition have driven the obesity epidemic over recent decades .
economic growth as well as modernization , urbanization and globalization of food markets are some of the elements that have contributed to the obesity epidemic .
has also been associated with increasing opportunities to use automated transport , have technology in the home , and engage in more passive leisure pursuits .
obesity is associated with premature death through increasing the risk of many chronic diseases , including type 2 diabetes , cardiovascular disease , and certain cancers ( figure 1 ) [ 3 , 4 ] .
in addition , obesity is associated with respiratory difficulties , chronic musculoskeletal problems , lumbago , skin problems , and infertility ( figure 1 ) .
most of the evidence proposing obesity - associated health problems has been obtained from epidemiological analyses of human subjects ; the precise molecular mechanisms of obesity - associated health problems have not yet been determined . in this paper
, we will summarize reports associated with obesity - related pathology using animal models and also propose further demand for animal research models to address the worldwide obesity epidemic .
lethal yellow mutant mouse ( a)among the several commonly existing obese mice currently used in research , the agouti mutation mouse was first reported more than century ago .   in 1992 ,
agouti is a pigment control gene transiently expressed in follicular melanocytes to induce the production of red / yellow pheomelanin pigment and inhibit black / brown pigment [ 68 ] .
the lethal yellow mutant mouse ( a ) is one of five dominant agouti mutations and has been found to be an excellent mouse model of obesity .
the a mutation is characterized by the deletion of 120170  kb genomic dna , resulting in ubiquitous agouti expression due to loss of the tissue - specific control promoter element [ 911 ] . a mice exhibit
several phenotypes such as a yellow coat color , mature - onset obesity , type - ii diabetes , hyperleptinemia , increased linear growth , higher tumor susceptibility , and infertility .
transgenic mice expressing ubiquitous agouti exhibited yellow coat color , obesity , hyperinsulinemia , and hyperglycemia similar to a mouse , revealing the molecular mechanism of agouti in mouse phenotype .
mice with adipose tissue - specific agouti overexpression exhibit an overgrowth of adipose tissue without alteration of food intake , suggesting that increased fat in this model is due to changes in energy metabolism .
the adipose tissue agouti overexpression model could be relevant to human obesity because agouti gene expression is found in human adipose tissue [ 14 , 15 ] and is increased in the adipose tissue of type 2 diabetic subjects .
likely the ectopic expression of agouti in mice pancreas stimulated the release of insulin by pancreatic -cells , which may further enhance agouti - stimulated lipogenesis .
transgenic agouti expression in skin did not induce obesity , suggesting that the obesogenic role of agouti is tissue dependent . 
  among the several commonly existing obese mice currently used in research ,
the agouti mutation mouse was first reported more than century ago .   in 1992 ,
agouti is a pigment control gene transiently expressed in follicular melanocytes to induce the production of red / yellow pheomelanin pigment and inhibit black / brown pigment [ 68 ] .
the lethal yellow mutant mouse ( a ) is one of five dominant agouti mutations and has been found to be an excellent mouse model of obesity .
the a mutation is characterized by the deletion of 120170  kb genomic dna , resulting in ubiquitous agouti expression due to loss of the tissue - specific control promoter element [ 911 ] .
a mice exhibit several phenotypes such as a yellow coat color , mature - onset obesity , type - ii diabetes , hyperleptinemia , increased linear growth , higher tumor susceptibility , and infertility .
transgenic mice expressing ubiquitous agouti exhibited yellow coat color , obesity , hyperinsulinemia , and hyperglycemia similar to a mouse , revealing the molecular mechanism of agouti in mouse phenotype .
mice with adipose tissue - specific agouti overexpression exhibit an overgrowth of adipose tissue without alteration of food intake , suggesting that increased fat in this model is due to changes in energy metabolism .
the adipose tissue agouti overexpression model could be relevant to human obesity because agouti gene expression is found in human adipose tissue [ 14 , 15 ] and is increased in the adipose tissue of type 2 diabetic subjects .
likely the ectopic expression of agouti in mice pancreas stimulated the release of insulin by pancreatic -cells , which may further enhance agouti - stimulated lipogenesis .
transgenic agouti expression in skin did not induce obesity , suggesting that the obesogenic role of agouti is tissue dependent .  

