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This series is intended for faculty, students, and technologists involved in biological and molecular research. This series would also be of interest if you would like to gain a better understand of the pathophysiology and molecular mechanisms of obesity and diabetes.
Dr Khosrow Adeli is currently a Senior Associate Scientist in the program in Molecular Structure and Function at the Hospital for Sick Children in the University of Toronto.
He is also the head and a full professor of Clinical Biochemistry at the Hospital for Sick Children, the Departments of Biochemistry, and Laboratory Medicine & Pathobiology at the University of Toronto, all in Canada.
Hello and thank you for joining us for today's webinar: Genetic and Dietary Animal Models of Obesity: Metabolic Syndrome and Type II Diabetes, the third webinar in the series. It is my pleasure to introduce today's presenter, Dr Khosrow Adeli. Dr Adeli is currently a Senior Associate Scientist in the program in Molecular Structure and Function at the Hospital for Sick Children in the University of Toronto. He is also the head and full professor of Clinical Biochemistry at the Hospital for Sick Children, and the Departments of Biochemistry, and Laboratory Medicine & Pathobiology at the University of Toronto, all in Canada.
Joining Dr Adeli today is Sambhav Dave, the Senior Associate in the Business Development team, with a primary focus in Neuroscience and Signal Transduction research areas.
If you have any questions throughout this presentation, we invite you to submit them on the right hand side of your screen in the Q&A panel. Questions will be answered during the troubleshooting portion of this webinar. At this time, I'd like to hand the presentation over to Dr Adeli.
KA: Thank you, Sarah, and I'm pleased to be here to present the third webinar. This is the third and the final webinar in this series on obesity metabolic syndrome and type II diabetes. Today, my focus will be on animal models used to study these conditions, but also as preclinical systems to screen novel pharmaceuticals and therapeutic strategies developed in recent years. So previously we had discussed the epidemiology of these common conditions, their mechanisms of disease and development. Today, the focus will be how do we apply certain models, physiological animal models to study and to screen for potential pharmaceuticals?
So my focus will be both on genetic models of obesity, insulin resistance and type II diabetes, as well as diet-induced models of these conditions. I will also focus on, in the last part, on fructose-induced hamster models, because this is a model that has been used by us, but by also a number of other labs, and also pharmaceutical companies to screen new therapeutic drugs. Then finally give you examples of some of the preclinical studies done in this area.
Now, first of all, why employ animal models? Well, animal models are, in many cases, can be used as representative of a specific human disease. In the case of many of the models such as mice, the genome is fully sequenced which provides a significant advantage. Also, these models tend to have acceptable reproduction time, allowing for studies to be done over a relatively short period of time. Large numbers can be produced and handled in the laboratory, and used to identify disease genes, in many cases, easier than one can do by focusing on human studies. Now, human studies, of course, are limited to measuring specific biomarkers in people's various body fluids, or doing very limited direct physiological experiments; but a lot of the mechanistic studies require the use of animal models.
The next slide, I talk about some of the major genetic and diet-induced models that have been used over the years, and then I'll give you some details on each of these. First, the genetic models include, particularly mouse models and rat models, and these models there are quite a few of them and I'll discuss some of them. Some of the hypothalamic models, because the hypothalamus is very important in weight control, and so models involving changes in hypothalamic function lead to obesity, and potentially diabetes and they have been used successfully. There are these surgically-induced models, again, surgically, basically intervening with the function of the hypothalamus can, for example, give you a model of obesity. There are these transgenic and knock-on models that have been used successfully as well, which I will discuss. In addition to genetic models, dietary models have been used quite successfully and they probably better represent the garden-variety obesity and diabetes that you see in humans, which are mostly environmentally- and dietary-induced. So these models have become very popular, such as high fat-induced mouse model, the sucrose- and fructose-induced rat models, and then the fructose-induced hamster model, which I will discuss in some detail.
For genetic models, mouse and rats are the most common forms; there are some well-known models such as ob/ob. Ob is standing for obesity and these are animals that are morbidly obese, and they have a mutation. Initially, it wasn't known what the mutation was when this model was developed, but later was found to be due to the leptin gene mutation. Then db/db mouse is a model of not only obesity, but also type II diabetes, and then they have a mutation actually in the receptor for leptin called the leptin receptor. Then there are other models such as the yellow obese mouse, the Japanese KK mouse and the New Zealand obese mouse, and these are some examples. The rat models that are being used quite commonly are the Zucker models, both the Zucker fatty rat and the Zucker diabetic fatty rat. There are several other models that have been used by researchers.
