Regulating Metabolism: From Obesity to Cancer

Carl F. Ware, PhD; Jorge Moscat, PhD

Disclosures

May 31, 2012

Editorial Collaboration

Medscape &

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Carl F. Ware, PhD: Hello. I'm Dr. Carl Ware, Director of the Infectious and Inflammatory Disease Center at Sanford-Burnham Medical Research Institute. Welcome to this segment of Developments to Watch from Sanford-Burnham and Medscape. Joining me today is my colleague, Dr. Jorge Moscat, Professor in the Cancer Center.

Today's program will focus on key research efforts in understanding how autophagy and other mechanisms regulate metabolism and cancer, and how this research will affect clinical practice. Thank you for joining us, Jorge.

Jorge Moscat, PhD: Thank you. It's good to be here.

Dr. Ware: Tell me a little bit about fitness. We all know that you want to be fit to look marvelous. But tell us about the biochemistry and the biology of fitness.

Dr. Moscat: Fitness is a very good thing from an aesthetic point of view; the problem is that when we are not fit, we may develop other diseases. If we don't exercise at the right time, or we don't eat properly, or we have mutations in our genes that make us more prone to burn less fat, then we develop obesity.

There are 2 levels of obesity: obesity with no clinical implications, and the metabolic syndrome. With the metabolic syndrome, as you know very well, you develop all sorts of diseases: diabetes, cardiovascular disease, and even cancer.

Dr. Ware: And obesity is often linked to diabetes.

Dr. Moscat: There is type 1 diabetes, which is an immune disease, and type 2 diabetes that is a consequence of obesity. When we become obese, we develop inflammation in our fat and in our liver. That leads to the secretion of inflammatory cytokines, such as interleukin (IL)-6, which prevents insulin from working properly, and therefore we develop insulin resistance. With insulin resistance, we're also not able to stop glucose production, which leads to accumulation of fat in the liver. All of these results in impairment of pancreatic function and diabetes.[1]

Dr. Ware: You mentioned cytokines. These are molecules produced by the immune system as well as the stromal tissue.

Dr. Moscat: Right.

Dr. Ware: Are research programs developing therapies based on these cytokines?

Dr. Moscat: There are 2 main areas in this camp. In one, people are working on how the immune system responds to obesity and fat. This research is focused on macrophages, which are cells that eat dead cells. When adipocytes become too big, they die, and then the macrophages clean up the mess. As a consequence of this, they develop hyperinflammation.

What is being shown is that we have 2 kinds of macrophages -- the good ones, called M2, and the bad ones, called M1. Normally, in our fat, we have M2, which are protective. They help the tissues to remodel, and they keep inflammation at bay. However, when we become obese, these M2 macrophages -- for reasons not totally understood -- are substituted by M1 macrophages that release inflammatory cytokines, such as IL-6, IL-1, and tumor necrosis factor-alpha, that cause insulin resistance and diabetes.[2]

Even the adipocyte can behave as an inflammatory cell. In experiments in which people manipulate the immune system in mice, it has been demonstrated that you can have inflammation in the adipose tissue, in the adipocytes themselves.[3] This means that we can design strategies to block that inflammation in the adipose tissue and not affect the immune system. You can imagine that these drugs are going to be much less toxic than those targeting the macrophages, which we need for fighting bacteria and infections.

Dr. Ware: Let's talk a little bit about the adipocyte, the central cell type that's accumulating lipid. What are the processes involved in how an adipocyte accumulates lipid and the processes of digesting fat?

Dr. Moscat: There are 3 major responses that you can envision in how the adipocyte controls energy and homeostasis. One is autophagy, which I will talk about in a minute; the other is adipogenesis, or how many adipocytes we make; and the third is energy expenditure, or how much fat we accumulate because we don't burn calories.

This can be related to exercise or can be related to, as I said before, genetic alterations. If we don't burn all the calories that we eat, in the end, we accumulate fat in the adipocyte. The adipocyte becomes bigger and then tries to compensate for it by eating the fat via autophagy.