leptin signaling defects in mice : ob / ob and db / db mouse modelsin 1949 , researchers from the jackson laboratory discovered obese mice by chance .
the ob / ob mutation is recessive , and neonatal mutant mice are normal when compared to unaffected control littermates .
mutant mice , however , gain weight rapidly throughout their lives , eventually reaching a weight that is three times that of control mice .
the phenotype is clear , but identification of the gene responsible for the obese phenotype took nearly 50 years . in 1994 , zhang et al . identified the mutation in the leptin gene as responsible for ob mutation by positional cloning .
characterization of this mutation revealed a single base pair deletion in the leptin coding region that results in a frame shift and a premature stop codon .
therefore , ob / ob mice exhibit uncontrollable food intake , obesity , type 2 diabetes , and insulin resistance with hyperinsulinemia .
the db / db mouse was identified initially in 1966 by researchers in the jackson laboratory as an obese mouse .
) mutation is an autosomal recessive trait that encodes for a g - to - t point mutation in the leptin receptor gene , resulting in defective leptin signaling [ 22 , 23 ] .
impaired leptin signaling in the hypothalamus leads to persistent hyperphagia and obesity , with consequent hyperleptinemia , insulin resistance , and increased insulin levels [ 22 , 23 ] . at 1 month of age ,
db / db mice are larger / obese when compared to control ( heterozygous ) littermates , and db / db mice present increased fat deposition in the inguinal and axillary regions .
consequently , these mice are widely used as a model for the study of type 2 diabetes [ 22 , 23 ] . 
  in 1949
the ob / ob mutation is recessive , and neonatal mutant mice are normal when compared to unaffected control littermates .
mutant mice , however , gain weight rapidly throughout their lives , eventually reaching a weight that is three times that of control mice .
the phenotype is clear , but identification of the gene responsible for the obese phenotype took nearly 50 years . in 1994 , zhang et al .
identified the mutation in the leptin gene as responsible for ob mutation by positional cloning .
characterization of this mutation revealed a single base pair deletion in the leptin coding region that results in a frame shift and a premature stop codon .
therefore , ob / ob mice exhibit uncontrollable food intake , obesity , type 2 diabetes , and insulin resistance with hyperinsulinemia .  
the db / db mouse was identified initially in 1966 by researchers in the jackson laboratory as an obese mouse .
) mutation is an autosomal recessive trait that encodes for a g - to - t point mutation in the leptin receptor gene , resulting in defective leptin signaling [ 22 , 23 ] .
impaired leptin signaling in the hypothalamus leads to persistent hyperphagia and obesity , with consequent hyperleptinemia , insulin resistance , and increased insulin levels [ 22 , 23 ] . at 1 month of age ,
db / db mice are larger / obese when compared to control ( heterozygous ) littermates , and db / db mice present increased fat deposition in the inguinal and axillary regions .
consequently , these mice are widely used as a model for the study of type 2 diabetes [ 22 , 23 ] . although monogenic models provide important information on the biology of obesity , human obesity is most likely mediated by multiple genes .
new zealand obese ( nzo ) mousethe nzo strain is a polygenic mouse model of obesity that exhibits type 2 diabetes only in males .  
nzo mice increase their body weight rapidly during the first 2 months of life because of hyperphagia that may be associated with leptin resistance , although they have genetically normal leptin and leptin receptors . among polygenic mouse models of obesity ,
nzo mice exhibit the most severe phenotype , with fat depots accounting for more than 40%   of total body weight at 6 months of age .
additionally , nzo mice exhibit decreased exercise activity when compared to control or even ob / ob mice .
this information suggests that like human obesity , obesity in nzo mice is due to a combination of hyperphagia , reduced energy expenditure , and insufficient physical activity . 
