PodcastDevelopmental Biology

Science Signaling Podcast: 1 December 2009

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Sci. Signal.  01 Dec 2009:
Vol. 2, Issue 99, pp. pc22
DOI: 10.1126/scisignal.299pc22

Abstract

This is a conversation with Alexander Pfeifer about a Research Article published in the 1 December 2009 issue of Science Signaling.

(Length: 14 min; file size: 6.9 MB; file format: mp3; location: http://podcasts.aaas.org/science_signaling/ScienceSignaling_091201.mp3)

Technical Details

Length: 14 min

File size: 6.9 MB

File Format: mp3

RSS Feed: http://stke.sciencemag.org/rss/podcast.xml

Download Podcast: http://podcasts.aaas.org/science_signaling/ScienceSignaling_091201.mp3

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Cell Biology, Developmental Biology, Metabolism, Physiology

Keywords: Science Signaling, adipose tissue, brown fat, energy, lipids, preadipocyte, thermogenesis

Transcript

Host – Annalisa VanHookWelcome to the Science Signaling Podcast for December 1st, 2009. I’m Annalisa VanHook. In this episode, I'll be speaking to Alexander Pfeifer about a paper from his group published in the current issue of Science Signaling about the signals that regulate the differentiation and the function of brown fat (1).

There are two types of fat in the body: white adipose tissue and brown adipose tissue. White adipose tissue primarily stores energy in the form of fat, whereas brown adipose tissue not only stores fat but also burns it to produce heat. In a paper published this week in Science Signaling, Haas and colleagues explore the molecular signals that regulate how preadipocytes differentiate into brown fat instead of white fat. Pfeifer spoke to me on the phone from his lab at the University of Bonn in Germany.

Interviewer – Annalisa VanHookHello, Dr. Pfeifer.

Interviewee – Alexander PfeiferHi, Annalisa.

Interviewer – Annalisa VanHookThere are two types of adipose tissue in the body—there’s brown fat, and there’s white fat. How are these types of fat similar, and how do they differ from one another?

Interviewee – Alexander PfeiferSo, white fat is, of course, the more or the more obvious, and it represents at least 10% of the body weight. And white fat stores energy in form of fat, and white fat cells are containing only a single droplet of fat, and they have only very few mitochondria. On the other hand, brown fat—they also store fat, but in multiple, small droplets, and they contain a lot of mitochondria. And the task of brown fat cells is not so much to store energy, but to use energy to create or to produce heat. So, they are essentially necessary for non-shivering heat, and they are predominantly found in the newborn.

Interviewer – Annalisa VanHookDoes brown fat persist into later stages—I mean, do adults have brown fat?

Interviewee – Alexander PfeiferYeah, that is a very, very interesting and very important question we believe, and others believe, because before previously it was always thought that brown adipose tissue is lost in adults because no one could find it, so to say—or no one was looking correctly, I should rather say. However, this dogma, so to say, has been recently refuted or proved wrong because, in several ground breaking papers published this year—for example, in the New England Journal of Medicine—several groups have shown that adults have brown fat in the neck area (2, 3). And, importantly, those people with increased body mass index, or obese people, so to say, have not so much brown fat or not brown fat at all. So, this clearly shows that adult people do have brown fat, and that, for example, if these people are confronted with cold air or something like that, this brown fat is activated.

Interviewer – Annalisa VanHookThe observation that there’s less brown fat in obese people—has it been determined whether that’s a cause or a consequence of obesity?

Interviewee – Alexander PfeiferObesity obviously comes from a certain imbalance of energy intake and energy expenditure. And so, for sure one could say, “Well, it’s just too much energy intake.” So, all those strategies where people or pharmacologic agents are aimed at energy intake, were always not so good in lowering body mass index in getting rid of obesity. So, on the other hand, several new options could be to increase energy expenditures. So, the theory would now be that those people have, that have less brown fat obviously have less expenditure—energy expenditure—and so this might be a reason for their becoming obese. There's an interesting calculation from these people that found the brown fat using energy tracers, and they said that if you fully activate normal brown fat that you find in a non-obese human being, you could burn approximately 5 kg of fat per year. So, this is amazing—I think 50 g of this small brown fat tissue equal like 20% of total resting energy.

