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Martins, T.; Ribeiro, C.; , .; Ferreira, T.; Nascimento-Gonçalves, E.; Oliveira, P.; Antunes, L. Murine Models of Obesity. Encyclopedia. Available online: https://encyclopedia.pub/entry/21763 (accessed on 19 December 2024).
Martins T, Ribeiro C,  , Ferreira T, Nascimento-Gonçalves E, Oliveira P, et al. Murine Models of Obesity. Encyclopedia. Available at: https://encyclopedia.pub/entry/21763. Accessed December 19, 2024.
Martins, Tânia, Catarina Ribeiro,  , Tiago Ferreira, Elisabete Nascimento-Gonçalves, Paula Oliveira, Luis Antunes. "Murine Models of Obesity" Encyclopedia, https://encyclopedia.pub/entry/21763 (accessed December 19, 2024).
Martins, T., Ribeiro, C., , ., Ferreira, T., Nascimento-Gonçalves, E., Oliveira, P., & Antunes, L. (2022, April 14). Murine Models of Obesity. In Encyclopedia. https://encyclopedia.pub/entry/21763
Martins, Tânia, et al. "Murine Models of Obesity." Encyclopedia. Web. 14 April, 2022.
Murine Models of Obesity
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This entry is adapted from the peer-reviewed paper 10.3390/obesities2020012

Obesity, classified as an epidemic by the WHO, is a disease that continues to grow worldwide. Obesity results from abnormal or excessive accumulation of fat and usually leads to the development of other associated diseases, such as type 2 diabetes, hypertension, cancer, cardiovascular diseases, among others. In vitro and in vivo models have been crucial for studying the underlying mechanisms of obesity, discovering new therapeutic targets, and developing and validating new pharmacological therapies against obesity. Preclinical animal models of obesity comprise a variety of species: invertebrates, fishes, and mammals. However, small rodents are the most widely used due to their cost-effectiveness, physiology, and easy genetic manipulation. The induction of obesity in rats or mice can be achieved by the occurrence of spontaneous single-gene mutations or polygenic mutations, by genetic modifications, by surgical or chemical induction, and by ingestion of hypercaloric diets. 

rodents monogenic polygenic genetically modified diet-induced chemically induced surgically induced obesity models

1. Introduction

According to the World Health Organization (WHO), in 2016, nearly 2 billion adults were overweight, of which more than 650 million were obese [1]. Obesity is common in both developed and developing countries, affecting all ages without distinguishing social classes [2][3]. Over the past 50 years, overweight and obesity have risen sharply. In 2016, the United Stated of America and Saudi Arabia registered the highest percentage of obese adults, 36.2% and 35.4%, respectively. Conversely, Vietnam, Japan, Ethiopia, and India had the lowest percentages of obese adults in 2016 [1]. Overweight and obesity are defined as abnormal or excessive fat accumulation typically resulting in negative health impacts. Although there is a genetic predisposition to developing obesity, the causes of this disease are multifactorial. Thus, the complex interactions between epigenetics, lifestyle, cultural and environmental influences play a fundamental role in the development of obesity (Figure 1) [3][4][5]. Additionally, economic growth, social changes, and the global nutritional transition are seen as contributing to this epidemic [6]. Obesity should not be seen only as a problem associated with physical image since people with excessive weight tend to have a higher risk of developing other comorbidities, such as type 2 diabetes, hypertension, and certain types of cancer, namely breast, ovary, liver, colon, and prostate [2]. Obesity is also a risk factor for cardiovascular diseases, chronic respiratory diseases, and osteoarthritis, which contribute to more than half of all deaths. More serious cases of obesity are associated with an increasing incidence of diseases such as asthma, gallstones, steatohepatitis, glomerulosclerosis, dyslipidemia, and endothelial dysfunction [7]. The list of health consequences is extensive, and in addition to affecting quality of life, it also contributes to a higher risk of premature death [8]. In the last two decades, the need to develop new therapies increased significantly. The physiological treatment forces the patient to make changes in diet and behavior, which is not always feasible due to the patient’s lack of motivation. Thus, the pharmacological approach is more attractive. Currently, pharmacological therapy includes the use of synthetic drugs [9], although the demand for natural substances that have fewer side effects is increasing. To determine the effectiveness of new drugs or promising natural compounds, these potential therapies must be first evaluated in preclinical models (in vitro and in vivo) and later clinically [10]. Cell cultures are important for obtaining information on the pharmacodynamics of compounds; however, more complex interactions, which are those that contribute to the pathophysiology of obesity, are not noticeable. Therefore, preclinical models, specifically animal models, are essential for identifying and validating pharmacological targets [11]. Animal models for studying obesity comprise a variety of species, from non-mammals (zebrafish, Caenorhabditis elegans and Drosophila) to mammals (rodents, large animals, and non-human primates) [7]. Within these animal models, small rodents (rats and mice) are the most widely used. Their cost-effectiveness and multiparity, physiology close to humans, and easy genetic manipulation are some of the advantages that make them the model of excellence [7]. In this entry, researchers describe some of the most commonly used rodent models of research on obesity.
Obesities 02 00012 g001 550
Figure 1. Risk factors of obesity.