 
the nzo strain is a polygenic mouse model of obesity that exhibits type 2 diabetes only in males .  
nzo mice increase their body weight rapidly during the first 2 months of life because of hyperphagia that may be associated with leptin resistance , although they have genetically normal leptin and leptin receptors . among polygenic mouse models of obesity ,
nzo mice exhibit the most severe phenotype , with fat depots accounting for more than 40%   of total body weight at 6 months of age .
additionally , nzo mice exhibit decreased exercise activity when compared to control or even ob / ob mice .
this information suggests that like human obesity , obesity in nzo mice is due to a combination of hyperphagia , reduced energy expenditure , and insufficient physical activity . 

tsumura suzuki obese diabetes ( tsod ) mousethrough the selection of obese and urine sugar positive colonies from the ddy strain of mice , tsumura and suzuki established two inbred strains .
the tsod strain develops obesity with diabetes , whereas the tsumara suzuki nonobese ( tsno ) strain does not become obese .
male tsod mice exhibit polygenic obesity with hyperglycemia and hyperinsulinemia [ 26 , 27 ] .
although the mean values of fed blood glucose concentrations in tsod mice are increased with age ( 232  mg / dl at 13 weeks , 269  mg / dl at 16 weeks , and 346  mg / dl at 24 weeks ) , severe diabetes does not develop because tsod mice display increased -cell mass and maintain insulin secretion to control blood glucose .
older tsod mice display similar lesion as diabetic nephropathy and neuropathy . 
  through the selection of obese and urine sugar positive colonies from the ddy strain of mice , tsumura and suzuki established two inbred strains .
the tsod strain develops obesity with diabetes , whereas the tsumara suzuki nonobese ( tsno ) strain does not become obese .
male tsod mice exhibit polygenic obesity with hyperglycemia and hyperinsulinemia [ 26 , 27 ] .
although the mean values of fed blood glucose concentrations in tsod mice are increased with age ( 232  mg / dl at 13 weeks , 269  mg / dl at 16 weeks , and 346  mg / dl at 24 weeks ) , severe diabetes does not develop because tsod mice display increased -cell mass and maintain insulin secretion to control blood glucose .
m16 mousethe m16 mouse , an outbred mouse model of early - onset polygenic obesity , was developed through long - term selection for 3- to 6-week weight gain in an icr background .
m16 males and females were found to be moderately hyperglycemic compared to icr controls , with 56% and 22% higher fasted plasma glucose levels , respectively , at 8 weeks of age . 
 
the m16 mouse , an outbred mouse model of early - onset polygenic obesity , was developed through long - term selection for 3- to 6-week weight gain in an icr background .
m16 males and females were found to be moderately hyperglycemic compared to icr controls , with 56% and 22% higher fasted plasma glucose levels , respectively , at 8 weeks of age . 

kuo kondo ( kk ) mousethe kk mouse is a polygenic model of obesity that also exhibits type 2 diabetes .
kk mice display hyperphagia , hyperinsulinemia , and insulin resistance and show moderate obesity by 2 months of age [ 31 , 32 ] . insulin resistance in kk mice
the kk mouse strain was modified to develop the kka mouse by transferring the lethal yellow obese gene ( a ) ; the kka mouse is widely used for obesity and diabetes research in the testing of experimental therapies . 
 
the kk mouse is a polygenic model of obesity that also exhibits type 2 diabetes .
kk mice display hyperphagia , hyperinsulinemia , and insulin resistance and show moderate obesity by 2 months of age [ 31 , 32 ] . insulin resistance in kk mice
the kk mouse strain was modified to develop the kka mouse by transferring the lethal yellow obese gene ( a ) ; the kka mouse is widely used for obesity and diabetes research in the testing of experimental therapies . 

