The diet-induced obesity model (DIO model) is an animal model used to study obesity using animals that have obesity caused by being fed high-fat or high-density diets. It is intended to mimic the most common cause of obesity in humans. Typically mice, rats, dogs, or non-human primates are used in these models. These animals can then be used to study in vivo obesity, obesity's comorbidities, and other related diseases. Users of such models must take into account the duration and type of diet (e.g. hydrated gels vs. dry pellets) as well as the environmental conditions and age of the animals, as each may promote different bodyweights, fat percentages, or behaviors.
Driven by the worldwide epidemic of obesity, particularly in the Western world, the DIO model has been integral in understanding the relationship between high-fat/high-density diets and obesity, including the discovery of Akt and mTOR, signals in the body linked to obesity and insulin resistance. However, while many insights into the control of obesity have come from experiments since its introduction in 1949, the use of animal models does restrict our ability to extrapolate findings to humans.
History The DIO model was developed in response to growing concerns over the health effects of obesity, as well as the rapid growth of the obesity rate in countries around the world. As such, the model was developed in order to create a controlled environment for the study of how obesity develops, as well as its effects. The model was used as early as 1949, and has expanded far and wide in its use and goals. Date Event September 1978 First study tested to find correlation between obesity and palatable foods high in fats and lipids, but no conclusion could be reached. 1982Study testing the effects of obesity on the sympathetic nervous system of rats, namely blood pressure. It was found that obesity had a stimulating effect, increasing blood pressure and increasing the risk of hypertension. 1995A study conducted in order to study the expression of the ob gene in rat adipose tissue through the control of their diets. The study also checked for the effects of diabetes on the gene expression. June 2002 Göttingen minipig "pilot" study: published paper on a three month long experiment testing a nonrodent model to see if results could be accepted in DIO research or be compared to results of those studies where rodents were tested. 2007 Continued exploration of diet-induced obesity led to a study of rats as a potential model subject. This genomic based study induced obesity in rats and subsequently analyzed RNA microarrays to characterize the rats metabolic response and resultant insulin sensitivity. 2009 The model is used to challenge beliefs about the causes of obesity in the population, as a group of scientists decided to test the notion that obesity is a result of overnutrition and could be controlled by limiting meal sizes. 2010 Continuing the trend of the model's usage in determining causes of obesity, a group of researchers notice the changes across the diets of several Americans and conduct an experiment to understand why obesity was up when fat consumption was down. For this, they investigate the connection between the types of fat, meal timings and size, and weight gain as well as the reversibility of diet-induced obesity. July 2011Different Diet Stimuli: Diets varying from hyperlipic, hypercaloric, cholesterol-rich, and cafeteria diets were tested on rodents to see which had the most impact on body size and to determine differences between metabolic responses in rodents and humans. 2012A 2012 study further explored the viability of the diet-induced obesity model by testing several mice for their reactivities to a high-caloric diet. The resulting data found some mice (the B6 mouse) responded to diet-induced obesity most similarly to humans with regards to several parameters including fat content, relative organ size, and general body composition.
Other causes of obesity
Social determinants
Social and environmental determinants may also induce the onset of obesity. Social class may affect individual access to proper nutritional education and may hinder an individual's ability to make healthy lifestyle choices. Additionally, samples of low-income women and children were also shown to have higher rates of obesity because of stress. Exposure to pollutants such as smoke and second-hand smoke have also shown direct correlations to obesity.
Gut bacteria
Studies on the relationship between infectious agents and weight gain show that certain species of gut flora can affect metabolic processes. This correlation links these gut bacteria to an inability to digest complex polysaccharides. Certain viruses, specifically the AD-36 adenovirus, have been shown to increase body fat in laboratory animals.
Sedentary lifestyle
Living a sedentary lifestyle is one of the leading factors in causing obesity. As of 2016, over 30% of people in the world do not get enough exercise."WHO | Physical Inactivity: A Global Public Health Problem". World Health Organization. Retrieved November 9, 2016.
Genetic-based obesity
Genetic mutations to genes monitoring metabolism and appetite predispose people to obesity. Various syndromes resulting in genetic polymorphisms lead to obesity. A few common examples are: Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, and MOMO syndrome.
Other illnesses Multiple mental and physical illnesses, along with some of the medications that treat such illnesses can increase someone's risk of obesity. Some examples of other illnesses are hypothyroidism, Cushing's syndrome, and growth hormone deficiency.