2. Rodent Models of Obesity

The use of animals for scientific purposes is a long-standing practice, dating back to ancient Greece [11][12]. Both humans and other mammals are highly complex organisms, where the organs perform different physiological functions in a regulated way. The anatomical and physiological similarities between human and animal, particularly mammal, led to the use of animals before applying new compounds on humans. To select an animal model, certain parameters must be met: pathophysiological similarities with the human disease; phenotypic correspondence with disease status; simplicity; replicability, reproducibility, and cost-efficiency [11]. Rats and mice are the most widely used preclinical animal models to study obesity [13][14][15]. These animal models help researchers to understand the biopathology and develop possible preventions and treatments against obesity (Figure 2) [14][16]. Nevertheless, each model presents its advantages and disadvantages (Table 1).
Figure 2. Potential rodent models that can be used to study obesity.
Table 1. Main advantages and disadvantages of murine monogenic, polygenic, genetically modified, diet-induced, chemically induced, and surgically induced models of obesity.
Models Advantages Disadvantages
Monogenic
  • Identification of specific genes and their role in the regulation of energy balance
  • Effective and reliable model
  • Well-organized molecular map
  • Does not allow to create a successful drug for obesity since food-intake behavior is controlled by more than a single molecular target
  • Targeting specific molecular targets leads to undesired collateral effects
  • Energy partitioning and fat deposition different from humans
  • Do not represent human obesity diseases
Polygenic
  • Are more representative of human obesity diseases
  • Cost-effective
  • Time-consuming
  • Lack of quality standardization
Genetically modified
  • Genetic characteristics identical to those described in obese humans
  • Understanding of the detailed molecular and neural energy-balance mechanisms
  • Requires technical know how
Diet-induced
  • Are more representative of human obesity diseases
  • Combines genetics and dietary influences
  • Mimics the gradual weight gain that occurs in the human population
  • Poor standardization of the diets and feeding protocols leading to inconsistent and irreproducible data
  • Long duration studies
Chemical or surgical
  • Understanding of the central control of energy balance
  • Reliable and effective
  • Requires anesthesia, surgical skills, and post-operative care
  • Mortality can occur
Based on Barrett et al. [13] and Suleiman et al. [17].

2.1. Monogenic Models

Monogenic animal models are animals with a single gene disorder. They are widely used to study obesity, very reliable, and effective. These models present a well-organized molecular map. However, they differ from humans in the way that they undertake their energy partitioning and fat deposition; and are generally not a good representative of human diseases [17]. Although it has been proven that a single manipulation of almost 250 genes can induce obesity in mice, monogenic models are mainly a result from mutation(s) in the leptin pathway [5][17]. Genetic manipulations or environmental/dietary factors will dictate the severity of obesity and comorbid metabolic modifications [5].

2.1.1. ob/ob Mice

The obese mice (ob/ob mice) were discovered in 1949 by investigators from the Jackson Laboratory [6]. However, only in 1994 was the genetic characterization of this mutation as a single base pair deletion performed and the gene product was called leptin [6][14][18]. This mutation prevents the secretion of bioactive leptin by positional cloning, causing its synthesis to be terminated prematurely [6][7]. Leptin is an adipocyte-derived hormone, the major function of which is related to food intake inhibition, metabolism, and reproduction, through interaction with the central nervous system mainly relating to the hypothalamus. The normal function of the leptin pathway is required for body weight and energy homeostasis [19][20][21]. Mutations in the leptin gene lead to animals with an obese phenotype [14].
The ob/ob mice are widely used because they display early-onset obesity, which is the result of hyperphagia and low energy expense [7][22]. This obesity model possesses the capacity to gain weight in a short period of time, eventually reaching three times the normal weight of wild-type controls [6][22]. These mice exhibit impaired glucose tolerance and insulin sensitivity, most likely as a secondary effect of obesity. Furthermore, they have high levels of circulating corticosterone, develop hypothyroidism, dyslipidemia, decreased body temperature, defective thermogenesis, and are infertile due to hypogonadism [23]. The ob/ob mice have been used to evaluate the influence of several natural compounds on the obesity development [24][25][26][27][28] as well as other concomitant diseases such as metabolic syndromes [29] and oxidative stress [30][31].

2.1.2. db/db Mice

The db/db mouse (db stands for diabetes) [6] is another option for studying the molecular basis of obesity but is commonly used for the investigation on type 2 diabetes [17]. These db/db mice were also developed by investigators from the Jackson Laboratories in 1966 and are phenotypically similar to the ob/ob mice model. They exhibit a mutation in the leptin receptor gene, in an autosomal recessive trait that encodes for a G-to-T point mutation, leading to defective leptin signaling [7][17]. The db/db mice are characterized by hyperphagia, a consequence of impaired leptin signing in the hypothalamus, develop early-onset obesity due to low energy expenditure, are insulin resistant, have decreased insulin levels, and are hypothermic. They also have slow growth due to growth hormone deficiency and are infertile [6][7][14][17][32]. Comparatively to the ob/ob mouse, the db/db model has a marked resistance to leptin, which is a consequence of a mutated leptin receptor, but its leptin levels are markedly elevated [14]. The db/db model can be used in the comprehensive study of diabetes and to evaluate the effect of natural compounds on disease development or as chemopreventive agents [33][34][35][36].

2.1.3. s/s Mice

The s/s mice were developed by Bates and collaborators (2003) to study the role of individual leptin signals, by disturbing the STAT3 pathway, even though it is regularly expressed on the cell surface and can mediate other leptin signals. In this model, the long-form signaling pathways by which leptin exerts its functions are compromised [17][18][37]. The s/s mice are hyperphagic and obese, present normal body length, and contrarily to the ob/ob or the db/db models, they are fertile [14]. The db/db mice and s/s mice are often compared, and share some characteristics such as early development of obesity, hyperphagia, and high leptin/insulin levels [23]. The improvement verified in s/s mice regarding glucose homeostasis is due to decreased insulin resistance and glucose intolerance. These facts are usually attributed to leptin mediation by STAT3, via melanocortin signaling, which affects body energy homeostasis. However, fertility, body growth, and glucose homeostasis are controlled through non-STAT3 signaling [14][38]. The transgenic s/s mouse has played its contribution to the research on obesity and diabetes [18].