zucker fatty rat ( zfr)in 1961 , l. m. zucker and t. f. zucker reported a seminal finding in obesity research : an autosomal recessive mutation in the fatty ( fa ) gene on chromosome 5 .
these rats are characterized by hyperphagia and early - onset obesity , which appears at 5 weeks of age as an accumulation of subcutaneous fat .
however , a substrain of the zfr that exhibits frank diabetes was discovered and was designated the zucker diabetic fatty ( zdf ) rats . 
  in 1961 , l. m. zucker and t. f. zucker reported a seminal finding in obesity research : an autosomal recessive mutation in the fatty ( fa ) gene on chromosome 5 .
these rats are characterized by hyperphagia and early - onset obesity , which appears at 5 weeks of age as an accumulation of subcutaneous fat .
however , a substrain of the zfr that exhibits frank diabetes was discovered and was designated the zucker diabetic fatty ( zdf ) rats .  

the wfr strain was derived by transferring the fa gene from zfr ( 13 m strain ) to wistar kyoto rats , which exhibit poor glucose tolerance .
wfr displays obesity from 3 weeks after birth and develops obesity - related diseases such as type 2 diabetes , hyperinsulinemia , and hyperlipidemia .
metabolic abnormalities are prominent in wfr males , but not in wfr females , which display only mild insulin resistance and some glucose intolerance .
the appearance of diabetes in wfr but not in zfr , despite the presence of the fa ( leptin receptor ) mutation in both strains , could be explained by the presence of other genetic factors in wfr .
the wfr strain is widely used for research in type 2 diabetes because aged wfr displays diabetic complications such as nephropathy and neuropathy [ 4144 ] . 
  in 1981 , ikeda et al .
the wfr strain was derived by transferring the fa gene from zfr ( 13 m strain ) to wistar kyoto rats , which exhibit poor glucose tolerance .
wfr displays obesity from 3 weeks after birth and develops obesity - related diseases such as type 2 diabetes , hyperinsulinemia , and hyperlipidemia .
metabolic abnormalities are prominent in wfr males , but not in wfr females , which display only mild insulin resistance and some glucose intolerance .
the appearance of diabetes in wfr but not in zfr , despite the presence of the fa ( leptin receptor ) mutation in both strains , could be explained by the presence of other genetic factors in wfr .
the wfr strain is widely used for research in type 2 diabetes because aged wfr displays diabetic complications such as nephropathy and neuropathy [ 4144 ] . 

otsuka long evans tokushima fatty ( oletf ) ratoletf rats , established by otsuka pharmaceuticals in tokushima , japan , were developed by the selection of spontaneously type 2 diabetic rats from the outbreeding of long evans rats in a closed colony of charles river .
oletf rats are hyperphagic beginning several weeks after birth , with increasing body weight eventually progressing to frank obesity . at approximately 25 weeks after birth
, all male oletf rats display diabetes , as determined by oral glucose tolerance test , whereas only 30% of female oletf rats develop diabetes even after 60 weeks of age .
hyperinsulinemia is observed beginning at 8 weeks of age , and insulin resistance is observed beginning at 12 weeks of age . at 25 weeks of age , male oletf rats display hyperplasia of pancreatic islets , but islets become atrophic by 60 weeks of age [ 46 , 47 ] .
in contrast to zdf rats , hyper - free fatty acidemia has not been observed in oletf rats . instead , hypertriglyceridemia is found to precede the onset of hyperglycemia and insulin resistance .
oletf rats , established by otsuka pharmaceuticals in tokushima , japan , were developed by the selection of spontaneously type 2 diabetic rats from the outbreeding of long evans rats in a closed colony of charles river .
oletf rats are hyperphagic beginning several weeks after birth , with increasing body weight eventually progressing to frank obesity . at approximately 25 weeks after birth
, all male oletf rats display diabetes , as determined by oral glucose tolerance test , whereas only 30% of female oletf rats develop diabetes even after 60 weeks of age .
hyperinsulinemia is observed beginning at 8 weeks of age , and insulin resistance is observed beginning at 12 weeks of age . at 25 weeks of age , male oletf rats display hyperplasia of pancreatic islets , but islets become atrophic by 60 weeks of age [ 46 , 47 ] .