Interviewer – Annalisa VanHookDo brown and white fat have a similar developmental history—do they develop from the same type of tissue?

Interviewee – Alexander PfeiferIt was previously thought that all fat cells are derived from one lineage, so called preadipocytes. But, recent findings completely redraw that picture, so there appear to be different lineages, different stem cells, that either give rise to muscle cells and brown fat cells, or, on the other hand white fat cells. And also certain specific transcription factors have been found that are needed very early in the differentiation process of these so to say predisposed stem cells—like BMP7 or PRDM16—and we were also looking for factors that are necessary for brown fat cell differentiation. And we found this nitric oxide–cyclic GMP signaling cascade very interesting and very important for that process.

Interviewer – Annalisa VanHookIs the brown fat found in the same places with the white fat? Are these cell types kind of mixed together?

Interviewee – Alexander PfeiferHa, yeah. Both is somehow true. So, the true brown fat is found in the neck area, and in infants also in the interclavicular and interscapular areas, whereas white fat is found predominantly around the stomach and subcutaneously. And the second part of your question is also interesting. It was perviously found that in some instances, when you stimulate white fat—over the sympathetic nervous system, for example—that you find then, after certain time period you find some brown fat cells—or brownish fat cells—and no one knows how that comes from. If you remember, the two different lineages of fat come from—it looks like two different lineages of stem cells, you know what I mean? So, and you find these stem cells inside the brown or the white fat. So, we isolated preadipocytes from brown fat and analyzed differentiation and came up with this new signal cascade.

Interviewer – Annalisa VanHookSo, you mentioned that nitric oxide signaling is important in the specification of brown fat or in the differentiation of brown fat from the preadipocytes. And in the paper you specifically focus on protein kinase G. What’s the connection between nitric oxide and protein kinase G, or PKG?

Interviewee – Alexander PfeiferSo, nitric oxide is a gaseous signaling molecule, and inside the cell it triggers the production of the second messenger cyclic GMP. And cyclic GMP has then at least three receptor proteins that are switched on or regulated by cyclic GMP, and one of these is protein kinase G, but also phosphodiesterases or certain ion channels could be regulated by cyclic GMP. So, it was not clear how nitric oxide–cyclic GMP exert their effects, through which signaling molecules. And so, we are focusing on protein kinase G because, well, we work on that for quite a while, and then we realized, when we isolated those cells and when we analyzed the animals, that they have a clear phenotype and that brown fat cell differentiation is dependent, clearly dependent on the presence of this kinase.

Interviewer – Annalisa VanHookSo, when you remove the kinase, PKG, from the mice what affect do you see on their ability to produce brown fat or on how that brown fat functions physiologically?

Interviewee – Alexander PfeiferSo, we see two different things. And first we see that mitochondria, which are the power plant, so to say, of the brown fat cells, which are so important for generation of heat, that they are not produced at a similar level as in normal cells, in normal mice. And then, we were expecting, well, if there are not so many mitochondria, there should be more fat because the brown fat cells cannot burn so much fat. But, interestingly and surprisingly we found that, well, those cells did not contain fat at all. So we were then following the trail of the signaling cascade and tried to figure out what happened to those cells. And we then figured out that PKG is essential not only for mitochondrial biogenesis, but also for the differentiation of the cells, so that they acquire fat cell phenotype.

Interviewer – Annalisa VanHookThe fact that they had reduced brown fat—did that affect their ability to regulate their body temperature, did they shiver more? And did these mice then maybe gain weight, as an effect of not being able to burn as much fat?

Interviewee – Alexander PfeiferSo, what we did is, we acquired a very sensitive infrared camera. And given the fact that brown adipose tissue is like a heat production plant below the skin, you can measure, especially in newborn mice, easily, with a sensitive infrared camera, the temperature of the skin which lies over the brown fat. And what we saw is a, that the newborn PKG-deficient mice have less brown fat activity, and that their body temperature or surface temperature is lower. And, importantly, when they are taken away from their mother (these newborn pups, they don’t have fur), so they were not surviving as long as a normal mouse in normal room temperature or in cold. So, clearly they have a defect in non-shivering thermogenesis and generation of heat. Unfortunately, the phenotype of the mice is so severe that they do not survive very long, and normally these mice die after several days or several weeks of age. And we are now generating new mice that have a conditional knockout where we can just switch off the kinase at a certain time and [in] a a certain fat tissue—for example, brown fat.