2.2. Polygenic Models

For the study of obesity, polygenic models provide more accurate information about the biology of obesity, when compared to monogenic models, since human obesity is mediated by multiple genes [6]. These models are some of the most used, are cost-effective, used regularly, and are considered more realistic models for studying human obesity. Among the different types of polygenic models, only the most frequently used models are included in this entry [17].

2.2.1. New Zealand Obese Mice

The New Zealand obese mice (NZO) strain is a polygenic model that develops obesity and type 2 diabetes only in males [6][7][39]. This mouse strain was obtained in the Hugh Adam Department of Cancer from the selective inbreeding of a stock colony [40]. Some gene variants involved in obesity and diabetes in NZO mice are the Tbc1d1 gene inactivation, causing enhanced transport and oxidation of fatty acids which in turn reduces glucose transport, and the transcription factor Zfp69, which is associated with altered triglyceride distribution and enhanced diabetes susceptibility [41][42]. Leptin receptor (Lepr), phosphatidyl choline transfer protein (Pctp), ATP-binding cassette transporter G1 (Abcg1), and neuromedin U receptor 2 (Nmur2) are other candidates potentially contributing to the polygenic obesity and diabetes of NZO mice [41][42]. These animals show the highest levels of adiposity among the polygenic models. They also share other characteristics that are similar to human type 2 diabetes, such as insulin resistance in brown adipose tissue and skeletal muscle at the age of 4–5 weeks old, that progress into diabetes. They show hypercholesterolemia and hypertension [7][43]. They display moderate hyperphagia and reduced energy expenditure and voluntary activity [7], especially when compared to control or even ob/ob mice [6][17][43]. This strain is similar to the ob/ob mice, except for its ability to maintain body temperature during a 20 h period of cold temperatures, whereas ob/ob mice would not be able to surpass a temperature of 4 °C [43]. NZO mice fed a high-fat diet develop liver steatosis, which is associated with a loss of autophagy efficiency that leads to the disturbance of proteostasis [44].

2.3. Genetically Modified Mice

Genetically modified mice are widely used in research to study genetic influence, modulate a disease, or analyze a biological process in vivo. Mice are considered to be the most suitable mammals for this purpose, as they share the same organ and tissue systems as humans [45]. Genetically models of obesity include transgenic and knockout mice.

2.3.1. Transgenic Mice

Transgenic models of obesity were created to promote access to animals with genetic characteristics identical to those described in obese humans [17].

Corticotropin-Releasing Factor Overexpressing Mice

The corticotropin-releasing factor (CRF) is a peptide that acts as a neuroendocrine hormone and neurotransmitter through the hypothalamic–pituitary–adrenal axis and hypothalamic and extrahypothalamic neuronal pathways [46]. CRF induces a rapid decrease in food intake and gastric emptying that leads to stress-related alterations in food intake and the gastric motor function. Hormones related to the pattern of eating, such as the neuropeptide Y and leptin, are also regulated by CRF [46]. The CRF-overexpressing mice exhibit truncal obesity, muscle wasting, thin skin and hair loss, and are commonly used for study conditions associated with hyperadrenocorticism such as Cushing’s syndrome [14]. This mouse model is often used for studies regarding the response to different feeding conditions [46][47] and studies related to chronic stress [48][49].

Melanin-Concentrating Hormone Overexpressing (MCH-OE) Mice

The melanin-concentrating hormone (MCH) is a hypothalamic peptide known for its role in the regulation of energy balance and feeding behavior [50][51]. MCH is also modulated in response to leptin and insulin [52]. The MCH-OE mice become obese, and display hyperphagia, hyperinsulinemia, and are insulin resistant when exposed to a high-fat diet (HFD) [14][53]. MCH-OE mice are commonly used to study the effects of different feeding behaviors on obesity and insulin resistance [50][52][54].

2.3.2. Knockout Mice

Knockout mice are a valuable tool used to explore potential strategies for the treatment of specific diseases, that includes pharmacological and genetic therapy approaches. Another major purpose of these mice models is to understand the function and significance of specific genes. They are an excellent tool for producing a model of human disease and to evaluate the physiological functions of specific genes [55].

Beta-3 Adrenergic Receptor Knockout Mice

In rodents, the β-3 adrenergic receptors (β3-ARs) are largely expressed in the white and brown adipose tissue [53][56][57]. β3-ARs are linked to the control of thermogenesis in brown adipocytes and stimulation of lipolysis in white adipocytes, through activation of the sympathetic nervous system [56]. The β3-AR knockout mice are moderately obese, a phenotype that is more common in females. Since food intake is similar to the control groups, changes are considered to be due to a decrease in activity of the sympathetic nervous system [14][53]. This mouse model can be helpful for the study of selectivity and function of β3-AR ligands and may present as an important model to distinguish physiology mediated by the sympathetic nervous system [53].