in contrast to zdf rats , hyper - free fatty acidemia has not been observed in oletf rats . instead , hypertriglyceridemia is found to precede the onset of hyperglycemia and insulin resistance .
high - fat dieta high - fat diet ( hfd ) is often utilized in obesity research as a non - leptin - deficient model .
there are mouse strain - specific differences in responses to the hfd ( table 1 ) .   among the various strains , c57bl/6j mice are the most widely used for hfd - induced obesity because they exhibit abnormalities similar to human metabolic syndrome when fed the hfd .
interestingly , within the c57 mouse strain , there are significant differences among substrains in response to the hfd .
for instance , whereas c57bl/6j mice exhibit hfd - induced obesity , hyperinsulinemia , and insulin resistance that closely parallel the progression of human disease , c57bl / ksj mice display a weak phenotype   . beside c57bl
/ j6 mice , sand mice and spiny mice are also used in obesity / type 2 diabetes research .
sprague dawley or long evans rats are also used for nonmouse rodent models of hfd - induced obesity .using such high - fat diet - induced obesity mice models , some clues to fight against human obesity have been reported ; manipulation of diet may rescue the obesity phenotype even in high - fat - fed condition .
watanabe et al . reported seminal finding about the antiobesitogenic role of bile acids ( bas ) in mice .
bas have been long recognized as simple lipid solubilizers , however , during the last decades researchers revealed that bas play pivotal roles in the complex metabolic regulations .
watanabe et al . found that high - fat diet supplemented with 0.5% cholic acid , the ba found in the largest amount , prevented weight gain and adiposity without alteration in the amount of food intake .
they found that bas activate g - protein - coupledtgr5 receptor and induce type 2 deiodinase activity .
such activation of type 2 deiodinase results in the conversion of thyroxine ( t4 ) to triiodothyronine ( t3 ) , which enhances energy expenditure .
furthermore , agonistic compound for tgr5 , int-777 , mimics such metabolic effect of bas and inhibited the onset of steatosis in high - fat - fed mice . furthermore , int-777 induces incretin effects via the secretion of glucagon - like peptide ( glp)-1 and therefore ameliorated glucose tolerance . these researches revealed the potential importance of bas for the prevention of diet - induced obesity and associated health problem .
interestingly postcholecystectomized patients have been shown to have high prevalence of type 2 diabetes .another nutritional intervention method , which could prevent metabolic abnormality , is the diet with high ketogenic essential amino acid ( kaa ) such as leucine , isoleucine , valine , lysine , and threonine .
zhang et al . have reported that high - leucine feeding in mice prevented high - fat diet - induced obesity .
such enhanced administration of high - kaa mixture diet modulated lipid synthetic pathway and prevented hepatic steatosis and insulin resistance with the reduction of body weight under the high - fat diet .
interestingly such high - kaa mixture has been shown to improve insulin sensitivity in elderly type 2 diabetic subjects .
these reports indicated that the high - fat diet - induced obesity animals could be the good model for the experimental therapy and the translational research to discover a novel therapeutic strategy for obesity epidemic . 
 
a high - fat diet ( hfd ) is often utilized in obesity research as a non - leptin - deficient model .
there are mouse strain - specific differences in responses to the hfd ( table 1 ) .   among the various strains , c57bl/6j mice are the most widely used for hfd - induced obesity because they exhibit abnormalities similar to human metabolic syndrome when fed the hfd .
interestingly , within the c57 mouse strain , there are significant differences among substrains in response to the hfd . for instance , whereas c57bl/6j mice exhibit hfd - induced obesity , hyperinsulinemia , and insulin resistance that closely parallel the progression of human disease , c57bl / ksj mice display a weak phenotype   . beside c57bl
/ j6 mice , sand mice and spiny mice are also used in obesity / type 2 diabetes research .