The next slide, I'm going to give you a bit more information of some of the more common models. The ob/ob mouse, as I mentioned, was initially discovered, actually, in the Jackson labs and it was found to be morbidly obese; they develop obesity very early, weeks after birth and then became morbidly obese. This picture actually on the right is from, I believe, about ten months of age, they're more than double the size of their normal litter mate. These mice have severe obesity due to a mutation in leptin; because leptin, as we discussed in the last webinar, regulates food intake and appetite. So these animals are hyperphagic, they have an uncontrolled appetite, and therefore constantly eating because of this lack of satiety factor, and become morbidly obese and insulin resistant. They also can develop a mild form of diabetes, although they're not really frankly diabetic.
The db/db mouse, on the other hand, is a frankly diabetic model; they are obese, but also have diabetes due to the mutation in the leptin receptor gene. These animals are also hyperphagic and obese, and hyperglycaemic and hyperinsulinemic, and clearly show frankly a type II diabetes and, therefore, they have been used over the years as a model of type II diabetes.
The other models that have been used commonly are, for example, the fat mouse and the tubby mouse, not as commonly as the ones that I have discussed, but these also have mutation-specific genes such as, for example, the fat mouse has a mutation in this gene called carboxypetidase E, which is involved in insulin metabolism. They develop a fairly severe insulin resistance in hyperinsulinemia, and that contributes to the obesity that they have. The tubby mouse has also been used in some of the studies by various labs, not so much for pharmaceutical studies, but mostly for mechanism of disease research studies.
The other models that are very commonly used are the rat models called the Zucker models. This is an example here, the fatty Zucker rat and these rates are basically obese, and the obesity shows up a few weeks after birth. They basically have a genetic obesity and they can also become diabetic, although this particular model is not overtly diabetic. There is another model I'll discuss called the Zucker diabetic rat that is a diabetic, and this model is largely obese mostly. There is another model called the SHR rat, and these animals are hypertensive, they have hypertension, high blood pressure and they have been used for some of the hypertension studies, for example, associated with obesity.
I mentioned that I wanted to talk about the Zucker diabetic fatty rat, and this model has been commonly used to study severe insulin resistance, hypoglycaemia and diabetes. They develop massive obesity as well as diabetes and hypoglycaemia weeks after birth, and they're called the ZDF rat; and very commonly used. They manifest a number of complications of diabetes that you also see in humans, such as nephropathy or kidney disease, and CVD or cardiovascular disease, and several other complications and, commonly, have been quite helpful.
Now, so far I've talked about - these are mostly monogenic models and that means that there is a mutation in a single gene causing the obesity or diabetes, but there are some polygenic models that I wanted to talk about. Actually, this is one other monogenic condition or a model called the GK rat, the Goto-Kakizaki rat. This is an interesting model in the sense that it's non-obese, but it has diabetes, so it's been commonly used as a lean model of diabetes, and it's been helpful in some of that research area.
I mentioned polygenic models, and there are these models that appear to develop obesity due to multiple genetic defects, instead of a single genetic defect. The examples given here are the Japanese KK mouse, and then the New Zealand obese mouse that's also used in some studies. But these are not as commonly used, the most common ones, I have talked about so far, used are the ob/ob, the db/db mouse, and then the Zucker diabetic rat model; the Zucker models are commonly used.
What about transgenic models? One can actually induce a number of these conditions that we have talked about obesity and metabolic syndrome diabetes, by creating genetically modified models or transgenic models. So these are described on this slide here, examples are given of some of the key targets one can use to create a phenotype of obesity. Examples shown here, for example, are the uncoupling protein in the brown fat, or the leptin gene, or the leptin receptor gene. So either mutating these genes or overexpressing some of them, depending on the gene, can lead to obesity and/or diabetic model.
The other examples are shown on this table, a number of knockout models and overexpression models have been used. For example, if your express is REBP, which is this phenol response bonding protein, this is really important and you're regulating cholesterol and fatty acid, and metabolism. If you overexpress this in the liver or in the adipose tissue, you get overt obesity and actually in some cases overt diabetes. So this is an example of a model you can generate by directly overexpressing a particular target.
In other cases, you could, for example, PTB-1B you could knockout and I discussed this briefly before. This is a gene that's important in regulation of insulin signaling, and if you knockout PTB-1B, well, you get a model that's actually resistant to obesity, so you have a resistant model that you can use to study specific molecules or mechanisms.