Bombesin Receptor Subtype 3 Knockout Mice

The bombesin-like peptides bind to G protein coupled receptors, such as gastrin releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R), and bombesin receptor subtype 3 (BRS-3). Bombesin-like peptides are found throughout the entire central nervous system and gastrointestinal tract and its main functions are the modulation of smooth-muscle contraction, exocrine and endocrine processes, metabolism, and behavior [53]. BRS-3 in both melanocortin receptor 4 (MC4R)- and single-minded homolog 1 (SIM1)-expressing neurons contributes to the regulation of food intake, body weight, adiposity, body temperature, and insulin sensitivity [58]. The BRS-3 knockout leads to mild obesity, hypertension, impaired glucose metabolism, reduced metabolic rates, increased feeding efficiency, and hyperphagia [59][60]. This mouse model is a great option for the study of moderate obesity, related with type-2 diabetes [53][60].

2.4. Chemical or Surgical Models of Obesity

The hypothalamus, despite its numerous functions, plays a fundamental role in the transmission of afferent signals from the intestine and brain stem, as well as in the processing of efferent signals that modulate food intake and energy expenditure. It is subdivided into nuclei connected to each other, of which the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial nucleus (VMN), dorsomedial nucleus (DMN), and lateral hypothalamic area (LHA) stand out [61]. The lesions produced in these nuclei can be obtained mechanically, through surgery, radiofrequency or electrolytically, or chemically using neuronal toxins such as monosodium glutamate, gold thioglucose, kainic acid, ibotenic acid, and bipiperidyl mustard [53]. Medial hypothalamic lesions (ARC, VMN, and DMN) are associated with strong hyperphagia and activation of the TLR4/NF-κB-pathway, as well as reduced expression of oxytocin in the hypothalamus [62]. Surgical removal of the ovaries is also used to study the incidence of obesity in women.

2.4.1. Lesions of the Ventromedial Hypothalamus

The ventromedial hypothalamus (VMH) nucleus, located in the hypothalamus, is a very complex and important nucleus, which receives several inputs that project to the brain stem and spinal cord, and is associated with the regulation of eating behavior and satiety. One of the first models developed to induce obesity in rodents used rats with lesions in the ventromedial region of the mediobasal hypothalamus (VMH lesions) [7][14][29]. VMH lesion further exaggerates insulin resistance and dyslipidemia in rats fed a sucrose diet, with males being more prone to this exacerbation [63]. Bilateral lesions of the VMH could be made using electrical current or the neurotoxin monosodium glutamate (MSG), leading to the development of hyperphagia, vagal hyperactivity, sympathetic hypoactivity, enlarged pancreatic islets, and hyperinsulinemia [10][64]. Obesity can develop in these animals even when food intake is restricted, although the mechanism by which hypothalamic injury induces obesity is still unknown [14][53]. Nevertheless, the nuclear receptor steroidogenic factor 1 (SF-1), exclusively expressed in the VMH region of the brain, seems to be a key component in the VMH-mediated regulation of energy homeostasis, playing a protective role against metabolic stressors including aging and high-fat diets [65].

Monosodium Glutamate (MSG)

MSG is a neurotoxin that can be administered subcutaneously or i.p. (2–4 mg/g of body weight) during the neonatal period, for 4–10 times to obtain obesity. It is a substance that can be found in many foods and therefore the effects of this substance when taken orally have been studied [10][66]. The administration of MSG in rats or mice will induce vagal hyperactivity and sympathetic-adrenal hypoactivity, which will result in obesity, due to the lack of control between nutrient absorption and energy expenditure. The administration of this neurotoxin induces changes related to the lack of control of the hypothalamic–pituitary axis with dose-dependent curve, including hypophagia, development of obesity, hypoactivity, late puberty, reduced ovaries weight, and elevated serum levels of corticosteroids [66]. In addition, the levels of glucose, triglycerides, and leptin are also increased, resulting in an increase in white adipose tissue deposition and insulin resistance. Adult rats who received MSG in the neonatal period developed endocrine dysfunction syndromes which is characterized by obesity development, disturbances in the regulation of caloric balance, reduced growth, behavioral changes, and hypogonadism [10][67].

2.5. Diet-Induced Obesity (DIO)

Animal models of diet-induced obesity (DIO) are useful for studying the polygenic causes of obesity since they allow to reproduce the most common cause of this disease in man: dietary imbalances [7][10][16][68][69]. Animals, usually laboratory rodents (rats and mice), are exposed to specifically tailored diets that induce obesity. These diets should be prepared by companies that are aware of the nutritional specificities of laboratory animals, modifying their formulation in accordance with the objectives of each researcher [11]. Additionally, different diets could be used such as a high-fat diet (HFD), high-sugar diet (HSD), and the combination of the last two, called Western diets [15][69]. The diet, especially in Western countries, is rich in saturated fat and carbohydrates such as fructose and sucrose, and when given to animals it allows them to mimic the signs and symptoms that are characteristic of human metabolic syndrome [70]. Nevertheless, the poor standardization of the diets and feeding protocols usually results in inconsistent and irreproducible data, leading to differences in experimental findings between similar studies [13].