sprague dawley or long evans rats are also used for nonmouse rodent models of hfd - induced obesity .
using such high - fat diet - induced obesity mice models , some clues to fight against human obesity have been reported ; manipulation of diet may rescue the obesity phenotype even in high - fat - fed condition .  
watanabe et al . reported seminal finding about the antiobesitogenic role of bile acids ( bas ) in mice .
bas have been long recognized as simple lipid solubilizers , however , during the last decades researchers revealed that bas play pivotal roles in the complex metabolic regulations .
watanabe et al . found that high - fat diet supplemented with 0.5% cholic acid , the ba found in the largest amount , prevented weight gain and adiposity without alteration in the amount of food intake .
they found that bas activate g - protein - coupledtgr5 receptor and induce type 2 deiodinase activity .
such activation of type 2 deiodinase results in the conversion of thyroxine ( t4 ) to triiodothyronine ( t3 ) , which enhances energy expenditure .
furthermore , agonistic compound for tgr5 , int-777 , mimics such metabolic effect of bas and inhibited the onset of steatosis in high - fat - fed mice . furthermore , int-777 induces incretin effects via the secretion of glucagon - like peptide ( glp)-1 and therefore ameliorated glucose tolerance .
these researches revealed the potential importance of bas for the prevention of diet - induced obesity and associated health problem .
another nutritional intervention method , which could prevent metabolic abnormality , is the diet with high ketogenic essential amino acid ( kaa ) such as leucine , isoleucine , valine , lysine , and threonine .
zhang et al . have reported that high - leucine feeding in mice prevented high - fat diet - induced obesity .
such enhanced administration of high - kaa mixture diet modulated lipid synthetic pathway and prevented hepatic steatosis and insulin resistance with the reduction of body weight under the high - fat diet .
interestingly such high - kaa mixture has been shown to improve insulin sensitivity in elderly type 2 diabetic subjects .
these reports indicated that the high - fat diet - induced obesity animals could be the good model for the experimental therapy and the translational research to discover a novel therapeutic strategy for obesity epidemic . 

obese monkeysduring evolution , primates diverged from rodent lineages about 6585 million years ago . in comparison , humans and other great apes ( hominoidea ) diverged from old world monkeys ( cercopithecoidea ) a relatively recent 25 million years ago .
obesity models in old world monkeys , such as macaques , rhesus monkey , and baboons , would therefore provide information relevant to human obesity . when raised in indoor cages , rhesus monkeys exhibit increased rates of obesity , with some of them developing obesity - associated diseases [ 5961 ] .
captive macaques display obesity in an age - dependent manner when given food ad libitum . like humans ,
it is likely that reduced exercise increases the risk of obesity in these monkeys [ 6264 ] .
spontaneous obesity is also found in wild baboons and in a pedigreed colony [ 6567 ] and occurs in free - ranging rhesus monkeys .
furthermore , a species of japanese monkey , macaca fuscata , develops obesity without frank diabetes . 
  during evolution , primates diverged from rodent lineages about 6585 million years ago . in comparison , humans and other great apes ( hominoidea ) diverged from old world monkeys ( cercopithecoidea ) a relatively recent 25 million years ago .
obesity models in old world monkeys , such as macaques , rhesus monkey , and baboons , would therefore provide information relevant to human obesity . when raised in indoor cages , rhesus monkeys exhibit increased rates of obesity , with some of them developing obesity - associated diseases [ 5961 ] .
captive macaques display obesity in an age - dependent manner when given food ad libitum . like humans ,
it is likely that reduced exercise increases the risk of obesity in these monkeys [ 6264 ] .
spontaneous obesity is also found in wild baboons and in a pedigreed colony [ 6567 ] and occurs in free - ranging rhesus monkeys .
furthermore , a species of japanese monkey , macaca fuscata , develops obesity without frank diabetes .
this does not mean , however , that these models can provide information on how obesity can cause other health problems . in this section ,
type 2 diabetes is associated with insulin resistance and is one of the most common metabolic diseases .