Let's move on to diet-induced models, so the disadvantage of the genetic models I have mentioned, is that they're not really representative in most cases of the garden-variety problem you see in humans. So dietary models have become more and more popular, because they are relatively simple, but they also represent more closely what we are seeing in terms of epidemic of obesity and diabetes in the human population. So the dieting models used are either feeding fat and high fat diets. Now, there are many different versions of this, and some use a high fat, plus high cholesterol, some use high fat and high carbohydrate mix and so on, and there are multiple versions of the high fat diet.
But this is a common approach to inducing an environmentally diet-induced model of obesity and diabetes. High sucrose-induced models are also used, and commonly used in quite a few publications on this, as well as high fructose models, which I will discuss in some detail.
The high fat model is also called a DIO mouse or diet-induced obese mouse model. This is a model that's commonly produced by feeding mice a high fat diet, and as I mentioned there are different versions of a high fat diet. But, commonly, they are fed high fat such that they have more than 60% of their calories coming from fat, and that tends to create a number of issues. These animals quickly become hyperphagic on the high fat diet, they over-consume calories, so their calorie intake is high. There appears to be a reduction in thermogenesis, which also is related to decreased energy expenditure. They basically become lazier and they burn fewer calories, and therefore there is a reduction in thermogenesis and in energy expenditure. If you look at the adipose tissue, liver and small intestine of these animals, you also see a number of abnormalities which are listed here. One of the common ones seen is hepatic steatosis or fatty liver, which is commonly seen. This is associated with development of insulin resistance and this is a risk factor for diabetes.
This is some data from the Jackson Lab showing what you see when you feed a high fat dieting mouse. This is from samples of body weight of these animals, so after several weeks, for example, after 20 to 26 weeks you see a significant increase in bodyweight gain, compared to the normal diet; and then you can see a significant weight gain and obesity in these animals. If you measure their glucose tolerance, this is done using a glucose tolerance test, this a direct measure of insulin sensitivity. You can see that these animals shown here in red on a high fat diet they become less tolerant for glucose, which means they're glucose-intolerant and this is a measure of insulin resistance. So meaning that these animals have insulin resistance on a high fat diet. So you're developing a model of what you normally typically see in the human population, who are overweight and insulin resistant. So this model has been commonly used in many studies, including a lot of the pharmaceutical studies.
I wanted to also turn to hamsters, because my own group in the last 15/20 years has studied and used this model for a number of both basic studies, but also working with a number of pharmaceutical partners, we have tested a large number of compounds in this model. So I wanted to share with you some of that information. First of all, why hamsters? Hamsters actually, interestingly, have a number of similarities to humans in lipid metabolism and physiology and, therefore, it seems to be a good representative model.
This slide gives you some more information about the hamster, and hamsters are actually used for many studies, including toxicological studies and so on. The focus of our webinar is on obesity and insulin resistance, and for that it's also a good model. So a cholesterol-fed hamster can be used as a model of atherosclerosis, and a fructose-fed hamster, which we have used, is a good model of insulin resistance and metabolic syndrome.
What you see is that hamsters on a fructose diet, they develop weight gain and they can become hypertriglyceridemic, hyperinsulinemic, and insulin resistant, and this is what you want to develop to simulate the human condition. So if you look at the literature, this model actually has been used for decades, but the people didn't quite understand how fructose induces this insulin resistant condition, but we have a much better understanding now. But if you look at the literature there is multiple studies showing that if you feed fructose in rats, you develop an insulin resistance condition, or pre-diabetic condition in hamsters, dogs and human studies. So this is almost all models, except certain mouse models appear to be resistant to fructose, and that is because of mutations in specific genes, such as SREBP-1C. I won't go through those details, but basically almost all animals are sensitive to fructose, except perhaps some certain strains of mice, which appear to be resistant due to specific mutations that appear to make them resistant to fructose-induced insulin resistance, but, otherwise, you see it in almost all models.
Why is fructose interesting and why it should be used a model in this case, is because fructose has been implicated in the current prevalence, the high prevalence of obesity that we discussed in the first webinar. Fructose intake consumption has gone up quite significantly over the last 30 years, and if you look at the correlation between the rates of obesity. This is US data from, I should say, the United States Department of Agriculture, you can see a fairly good relationship between increased rates of obesity since the 1970s, and the increased rates of the consumption of the high fructose corn syrup, and this is the source of high intake of fructose. So there have been several studies trying to test this hypothesis of this association, and most studies I would say support a causative link between high fructose intake and obesity. There has been a lot of controversy as well, but in general if you look at the data in humans and in animal models, I think pretty strong evidence that fructose is a causative factor, especially high fructose intake.