2.5.1. High-Fat Diet (HFD)/Exposure to High-Fat and Palatable Diets

The obese mouse model, induced by a HFD, is one of the most important tools for understanding the relationship between hyperlipidemic diets and the pathophysiology of obesity development [68]. There are several strains of mice susceptible to DIO, although there are also animals that appear to be resistant to increasing body weight when exposed to HFDs, termed ‘diet resistant (DR)’ [16][70]. The mouse C57BL/6 strain is highly susceptible in contrast to the mouse strains SWR/J, A/J and CAST/Ei which tend to be resistant to these diets. The C57BL/6J mouse, an inbred strain, is the most commonly used due to the similarities that are observed between them and humans in relation to the development of the metabolic syndrome when fed a HFD, resulting in an obese phenotype. After eating a HFD these animals develop obesity, high adiposity accumulation, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. They are also susceptible to non-alcoholic fatty liver disease and endothelium damage, commonly associated with cardiovascular diseases. All the characteristics described above are described in humans with complex metabolic syndrome [6][7][68][71][72].
In addition to mice, some rat strains can also be used for HFD-induced obesity models, such as outbred Sprague Dawley, Wistar, or Long-Evans rats [14]. Weight gain induced by diet changes causes defects in the neuronal response to negative feedback signals from circulating adiposity, such as insulin. Insulin resistance involves cellular inflammatory responses caused by excess lipids. This model of diet-induced obesity (DIO with HFD diets) has become one of the most important tools for understanding the interaction of these diets high in saturated fat and the development of this disease [68]. Outbred Sprague-Dawley rats showed diverse responses, where some animals show DIO while others show DR responses [16].

2.5.2. High-Carbohydrate Diet (HCD)

A high-carbohydrate diet combined with animal or vegetable fat can mimic the human diet. This diet, in rodents, induces metabolic syndrome. The fat source can vary, and fructose and sucrose are the most common carbohydrates present in these diets, also varying their amounts [70]. When fed diets high in fat and sucrose, rodents tend to increase their body weight and deposition of abdominal fat, as well as develop hyperglycemia, hyperinsulinemia, and hyperleptinemia [70][73]. In addition, consumption of these diets can also cause fatty liver and increase liver lipogenic enzymes [74][75]. Fructose ingestion in animals induces an increase in body weight and deposition of abdominal fat, increases plasma levels of triglycerides, cholesterol, free fatty acids and leptin, induces insulin resistance, hyperglycemia, and is associated with fatty liver and inflammation [76]. These animals also show cardiac hypertrophy, ventricular stiffness and dilation, hypertension, cardiac inflammation and fibrosis, decreased cardiac function and endothelial dysfunction together with mild renal damage and increased pancreatic islet mass [70]. Hypercaloric diets induce hyperglycemia and consequently induce glucose tolerance and increase plasma levels of TAG, TNF-α, and MCP-1/JE, as well as MCP-1/JE levels in organs such as the liver and adipose tissue [77]. Animals fed with a HCD show, however, a lower body weight gain when compared to animals fed with a HFD [68].