the incidence of type 2 diabetes has dramatically increased in the past two decades , coinciding with the epidemic of obesity .
research on type 2 diabetes using animal models of obesity is therefore quite significant .  
models of obesity with type 2 diabetes are classified into two categories : ( 1 ) those containing a mutation in the leptin or leptin receptor gene and ( 2 ) polygenic models .
obese rodents , such as zucker rats , ob / ob mice , and db / db mice , are used as models for type 2 diabetes .
these rodent models exhibit microvascular complications similar to humans , such as diabetic retinopathy and nephropathy , and provide important models for testing experimental therapeutics .
however , leptin abnormalities only comprise a minority of obesity / diabetes cases in humans [ 7072 ] and are not the same condition of type 2 diabetes that is a worldwide epidemic .   
certain inbred strains of mice exhibit remarkable obesity when fed on hfd , whereas others remain lean [ 48 , 49 , 73 ] , suggesting gene - diet interactions .
furthermore , some of the strains exhibit obesity with severe insulin resistance and glucose intolerance , whereas others are highly sensitive to insulin - mediated glucose uptake and are resistant to the onset of diabetes ( table 1 ) [ 50 , 74 , 75 ] .
in contrast , some strains are very prone to type 2 diabetes but not severely obese .
those polygenic models allow for analysis of diabetic phenotypes alone , or the mice can be fed on hfd or crossed with another obesity mouse model , such as ob / ob , db / db , or a ( table 1 ) [ 50 , 74 , 75 ] .  
several mechanisms have been proposed to explain the interaction between obesity and cancer development , including the prevalence of type 2 diabetes , increased insulin resistance , elevated levels of insulin - like growth factor 1 ( igf-1 ) , and increased production of sex steroid hormones and adipocytokines [ 7680 ] . however , clear molecular mechanisms that explain obesity - associated cancer have yet to be determined .
they found that diethylnitrosamine - induced hcc is significantly higher in both genetically ( ob / ob ) and hfd - induced ( 59% fat , 15% protein , 26% carbohydrates ) obese mice .
furthermore , hfd induced the growth of subcutaneously injected hcc , suggesting that obesity has a systemic effect on tumorigenesis . with regard to the mechanisms of tumorigenesis in obesity
, they found that obesity is associated with increased intracellular transcriptional factor stat signaling and liver inflammation .
this inflammation was demonstrated to be essential for the tumor promoting effects of obesity because the depletion of signaling by inflammatory cytokines il-6 and tnf- abolished the tumor promoting effects of obesity .
metformin belongs to the biguanide class of antitype 2 diabetic drugs . since the middle ages , the biguanide
galega officinalis ( goat 's rue or french lilac ) has been used to treat diabetic patients .
metformin activates ampk and inhibits the mtor signaling pathway via various mechanisms [ 8286 ] .
metformin treatment has been shown to result in a gene expression profile similar to that of long - term caloric restriction , which can reduce the incidence of many age - related diseases , including cancer [ 88 , 89 ] .
metformin treatment inhibits high - energy diet - stimulated colon cancer cell growth   and breast tumor growth in hfd - fed mice but did not inhibit tumor growth in mice fed normal chow . although the effects of metformin in obesity - related cancer biology are not clear , these reports suggest that the tumor suppressive effect of metformin may involve the amelioration of a systemic metabolic profile associated with a high - energy diet and obesity .
recently , ribeiro et al . injected androgen - insensitive murine prostate carcinoma rm1 cells into control male c57bl6 and genetic ( ob / ob mice and db / db mice ) and hfd mouse models of obesity .
they found that low - leptin models ( ob / ob and hfd mice ) exhibited large tumors , whereas high - leptin ( db / db ) mice exhibited small tumors , suggesting that leptin may inhibit rm1 tumor growth .
in contrast , gonzalez et al . reported that leptin may accelerate the growth of breast tumors in mice via induction of vegf - vegfr2-mediated angiogenesis , although their study used immunodeficient scid mice   and not a mouse model of obesity .