Where is fructose coming from? Fructose typically comes from fruit, but we only consume 15 to 16 g of fructose from fruit consumption. Most of the fructose that is consumed nowadays comes from other sources, such as soft drinks, so a couple of cans of soft drinks, for example, have up to 50 g of fructose, so they can be major sources of synthetic fructose. So it's the synthetic fructose that's the problem. Now this is actually all the data showing that up to 100 g of fructose being consumed, which most of the excessive fructose that's not coming from natural sources, but from added fructose. So this is thought to be one factor in the obesity problem.
Now, if you look at - this is a human study done by Peter Howell's group in California, and that group has looked at fructose and human obesity, and insulin resistance. This study shows that humans given a high fructose diet for ten weeks, compared to humans getting the same number of calories, but instead a high glucose diet. Glucose is what you find in pasta and in rice, and so most of the carbohydrate we eat is actually glucose. So it looks like those taking a high glucose diet do not develop this thing called hypertriglyceridemia, which is high circulating triglyceride. If you've monitored them for over a 24-hour period here, you see that patients on a high fructose diet do develop quite significant hypertriglyceridemia. So this is one of many pieces of evidence suggesting that fructose in humans can induce the same type of response that you see, for example, in the hamster model. So fructose-induced models can be potentially very representative of what is seen in the human population.
We have actually reviewed this recently, and we have a few reviews and this is one of them in the American Journal of Physiology, so I welcome those interested to look at this review. Where we talk about fructose and how it impacts on a number of organs involved in metabolism, including CNS affecting satiety, the intestine, the adipose tissue. It's been shown to induce inflammation and it's been shown to induce dyslipidemia, and high lipid levels and steatosis that I mentioned.
I have a little bit more information here, so if you take hamsters that I mentioned initially, and you give them fructose, only after two weeks of a high fructose diet, you see this elevation, significant elevation in triglyceride. You see some elevation in cholesterol, but most of the fat is under triglyceride and also they become hyperinsulinemic. This is indirect evidence of insulin resistance, so these animals are developing insulin resistance. This model also has high circulating free fatty acids, as well as - but normal circulating glucose levels. So they're not diabetic, but they are insulin resistant and they have high lipids as well. So this is a model that could potentially model what, or assimilate what you see in the human overweight, obese, insulin-resistant individual.
We have previously published that these animals are indeed insulin resistant using this test called the euglycemic-hyperinsulinemic clamp. So as you can see on the lower right here, there is a decrease in this index called the insulin sensitivity index, more than a 50% decline. So after only two weeks of diet, high fructose diet, they become insulin resistant, or there is reduced insulin sensitivity.
Why is this occurring, what is unique about fructose? Fructose, it's very different in its metabolism convert of glucose. This slide just shows you that fructose typically, very rapidly after a few steps, once it's absorbed by the liver, in the liver it can become very rapidly converted to glycerol-3-phosphate. This is the backbone of triglyceride. This, therefore, fructose is a good substrate for a synthesis of triglyceride. This triglyceride can store in the liver or can be secreted as VLDL. If it's stored in the liver, and in many cases it is, it causes fatty liver, also referred to as hepatic steatosis. Well, that can induce inflammation and hepatic insulin resistance, and this has been directly shown in multiple models. Also, our problem is that fructose induces a triglyceride accumulation, which can lead to production of VLDL that gives you hypertriglyceridemia, so high circulating triglyceride, which you also see commonly in both this model, the hamster model, but also in the human model of obesity and overweight.
On the other hand, glucose is under a tight control of leptin and insulin, and its metabolism is tightly controlled, and it's not a good substrate for triglyceride synthesis, except under certain conditions. Therefore, fructose is also referred to as a lipogenic nutrient, meaning that it's a very good substrate for triglyceride synthesis.
This is just to emphasize the same point as fructose can be a very good substrate, and can induce the production of triglyceride and VLDL. Basically, in support of the slide, giving you a little bit more detail on the mechanism.