References

  1. WHO. Obesity and Overweight. Available online: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (accessed on 10 January 2022).
  2. Lau, D.C.; Douketis, J.D.; Morrison, K.M.; Hramiak, I.M.; Sharma, A.M.; Ur, E.; Obesity Canada Clinical Practice Guidelines Expert Panel. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children . CMAJ 2007, 176, S1–S13.
  3. Novelli, E.L.; Diniz, Y.S.; Galhardi, C.M.; Ebaid, G.M.; Rodrigues, H.G.; Mani, F.; Fernandes, A.A.; Cicogna, A.C.; Novelli Filho, J.L. Anthropometrical parameters and markers of obesity in rats. Lab. Anim. 2007, 41, 111–119.
  4. Kaila, B.; Raman, M. Obesity: A review of pathogenesis and management strategies. Can. J. Gastroenterol. 2008, 22, 61–68.
  5. Mittwede, P.N.; Clemmer, J.S.; Bergin, P.F.; Xiang, L. Obesity and Critical Illness: Insights from Animal Models. Shock 2016, 45, 349–358.
  6. Kanasaki, K.; Koya, D. Biology of obesity: Lessons from animal models of obesity. J. Biomed. Biotechnol. 2011, 2011, 197636.
  7. Kleinert, M.; Clemmensen, C.; Hofmann, S.M.; Moore, M.C.; Renner, S.; Woods, S.C.; Huypens, P.; Beckers, J.; de Angelis, M.H.; Schurmann, A.; et al. Animal models of obesity and diabetes mellitus. Nat. Rev. Endocrinol. 2018, 14, 140–162.
  8. Grotto, D.; Camargo, I.F.; Kodaira, K.; Mazzei, L.G.; Castro, J.; Vieira, R.A.L.; Bergamaschi, C.C.; Lopes, L.C. Effect of mushrooms on obesity in animal models: Study protocol for a systematic review and meta-analysis. Syst. Rev. 2019, 8, 288.
  9. Mohamed, G.A.; Ibrahim, S.R.M.; Elkhayat, E.S.; El Dine, R.S. Natural anti-obesity agents. Bull. Fac. Pharm. Cairo Univ. 2014, 52, 269–284.
  10. Parasuraman, S.; Wen, L.E. Animal Model for Obesity-An Overview. Syst. Rev. Pharm. 2016, 6, 9–12.
  11. Geiger, B.M.; Pothos, E.N. Chapter 1—Translating Animal Models of Obesity and Diabetes to the Clinic. In Handbook of Behavioral Neuroscience; Nomikos, G.G., Feltner, D.E., Eds.; Elsevier: Amsterdam, The Netherlands, 2019; Volume 29, pp. 1–16.
  12. Barré-Sinoussi, F.; Montagutelli, X. Animal models are essential to biological research: Issues and perspectives. Future Sci. OA 2015, 1, FSO63.
  13. Barrett, P.; Mercer, J.G.; Morgan, P.J. Preclinical models for obesity research. Dis. Models Mech. 2016, 9, 1245–1255.
  14. Lutz, T.A.; Woods, S.C. Overview of animal models of obesity. Curr. Protoc. Pharm. 2012, 58, 5–61.
  15. Preguica, I.; Alves, A.; Nunes, S.; Fernandes, R.; Gomes, P.; Viana, S.D.; Reis, F. Diet-induced rodent models of obesity-related metabolic disorders-A guide to a translational perspective. Obes. Rev. 2020, 21, e13081.
  16. Speakman, J.; Hambly, C.; Mitchell, S.; Krol, E. Animal models of obesity. Obes. Rev. 2007, 8 (Suppl. 1), 55–61.
  17. Suleiman, J.B.; Mohamed, M.; Bakar, A.B.A. A systematic review on different models of inducing obesity in animals: Advantages and limitations. J. Adv. Vet. Anim. Res. 2020, 7, 103–114.
  18. Speakman, J.; Hambly, C.; Mitchell, S.; Krol, E. The contribution of animal models to the study of obesity. Lab. Anim. 2008, 42, 413–432.
  19. Crujeiras, A.B.; Carreira, M.C.; Cabia, B.; Andrade, S.; Amil, M.; Casanueva, F.F. Leptin resistance in obesity: An epigenetic landscape. Life Sci. 2015, 140, 57–63.
  20. Liu, J.; Lee, J.; Salazar Hernandez, M.A.; Mazitschek, R.; Ozcan, U. Treatment of obesity with celastrol. Cell 2015, 161, 999–1011.
  21. Smith, J.T.; Acohido, B.V.; Clifton, D.K.; Steiner, R.A. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J. Neuroendocr. 2006, 18, 298–303.
  22. Ferguson, D.; Blenden, M.; Hutson, I.; Du, Y.; Harris, C.A. Mouse Embryonic Fibroblasts Protect ob/ob Mice From Obesity and Metabolic Complications. Endocrinology 2018, 159, 3275–3286.
  23. van der Spek, R.; Kreier, F.; Fliers, E.; Kalsbeek, A. Chapter 11—Circadian rhythms in white adipose tissue. In Progress in Brain Research; Kalsbeek, A., Merrow, M., Roenneberg, T., Foster, R.G., Eds.; Elsevier: Amsterdam, The Netherlands, 2012; Volume 199, pp. 183–201.
  24. Bao, R.; Meng, Y.; Zhang, H.; Yang, C.; Li, W.; Zhang, C.; Zhang, J.; Sun, R.; Li, Z.; Jiang, W.; et al. Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK. Cell Death Dis. 2021, 12, 972.
  25. Hua, H.; Zhang, Y.; Zhao, F.; Chen, K.; Wu, T.; Liu, Q.; Huang, S.; Zhang, A.; Jia, Z. Celastrol inhibits intestinal lipid absorption by reprofiling the gut microbiota to attenuate high-fat diet-induced obesity. iScience 2021, 24, 102077.
  26. Liu, M.; Wang, L.; Li, X.; Wu, Y.; Yin, F.; Liu, J. Trilobatin ameliorates insulin resistance through IRS-AKT-GLUT4 signaling pathway in C2C12 myotubes and ob/ob mice. Chin. Med. 2020, 15, 110.
  27. Simperova, A.; Al-Nakkash, L.; Faust, J.J.; Sweazea, K.L. Genistein supplementation prevents weight gain but promotes oxidative stress and inflammation in the vasculature of female obese ob/ob mice. Nutr. Res. 2016, 36, 789–797.
  28. Wargent, E.T.; Zaibi, M.S.; Silvestri, C.; Hislop, D.C.; Stocker, C.J.; Stott, C.G.; Guy, G.W.; Duncan, M.; Di Marzo, V.; Cawthorne, M.A. The cannabinoid Delta(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr. Diabetes 2013, 3, e68.