reported that colorectal cancer stem cells express leptin receptors , and therefore leptin may induce tumor growth and interfere with the cytotoxic effects of the anticancer drug 5-fu .
the reports regarding the role of leptin in carcinogenesis are still very controversial and require further followup studies .
obstructive sleep apnea ( osa ) is an important obesity - associated health problem that is characterized by obstruction of the airway and depletion of oxygen tone in the blood .
osa may be associated with the onset of hypertension , diabetes , and coronary heart disease .
although osa is of clinical importance , the etiology of osa is not yet clear , perhaps due to the lack of appropriate animal models .  
these animals exhibit respiration disorders and decreased o2 saturation that worsen during rapid - eye - movement sleep .
two varieties of obese pigs were also found to be good models of osa [ 98 , 99 ] . although these models provide important information about the pathomechanisms of osa , large - animal - based research is technically difficult .
therefore , for the development of experimental therapies and drugs , rodent models are superior . in 1996 , van lunteren et al . reported altered respiratory - associated muscle contraction in genetically obese zfr .
zfrs have since been used for various experimental therapies and have provided important information about osa [ 102104 ] . although these dog , pig , and rat models help improve our understanding of the pathophysiology of osa , mouse models are critical in identifying the genes conferring disease risk .
developed a gas - delivery system that alters o2 levels depending on the sleep - wake status of c57bl/6 male mice .
however , this model is not a natural osa model and is not a good representation of osa .
nzo mice exhibit polygenic obesity and metabolic syndromes , such as insulin resistance , diabetes , hyperlipidemia , and hypertension ( table 1 ) , much like a human sleep apnea patient .
this report suggests that the nzo mouse may be a useful model for testing new drugs and experimental therapies for osa .
all the data above might be focused mainly on the pathogenesis of obesity / obesity - related complications . most publications may shed light on the pathology of obesity by forcing hfd or genetic mutations in rodents ; however , the conditions are very different from the real problems that humans are facing . for example , although leptin - deficient rodents have been used in many obesity - associated studies , leptin / leptin receptor mutations are rare in humans [ 7072 ] .
the main difference between experimental animal models and human obesity is that humans do not have induced gene mutations and are not forced to eat hfds .
if we can answer the question of why some individuals prefer to eat high - fat food and others do not , we would have a direct solution for obesity .
little evidence is currently available on this topic , but some seminal results have been shown [ 108 , 109 ] . it has also been reported that the variation in fat consumption ( ranging from 26 to 83% of total energy ) is dependent on the response of inbred mouse strains to the macronutrient diet selection paradigm .
this theory suggests that there are strain - specific differences in food selection behavior , which could potentially be mediated by differences in brain neuropeptides [ 111116 ] .
these reports indicate that further investigation on this topic in conjunction with human epidemiological and genetic studies is required .
we have summarized many current animal models of obesity and obesity - associated human diseases .
however , animal models have not yet been established for some devastating obesity - associated human diseases , including polycystic ovary syndrome [ 117 , 118 ] , which is extremely prevalent and constitutes one of the most common endocrinopathy in women of reproductive age .  
therefore , intensive and continuous efforts should be made to establish novel obesity - associated animal models that mimic human health problems .
 obesity is an epidemic problem in the world and is associated with several health 
 problems , including diabetes , cardiovascular disease , respiratory failure , muscle weakness , and cancer . 
 the precise molecular mechanisms by which obesity induces these health problems are not yet clear . to better understand the pathomechanisms of human disease , good animal models are essential . in this paper 
 , we will analyze animal models of obesity and their use in the research of obesity - associated human health conditions and diseases such as diabetes , cancer , and obstructive sleep apnea syndrome . 
1. Introduction
2. Animal Models of Obesity
3. Human Disease and Obesity Animal Models
4. Why Do Humans Gain Weight? Why Do  Humans Like to Eat Fat?
5. Conclusion