In the hamster model when we feed fructose, and we do this profile called the FPLC profile, so you take the serum sample or plasma sample and you subject it to FPLC fractionation. This is a form of HPLC, and you can fractionate lipoproteins and this is the VLDL, this is the LDL, and this is the HDL peak and you can see that normally these hamsters have very little VLDL. But this is triglyceride, by the way, and this is cholesterol, so you can measure both lipids in these fractions. You can see that on the high fructose diet they become hypertriglyceridemic, because they have very high VLDL levels. So, again, fructose causes hypertriglyceridemia through the induction of VLDL.
So we have published - as well as other groups - have published a number of studies showing fructose-induced metabolic defects, similar to what you see in the human. Hamsters could be a good model, although some people use rats and so you could use fructose-induced rat models as well for some studies. Some of these articles discuss some of the major complications, for example, you see whole body insulin resistance, you see evidence of dyslipidemia, hepatic insulin resistance. You also see evidence of intestinal insulin resistance in chylomicron overproduction. Then over the years we have used, and others have used this model to study various compounds, for example, some of the PPAR gamma agonists, as well as statins and other drugs, and I'll talk about some of these in some detail.
One of the studies we performed was we used the fructose-fed hamster model to study, for example, the effect of these insulin sensitizer agents. Now, you would be familiar with some of these drugs. Actually, some of them, for example, rosiglitazone is still used to treat patients with diabetes, it's an insulin sensitizer and it improves insulin sensitivity. So we had a study in collaboration with GlaxoSmithKline, GSK, a few years ago, where we studied, for example, the effect of this drug on the model. Our focus was on lipids, and you can see that - you can actually see a significant reduction in VLDL triglyceride production when you give rosiglitazone. So if you sensitize these animals to insulin, there is a lowering of VLDL triglyceride, and this is shown here as approximately a 50% drop.
We have also used this model to study statins. We have actually done the studies with a atorvastatin with Pfizer, we, initially, several years ago when atorvastatin was actually initially developed, we tested it in this model. Later on, in collaboration with AstraZeneca, we have tested the rosuvastatin, so this model is sensitive to statins. So what we do is we feed fructose for a couple of weeks, and then we give them the fructose plus and minus the drug; in this case rosuvastatin, and then we monitored these animals. You could look at various aspects - our focus was lipid metabolism, but one could look at effects on glucose homeostasis, look at hypertension, because the fructose also induces hypertension. So you could look at all sorts of other end points in this model.
This is an example of the rosuvastatin data that has been published in atherosclerosis a couple of years ago, where we find, for example, if you feed these fructose-fed, insulin-resistant hamsters with rosuvastatin, you can get a significant lowering of VLDL, which is what we expected. So this suggests that statins can inhibit that fructose-induced VLDL rise, and therefore improve the lipid profile in these animals.
I wanted to end by talking about another dietary model that we have worked on, and that is a model that I think more closely mimics what we regard as the atherogenic diet, or the McDonald-type diet that basically has everything that we regard as a potential risk factor. For example, it has high fat, high cholesterol and high fructose, so we try to develop a combination model, basically. A model of a high fat diet, high fructose diet supplemented with some cholesterol, which is basically what we typically consume in the western diet.
So this model we have found and published a few years ago in the American Journal of Physiology, an article showing that this model has evidence of insulin resistance with progression to type II diabetes. They have dyslipidemia, high triglyceride, particularly, but also high cholesterol, they have a fatty liver, things you see in the more severe forms of human metabolic syndrome.
Then this is some of the data, so if you put the hamsters on this diet of high fructose, high fat and high cholesterol you see a significant increase in body weight, but the interesting thing was, and that was the key observation, that cholesterol seemed to contribute to the phenotype. So you get more weight gain with increasing levels of cholesterol, so here 0.25% cholesterol gives us the highest weight gain compared to a lower concentration of this diet. Now, you see the same differences when measuring cholesterol or triglyceride, you see significantly elevated levels the higher the cholesterol concentration.
So the next slide shows you also some of the pathology of what we see. So if you look at FFCs, the diet, the high fat, high fructose and high cholesterol diet, you can see that these animals actually develop fatty liver. On the right here shows the presence of a significant amount of fat and cholesterol in the liver of these animals. So this is a more severe form of fatty liver that's induced within 20 weeks of the diet, and these animals start becoming mildly diabetic and hyperglycaemic. If you look at the liver, there is evidence of inflammation as well as other pathology/pathological mechanisms going on. So these animals clearly on this diet become a model of obesity, they also have significant weight gain, they have hyperlipidemia, insulin resistant and initial stages of type II diabetes.