Limitations
Obesity is affected by "environmental, biological, and psychosocial pressures", therefore it is understandable that several limitations are established when translating results between the results of a diet induced obesity model in a lab and humans. While models are an important method of investigating the influences of obesity and drug testing, it is important to understand the limits of the model's overall ability to resemble the human obesogenic pathophysiology. Such limitations can be divided into three broad categories—biological, dietary and experimental differences—factors including, but not limited to, the genetic makeup of the species or strain, the environment in which the specimen is held (temperature, light, number of animals), age, sex, the duration of the experiment, and the texture or type of rations fed to the animals.
Biological Numerous sources of biological variation arise in rodents before translating results to humans is even considered. For instance, the age at which mice begin the high-fat diet greatly impacts the metabolic effects. In the strain of mice most commonly used for DIO models, C57BL/6J, mice who started the diet at 10 weeks old showed lower increases in body weight and cholesterol than mice who started at 54 weeks, despite the same diet type and duration. Similarly, 6-week-old mice did not develop type diabetes, while 7-8-month old mice did become diabetic due to differences in β-cell activity.
Furthermore, the strain and sex of the rodent impacts the response to the model. Some common mouse strains show large variations in their level of resistance to obesity. Further variation is seen when the sex is also factored in; males of the S5B/P1 strain showed 12% weight gain, while females gained no weight at all. Even within a single strain, large amounts of variation in the phenotype can be seen, despite each mouse having identical genetic backgrounds, which greatly hinders reproducibility.
This has led to cases of studies that used the same strain of mice concluding that the strain is prone to becoming obese in one study and resistant in the other study. So, despite the fact that variability is clearly present in humans, variability in mice is once again detrimental to the reproducibility of results obtained from the diet induced obesity model.
When functional genomics is applied, few commonalities between the gene expression of DIO vs control rodents and obese vs non-obese humans are found. This is particularly true in the case of glucose regulation, which greatly hinders the ability to apply the results of the DIO model to humans, especially for drug development.
Dietary There high fat diet experiments that have been done in rodents realizing the difficulties in interpreting the literature composition of high fat diet into actual experiment.
With varied sources and types of fat, researches have shown the complexity of defining a model of a high fat diet that can both resemble human meals and accurately quantify the nutrient contents. In fact, recent studies prefer to use purified ingredients to exams the effect of each dietary on rodents' metabolism and their phenotype.
There is significant variation in the results appearing in either experimental rodents that were fed with high fat diets made up from different ingredients and from purified ingredient. Moreover, the sources of fat were diverse from butter, beef tallow, and lard, to vegetable and fish oils. The weight gaining effects on mice when feeding those with high beef fat diet is 1.38 times more remarkable than feeding them with canola oil.
Additionally, they both can be found in rodents' and humans' diets. Researchers have created the study models of high carbohydrate and high proteins. However, the variation in the results of those models has caused the difficulties to interpret and find the relation to human case. According to a review on Nutrition & Diet, there were number of studies ignoring the nutrient composition differences between the control and the high fat diets, but comparing the phenotype expression of these two groups to conclude the influence of hypercaloric diets in causing obesity.
Similar to fat (lipid), the sources of protein and carbohydrate are also essential contributors to the outcomes of high fat diets and control diets rodents group. For instance, casein causes more weight gaining compared to soy. Moreover, different mouse strains can express contradicting results, even though they are both fed with same protein and carbohydrate ratios. In addition to protein, Fructose, a carbohydrate, has impact on fat deposition, plasma insulin, leptin, thyroid, estradiol, and corticosterone levels, lipogenesis, and lipolysis in the adipose tissue of the rat. "Glucose-sweetened beverages," however, did not cause as significant influence as "fructose-sweetened beverages" in promoting visceral adipose, gaining weight, interrupting lipid syntheses, and damaging lipoprotein rebuilding process.
Given the diversity in human food and each human individually distinguished metabolic capacity, the results of testing the diet induce obesity in rodents are limited in term of translatability. Furthermore, dietary components would provide a spectrum of results since both type of diets one with mixture of ingredients-"cafeteria diet" and one with predefined ingredients would alter different impact on the metabolism of the body.
Experimental
Intra and Inter Laboratories results can differ due to variation in the experimental factors such as the protocol used, housing, temperature, light/dark cycle and the duration of study.
Laboratories temperature which are usually (18-22 °C) are lower than the thermoneutrality of model organisms like mice which are about 30 °C. That can introduce hyperphagia in the organism in effort of increasing their metabolism to generate heat energy for the body. This level of thermal stress can also have unaccounted effects on the organism's other metabolic processes.