  29. Sun, S.-S.; Wang, K.; Ma, K.; Bao, L.; Liu, H.-W. An insoluble polysaccharide from the sclerotium of Poria cocos improves hyperglycemia, hyperlipidemia and hepatic steatosis in ob/ob mice via modulation of gut microbiota. Chin. J. Nat. Med. 2019, 17, 3–14.
  30. Chung, M.Y.; Park, H.J.; Manautou, J.E.; Koo, S.I.; Bruno, R.S. Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes. J. Nutr. Biochem. 2012, 23, 361–367.
  31. Zheng, J.; Manabe, Y.; Sugawara, T. Siphonaxanthin, a carotenoid from green algae Codium cylindricum, protects Ob/Ob mice fed on a high-fat diet against lipotoxicity by ameliorating somatic stresses and restoring anti-oxidative capacity. Nutr. Res. 2020, 77, 29–42.
  32. Kitada, M.; Ogura, Y.; Koya, D. Rodent models of diabetic nephropathy: Their utility and limitations. Int. J. Nephrol. Renov. Dis. 2016, 9, 279–290.
  33. Garcia-Mazcorro, J.F.; Mills, D.A.; Murphy, K.; Noratto, G. Effect of barley supplementation on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation in obese db/db mice. Eur. J. Nutr. 2018, 57, 2513–2528.
  34. Guo, Y.; Fu, W.; Xin, Y.; Bai, J.; Peng, H.; Fu, L.; Liu, J.; Li, L.; Ma, Y.; Jiang, H. Antidiabetic and Antiobesity Effects of Artemether in db/db Mice. BioMed Res. Int. 2018, 2018, 8639523.
  35. Lee, A.; Koh, E.; Kim, D.; Lee, N.; Cho, S.M.; Lee, Y.J.; Cho, I.H.; Yang, H.J. Dendropanax trifidus Sap-Mediated Suppression of Obese Mouse Body Weight and the Metabolic Changes Related with Estrogen Receptor Alpha and AMPK-ACC Pathways in Muscle Cells. Nutrients 2022, 14, 1098.
  36. Luo, L.; Fang, K.; Dan, X.; Gu, M. Crocin ameliorates hepatic steatosis through activation of AMPK signaling in db/db mice. Lipids Health Dis. 2019, 18, 11.
  37. Bates, S.H.; Stearns, W.H.; Dundon, T.A.; Schubert, M.; Tso, A.W.; Wang, Y.; Banks, A.S.; Lavery, H.J.; Haq, A.K.; Maratos-Flier, E.; et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 2003, 421, 856–859.
  38. Saadat, N.; IglayReger, H.B.; Myers, M.G., Jr.; Bodary, P.; Gupta, S.V. Differences in metabolomic profiles of male db/db and s/s, leptin receptor mutant mice. Physiol. Genom. 2012, 44, 374–381.
  39. Fang, J.-Y.; Lin, C.-H.; Huang, T.-H.; Chuang, S.-Y. In Vivo Rodent Models of Type 2 Diabetes and Their Usefulness for Evaluating Flavonoid Bioactivity. Nutrients 2019, 11, 530.
  40. Wang, Y.W.; Sun, G.D.; Sun, J.; Liu, S.J.; Wang, J.; Xu, X.H.; Miao, L.N. Spontaneous type 2 diabetic rodent models. J. Diabetes Res. 2013, 2013, 401723.
  41. Joost, H.G. The genetic basis of obesity and type 2 diabetes: Lessons from the new zealand obese mouse, a polygenic model of the metabolic syndrome. Results Probl. Cell Differ. 2010, 52, 1–11.
  42. Kluge, R.; Scherneck, S.; Schürmann, A.; Joost, H.G. Pathophysiology and genetics of obesity and diabetes in the New Zealand obese mouse: A model of the human metabolic syndrome. Methods Mol. Biol. 2012, 933, 59–73.
  43. Jurgens, H.S.; Schurmann, A.; Kluge, R.; Ortmann, S.; Klaus, S.; Joost, H.G.; Tschop, M.H. Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice. Physiol. Genom. 2006, 25, 234–241.
  44. Korovila, I.; Höhn, A.; Jung, T.; Grune, T.; Ott, C. Reduced Liver Autophagy in High-Fat Diet Induced Liver Steatosis in New Zealand Obese Mice. Antioxidants 2021, 10, 501.
  45. Huijbers, I.J. Generating Genetically Modified Mice: A Decision Guide. In Site-Specific Recombinases, 2017/08/18 ed.; Eroshenko, N., Ed.; Methods in Molecular Biology; Humana Press: New York, NY, USA, 2017; Volume 1642, pp. 1–19.
  46. Stengel, A.; Goebel, M.; Million, M.; Stenzel-Poore, M.P.; Kobelt, P.; Monnikes, H.; Tache, Y.; Wang, L. Corticotropin-releasing factor-overexpressing mice exhibit reduced neuronal activation in the arcuate nucleus and food intake in response to fasting. Endocrinology 2009, 150, 153–160.
  47. Wang, L.; Goebel-Stengel, M.; Yuan, P.Q.; Stengel, A.; Tache, Y. Corticotropin-releasing factor overexpression in mice abrogates sex differences in body weight, visceral fat, and food intake response to a fast and alters levels of feeding regulatory hormones. Biol. Sex Differ. 2017, 8, 2.
  48. Kang, W.; Tong, T.; Park, T. Corticotropin releasing factor-overexpressing mouse is a model of chronic stress-induced muscle atrophy. PLoS ONE 2020, 15, e0229048.
  49. Ross, J.A.; Alexis, R.; Reyes, B.A.S.; Risbrough, V.; Van Bockstaele, E.J. Localization of amyloid beta peptides to locus coeruleus and medial prefrontal cortex in corticotropin releasing factor overexpressing male and female mice. Brain Struct. Funct. 2019, 224, 2385–2405.
  50. 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. Investig. 2001, 107, 379–386.
  51. Pissios, P.; Ozcan, U.; Kokkotou, E.; Okada, T.; Liew, C.W.; Liu, S.; Peters, J.N.; Dahlgren, G.; Karamchandani, J.; Kudva, Y.C.; et al. Melanin concentrating hormone is a novel regulator of islet function and growth. Diabetes 2007, 56, 311–319.
  52. Pereira-da-Silva, M.; De Souza, C.T.; Gasparetti, A.L.; Saad, M.J.; Velloso, L.A. Melanin-concentrating hormone induces insulin resistance through a mechanism independent of body weight gain. J. Endocrinol. 2005, 186, 193–201.