This slide here shows you a closer look at the liver of these animals, and you can see that at 22 weeks those with a higher cholesterol supplementation of the diet have the worst steatosis. If you look at the graph here, this is a glucose tolerance test and you can see that animals on a high cholesterol diet in the presence of high fat and high fructose, have the worst insulin sensitivity; that means they're more insulin resistant. So what this suggests is that cholesterol can potentially interact and have a synergistic interaction with a high fact and high fructose diet, to give you a worse insulin resistant state. So we think that this model could potentially be very helpful, and we have used and published the application of this model for some of the mechanistic studies that we have done/performed.
So a little bit more data on this model, you can see this is a ten-day study where if you look at the body weight or look at, in this case, triglyceride and plasma cholesterol there is a significant rise in all of these. This is actually looking at, I should say, the first ten days, not ten - I previously showed you 20 weeks, this is just the first ten days. Actually, in the first ten days it looks like there is already evidence of dyslipidemia, so dyslipidemia is seen within days of feeding. Although they're not more obese yet, they're actually, if anything, they are less of a body weight because the animals, I think, do not like eating the FFC diet, it's mushier than the chow diet. But, eventually, they start eating it because they're hungry and then they become obese. But initially we see evidence of hypertriglyceridemia in these animals very early on.
So this concludes my third webinar. I basically wanted to introduce both genetic and animal models, and focus at the end on some of the fructose models that we have used for some of the mechanistic, but also pharmaceutical studies. So thank you very much for listening. I would be happy to answer questions, but first I want to introduce Sambhav Dave from Abcam who will be giving you another presentation.
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To conclude, our next Abcam event is on February 26th, and the meeting is on Mitochondria, Energy Metabolism and Cancer. The registration for this meeting is still open. So with this, from all of us in Abcam, I would like to thank you for listening in and hand over to Professor Adeli to answer the questions you have submitted. Thank you.
KA: Thank you, Sambhav. I am happy to answer questions and I believe there is a question here that I see, and that is are they the same mutations in mice and humans, in genes, in coding for leptin receptor? So, as we discussed, the mutation in mice creates the db/db model, which is the diabetic mouse model, and this is not always the same as what you see in humans. There are different mutations that have been seen in humans, and they're not necessarily the same mutations as what you see in the db/db mouse. So polymorphisms in the human gene for leptin receptor could affect activity of this receptor and its signaling cascade, and that can alter sensitivity to leptin. You can potentially use this thing called leptin resistance, but there could be different forms of mutations causing different levels of leptin resistance. This is not the same as what you see in db/db mouse, because the db/db mouse has a mutation that causes the loss of the intracellular part of the leptin receptor, that basically means no leptin signaling and so it's a very severe form of leptin receptor defect.
The other question I see here is I'd said that the last slide with graphics showed that rats consumed the control diet had greater weight gain, would not expect otherwise. So I wanted to explain that. First of all, these are not rats, these were hamsters, but you could probably see the same response in rats. But the difference is that the last graph I showed was a very short-term study looking at the first few days after the diet started. Apparently, the lack of weight gain or the lesser weight gain seen on the high fat, high fructose, high cholesterol diet is due to animals not consuming the diet, because they're not used to it. But after a week or so they start consuming it for several weeks, therefore, several weeks' later they actually have a greater weight gain and they become obese. But, initially, the first week, it's true the weight gain was actually less than the control, and that is largely because of avoidance of food by the animals, because the FFC diet tends doesn't have the same texture as the chow diet, and it takes the animals a little bit of time to get used to that diet.
So those are the two questions, and one common question that perhaps I can go through is that commonly I'm asked if I'm doing a study, what model should I use? This is a general question, and the answer is it's really varied depending on what you're trying to study. For example, genetic models can be very good when you're trying to study, especially monogenic models. If you're trying to study the role of a specific gene or a specific signaling pathway, then you would want to use a specific genetic model that has a defect in that particular pathway. But for a lot of the pharmaceutical studies and also a lot of diet-induced studies or mechanisms, one should really probably stay with diet-induced models, in my opinion, they tend to be more representative. But, I should say, that pharmaceutical companies tend to use multiple models when they test their specific compounds, so they may test them in a couple of different genetic models as well as a couple of different dietary models to get the full picture of the mechanisms of action.
So that concludes this webinar. Thank you for listening. I hope the series has been helpful in providing more information both on the disease, mechanisms of disease and also some of the models to study these conditions. Thank you.