Interviewer – Annalisa VanHookGet the young mice through that critical period, and then take the gene away.

Interviewee – Alexander PfeiferThat’s correct. That’s correct. And we don’t know whether they die—it might be multiple things, but one fact could be that they don’t have brown fat, and they, how should I say are more susceptible to coldness. But this might be only one fact—this kinase is very important for many different things.

Interviewer – Annalisa VanHookYou mentioned that in your PKG knockout mouse that you have not only less brown fat cells, but the cells have less mitochondria in them. Did you look at the mechanism? Do you know how PKG affects the biogenesis of mitochondria?

Interviewee – Alexander PfeiferSo, an interesting point is, all cells have mitochondria for sure, and brown adipose cells and cardiomyocytes, they possess the highest amount of mitochondria. So, it was striking to see that they, that these mutant cells—these cells that don’t contain or don’t have protein kinase G—do not have that many mitochondria. And so, the kinase and the signaling pathways that it regulates are necessary for the production of mitochondria. The kinase is, in the end, necessary to switch on master transcription factors that then lead to the production of mitochondria, for example something like PGC1α is one of these master transcription factors that are needed to produce mitochondria within a cell.

Interviewer – Annalisa VanHookSo, you mentioned that in a normal animal, that both brown fat and cardiac myocytes have more mitochondria than other cell types. In the PKG knockout mouse, did those cardiomyocytes have less mitochondria in the cells?

Interviewee – Alexander PfeiferAh, that is a very good question. So, presently we are looking at that right now, but as I said it’s a very good question. It looks that also other cells are dependent on this signaling pathway that their mitochondria content is regulated by, nitric oxide–cyclic GMP then protein kinase G.

Interviewer – Annalisa VanHookIs the overall idea of this research, sort of the end goal, not only to understand how this specific cell type develops and how it functions but also you want to begin to think about ways to maybe boost brown fat function in patients that have reduced brown fat or reduced brown fat function?

Interviewee – Alexander PfeiferWe are pharmacologists, or in the pharmacology department, so we are prone to think in that direction. And, as I said before, obesity is the result of an imbalance between energy intake and energy expenditure, so all these strategies aimed at energy intake, or reduced energy intake, are not as successful, as we all know. But it would be a different way to now boost, as you were suggesting in your question, energy expenditure, so how to boost brown fat cells. So, there are two pathways—one is the well-known adrenaline sympathetic pathway, and now this new pathway so to say (nitric oxide–cyclic GMP–protein kinase G), the idea would be if we could have increase in cyclic GMP in the brown fat cells, either by local administration or by finding a way to, how should I say, bring cyclic GMP there or increase cyclic GMP production of these cells or activate PKG, I should say—we could boost brown fat cell function. These cells, which we treat with constitutive active protein kinase G, they are like super brown fat cells: They contain a lot of fat; they contain a lot of mitochondria; and they are able to waste energy and produce heat like very well-trained brown fat cells, if I might say so.

Interviewer – Annalisa VanHookWell, thank you for speaking with me, Dr. Pfeifer.

Interviewee – Alexander PfeiferThank you very much for your interest and thank you very much for these interesting questions.

Host – Annalisa VanHookThat was Alexander Pfeifer discussing a paper from his group published in today's issue of Science Signaling. That paper is titled “Protein Kinase G Controls Brown Fat Cell Differentiation and Mitochondrial Biogenesis” (1).

music

And that wraps up this Science Signaling Podcast. If you have any questions or suggestions, please write to us at sciencesignalingeditors@aaas.org. This show is a production of Science Signaling and of AAAS—Advancing Science, Serving Society. I'm Annalisa VanHook, and on behalf of Science Signaling and its publisher, the American Association for the Advancement of Science, thanks for listening.

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