  53. Tschop, M.; Heiman, M.L. Overview of rodent models for obesity research. Curr. Protoc. Neurosci. 2002, 17, 9–10.
  54. Lord, M.N.; Subramanian, K.; Kanoski, S.E.; Noble, E.E. Melanin-concentrating hormone and food intake control: Sites of action, peptide interactions, and appetition. Peptides 2021, 137, 170476.
  55. Hui, D.Y. Utility and importance of gene knockout animals for nutritional and metabolic research. J. Nutr. 1998, 128, 2052–2057.
  56. Sakamoto, Y.; Oniki, K.; Kumagae, N.; Morita, K.; Otake, K.; Ogata, Y.; Saruwatari, J. Beta-3-adrenergic Receptor rs4994 Polymorphism Is a Potential Biomarker for the Development of Nonalcoholic Fatty Liver Disease in Overweight/Obese Individuals. Dis. Markers 2019, 2019, 4065327.
  57. Schena, G.; Caplan, M.J. Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask). Cells 2019, 8, 357.
  58. Xiao, C.; Liu, N.; Province, H.; Piñol, R.A.; Gavrilova, O.; Reitman, M.L. BRS3 in both MC4R- and SIM1-expressing neurons regulates energy homeostasis in mice. Mol. Metab. 2020, 36, 100969.
  59. Fruhbeck, G.; Gomez-Ambrosi, J. Control of body weight: A physiologic and transgenic perspective. Diabetologia 2003, 46, 143–172.
  60. Gonzalez, N.; Moreno, P.; Jensen, R.T. Bombesin receptor subtype 3 as a potential target for obesity and diabetes. Expert Opin. Targets 2015, 19, 1153–1170.
  61. Simpson, K.A.; Martin, N.M.; Bloom, S.R. Hypothalamic regulation of food intake and clinical therapeutic applications. Arq. Bras. Endocrinol. Metabol. 2009, 53, 120–128.
  62. Roth, C.L.; D’Ambrosio, G.; Elfers, C. Activation of nuclear factor kappa B pathway and reduction of hypothalamic oxytocin following hypothalamic lesions. J. Syst. Integr. Neurosci. 2016, 2, 79–84.
  63. Gaur, A.; Pal, G.K.; Pal, P. Role of Ventromedial Hypothalamus in Sucrose-Induced Obesity on Metabolic Parameters. Ann. Neurosci. 2021, 28, 39–46.
  64. Kiba, T.; Tanaka, K.; Numata, K.; Hoshino, M.; Misugi, K.; Inoue, S. Ventromedial hypothalamic lesion-induced vagal hyperactivity stimulates rat pancreatic cell proliferation. Gastroenterology 1996, 110, 885–893.
  65. Kinyua, A.W.; Yang, D.J.; Chang, I.; Kim, K.W. Steroidogenic Factor 1 in the Ventromedial Nucleus of the Hypothalamus Regulates Age-Dependent Obesity. PLoS ONE 2016, 11, e0162352.
  66. Von Diemen, V.; Trindade, E.N.; Trindade, M.R. Experimental model to induce obesity in rats. Acta Cir. Bras. 2006, 21, 425–429.
  67. Miśkowiak, B.; Partyka, M. Effects of neonatal treatment with MSG (monosodium glutamate) on hypothalamo-pituitary-thyroid axis in adult male rats. Histol. Histopathol. 1993, 8, 731–734.
  68. Hernández-Granados, M.J.; Ramírez-Emiliano, J.; Elena Franco-Robles, E. Rodent Models of Obesity and Diabetes. In Experimental Animal Models of Human Diseases—An Effective Therapeutic Strategy; Bartholomew, I., Ed.; IntechOpen: London, UK, 2018.
  69. de Moura e Dias, M.; dos Reis, S.A.; da Conceição, L.L.; Sediyama, C.M.N.O.; Pereira, S.S.; de Oliveira, L.L.; Gouveia Peluzio, M.C.; Martinez, J.A.; Milagro, F.I. Diet-induced obesity in animal models: Points to consider and influence on metabolic markers. Diabetol. Metab. Syndr. 2021, 13, 32.
  70. Panchal, S.K.; Brown, L. Rodent models for metabolic syndrome research. J. Biomed. Biotechnol. 2011, 2011, 351982.
  71. Glastras, S.J.; Chen, H.; Teh, R.; McGrath, R.T.; Chen, J.; Pollock, C.A.; Wong, M.G.; Saad, S. Mouse Models of Diabetes, Obesity and Related Kidney Disease. PLoS ONE 2016, 11, e0162131.
  72. Yang, Y.; Smith, D.L., Jr.; Keating, K.D.; Allison, D.B.; Nagy, T.R. Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice. Obesity 2014, 22, 2147–2155.
  73. Lai, M.; Chandrasekera, P.C.; Barnard, N.D. You are what you eat, or are you? The challenges of translating high-fat-fed rodents to human obesity and diabetes. Nutr. Diabetes 2014, 4, e135.
  74. Eng, J.M.; Estall, J.L. Diet-Induced Models of Non-Alcoholic Fatty Liver Disease: Food for Thought on Sugar, Fat, and Cholesterol. Cells 2021, 10, 1805.
  75. He, J.; Chen, D.; Zhang, K.; Yu, B. A high-amylopectin diet caused hepatic steatosis associated with more lipogenic enzymes and increased serum insulin concentration. Br. J. Nutr. 2011, 106, 1470–1475.
  76. Wong, S.K.; Chin, K.Y.; Suhaimi, F.H.; Fairus, A.; Ima-Nirwana, S. Animal models of metabolic syndrome: A review. Nutr. Metab. 2016, 13, 65.
  77. Gloy, V.; Langhans, W.; Hillebrand, J.J.; Geary, N.; Asarian, L. Ovariectomy and overeating palatable, energy-dense food increase subcutaneous adipose tissue more than intra-abdominal adipose tissue in rats. Biol. Sex Differ. 2011, 2, 6.
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Subjects: Endocrinology & Metabolism
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Tânia Martins
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Elisabete Nascimento-Gonçalves
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Paula Oliveira
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Luis Antunes
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