Autophagy is a very interesting process that happens in cells, whereby cells eat themselves to sustain their viability in times of nutrient stress. In the case of the adipocyte, it's not very well developed, but it's already known that if we mutate genes that control autophagy, we can affect the biology of the adipocyte.[4] Again, autophagy will be another potential root source of therapeutic targets to this problem, not by addressing inflammation but by addressing the real problem itself.

Dr. Ware: What genetic elements do you think are leading the current thinking in terms of regulating lipid accumulation in adipocytes?

Dr. Moscat: Proteins or genes related to autophagy are the ATG genes. We know, for example, if we knock out ATG-7, a very famous gene in the control of autophagy, we can make mice lean. However, if we knock out a protein called p62 that my laboratory has invested a lot of energy and intellect on, it turns out is that p62-knockout mice develop obesity.[5]

We have very nice clinical data in collaboration with our colleagues at Sanford-Burnham in Lake Nona linking p62 and its partners in autophagy to metabolic syndrome in patients. The idea is that autophagy controls not only lipid degradation but also the expression of proteins that are involved in adipogenesis.

So if we don't have enough p62 in our bodies, we become obese because we make more adipocytes, we burn less energy, we fill those adipocytes, and we turn out diabetic over time. This has been proven genetically in experiments with mice but also has been proven in patients, establishing correlation with genetic alterations.

Dr. Ware: This is a fascinating area, to be able to identify genetic elements that control leanness or fatness. As individuals and as practicing physicians, you are also telling your patients to exercise. What's the link between exercise and obesity?

Dr. Moscat: Well, as you know, fat burning obviously is a very nice link, but autophagy is also involved in that. There have been very recent developments published in Nature, for example, linking proteins that we never thought would be involved in the control of energy expenditure, but are linked to autophagy and apoptosis.[6] For example, the protein Bcl-2 controls autophagy. By controlling autophagy in the muscle, it was able to make mice -- and presumably also humans -- leaner than those that don't have these proteins overexpressed.

I think there's a lot of cross-talk between genetic alterations in our muscles, our fat, and the ability of our bodies to control energy homeostasis.

Dr. Ware: You mentioned a very interesting process: apoptosis, which is programmed cell death. It's a natural process that many cells undergo. In fact, it's a necessary physiologic process that part of us has to die every day to maintain organ homeostasis. You also mentioned Bcl-2. I think that catches everybody's attention because it's been identified as an oncogene, a cancer-causing gene. How are the 2 related?

Dr. Moscat: The way we kill tumor cells is by inducing apoptosis, and Bcl-2 prevents cells from dying and therefore promotes tumorigenesis.[7] This new connection among Bcl-2, energy expenditure, obesity, and the ability of Bcl-2 to prevent tumor cells from dying brings a very interesting connection between metabolism and cancer.

Dr. Ware: How do you see the link between obesity and cancer now?

Dr. Moscat: There are 2 major areas of research in that respect. One is on the metabolism of the cancer cell -- and that's again related to autophagy -- and then there's the relation between cancer and the metabolic syndrome. If you are obese, as has been discussed before, you burn less energy. You accumulate fat, you accumulate glucose, and you accumulate insulin, because if you're insulin-resistant, your insulin is not working in the tissues where it should be working.

If a person who is obese has a tumor, this tumor has an advantage over a person who is lean because the obese person is going to be providing this tumor with nutrients and with insulin, which is a growth factor. There's a lot of research now going on, trying to identify the metabolic and chemical links between obesity and cancer, and those are related particularly to the action of insulin, glucose, and fatty acids. In fact, if you have benign prostate cancer and you are obese, you have a 40% greater chance of that prostate cancer moving from benign to aggressive than if you are a lean person.[8]

There's another aspect that's very important, and that is the metabolic features of the tumor cell itself. Tumor cells normally are exposed to nutrient stress. They are not like normal cells with perfect access to blood; they are constrained. They have very poor access to nutrients and have evolved mechanisms to survive with few nutrients. What they do is reprogram their metabolism to utilize things that normally they don't need to use, and for that, they use autophagy. When they are nutrient-stressed, they activate this autophagy program, meaning that they eat themselves, and they produce intracellular nutrients that allow them to survive until they can gain access to blood. There are a lot of clinical trials now trying to block autophagy as a mechanism to enhance more classical therapies in cancer.[9]

Dr. Ware: For individual cancer patients, would you recommend that they limit their caloric intake and the amount of lipids to literally starve the cancer? Is that a feasible idea?

Dr. Moscat: Not only to starve the cancer, but also to reduce the inflammation associated with obesity. As we discussed before, this inflammation induced by obesity generates IL-6, for example, which is a powerful mitogen for tumor cells. Experiments in mice -- and hopefully in humans soon -- show that if you limit the amount of IL-6 that is produced, even though the mice are obese, they are completely protected from cancer. This has been shown, for example, in liver cancer.[10]

Dr. Ware: The function of the immune system and the inflammatory system, the malignant cell, and your diet all interrelate in this complex process, and autophagy is a major pathway that's involved in this system.

Tell me a little bit about the idea of caloric restriction. Roy Walford at UCLA championed this years ago, and it was clearly linked to longevity in mice.[11] Is that still the situation today?

Dr. Moscat: I think it is. I think it is the situation not only in mice, but also in lower organisms, such as C elegans and Drosophila. If you starve an organism -- it's not clear why, there are many theories, as we discussed a minute ago -- but it all boils down to controlling the activity of a protein complex called mammalian target of rapamycin complex 1 (mTORC1).

mTORC1 is a very interesting protein complex that senses the nutrient state of our bodies and our cells. If you have a lot of nutrients, mTORC tells the cells that they have to accumulate fat. If we accumulate fat, we're in bad shape. But if you use calorie restriction, mTORC tells the cells to stop accumulating fat, stop accumulating bad products, and live within its means. It also activates autophagy to eat all of the things that are not useful for the cells to survive, such as organelles that have dysfunctional proteins that are mutated.

So by having this calorie restriction, having mTORC reduced and autophagy increased, there is a good opportunity for cells in our bodies to clean up the mess that occurs when they eat too much.[12]

Dr. Ware: What do you think are the next steps as we move forward in the future? What can clinicians be doing for their patients in the near future and over the next 10 years?

Dr. Moscat: In the case of obesity, I think it's clear how to reduce our calorie intake. That's easy. Everybody can do it.

In those situations that cannot be solved so easily, we'll have to focus on how to understand the metabolic homeostasis between white adipose and brown adipose tissue. White adipose tissue is bad because it accumulates fat; brown adipose tissue burns that fat. There is a lot of research now trying to convert white adipose tissue into brown adipose tissue by manipulating stem cells in the white adipose tissues -- we have a lot of fantastic researchers in our institution working on stem cell research -- or just by understanding how these cells can transdifferentiate. This is 1 line of research that is going on.[13]

In terms of autophagy in cancer, I think this is extremely exciting -- looking at how we can take the classical therapeutics that we already know and have, and how we can make them work much better if we're able to prevent autophagy. But we have to understand the process very well; if we block autophagy, we can get into other trouble, because autophagy also helps normal cells to keep potential tumorigenic proteins at bay. If you mess around too much with autophagy, you may end up making things worse. That's why all of these clinical trials have to be constantly checking with us basic scientists and going from bed to bench, bench to bed, in order to generate new and more efficient therapies for the future.

That's why it's so fascinating investigating cancer: not only because we aim to cure our patients, but also because it allows us to understand how biology works. It's an extreme situation where you see how things go wrong and how to fix them. By fixing them, you understand how they work in a normal situation and that helps you to prevent disease. It's not just about finding a cure. It's about being able to prevent. The more we understand how the cell works, the more we invest in research, the more we'll be able to prevent diseases from coming. Then we don't have to cure patients, because nobody will get sick.

Dr. Ware: That was a very interesting topic. Thanks, Jorge, for participating in the program today.

Dr. Moscat: Thank you very much. It was a pleasure being here.

Dr. Ware: We would both like to thank you for joining us today. I hope you will join for additional programs in the Developments to Watch series on Medscape.

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