Vishwa Deep Dixit, DVM, PhD - Thermogenic Checkpoints of Weight Loss

March 07, 2024

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00:00So next, it's my pleasure to
00:03introduce Doctor Deep Dixit,
00:04who studied veterinary medicine
00:06in India and did his PhD research
00:08at the University of Hanover,
00:09Germany, and postdoctoral research
00:11at Morehouse School of Medicine,
00:13Atlanta and the National Institutes
00:15of On Aging in Baltimore.
00:18He currently holds the Valdemar von
00:21Zewitz Endowed Chair and is the professor
00:23in the Department of Pathology,
00:26Comparative Medicine and
00:27Immunobiology at Yale University.
00:30Doctor Dixit is also the director of
00:32the Yale Center for Research on Aging,
00:35or Y age, at Yale School of Medicine.
00:41Doctor Dixit,
00:46thank you. Thank you, Anya.
00:48You know, it's always the hardest
00:49thing to do is to give a talk,
00:51intramural talk, in a Yale symposium
00:54among the audience from Yale.
00:55Because it's the hardest
00:57because everybody's so great.
00:59So let me see if I can do justice to it.
01:02Now I think we've heard about obesity
01:04and we'll talk more about obesity.
01:05But I just want to remind those of you who
01:08don't think about this as much as we do,
01:11which is that if you compare the
01:14risk factors of various situations
01:17that we are dealing with in life,
01:19actually aging, just getting old,
01:22the process of getting old is
01:24the single biggest risk factor
01:26for each one of these diseases,
01:29including heart disease,
01:30Alzheimer's and cancers.
01:32And this is something that
01:34we're extremely interested in.
01:35And what we are also extremely
01:38interested in is the interaction
01:40that occurs between development of
01:44obesity and chronic obesity that
01:48spills into age as we get older.
01:51So these are data from CDC and
01:53you can see that individuals that
01:57are older adults that are between
02:00the ages of 65 and 74,
02:02in this case the the incidence
02:04of obesity is fairly high,
02:06almost 40% of older adults have obesity.
02:10And what in terms of mechanisms,
02:12we know very little about how
02:15the basic biology of aging and
02:19the aging processes are impacted
02:22when we have this chronic obesity
02:24that is present in aging.
02:26There are some studies,
02:28including some from Yale.
02:30But what's very intriguing is this
02:34response that you see in all 'cause
02:37mortality and the BMI with age, right.
02:40So it's a paradox.
02:42So you will notice that on the Y axis,
02:45this is the mortality hazard
02:47ratio and the BMI listed here
02:49that if as we get older and the
02:51chances of mortality increases.
02:53If the BMI is high,
02:55obviously that is expected.
02:57But also the chances of mortality
03:00are much higher if the BMI is on
03:03the lower end of the spectrum.
03:05How these things are actually mechanistically
03:08related are not very well known.
03:11It's also not known whether you know the
03:17point of time. But it's also well
03:20not known whether if one carries on
03:22obesity and aging risk all this way,
03:25whether this is already a fait accompli,
03:27Is there anything we can do to this
03:30process that would enhance our health?
03:32So we have been interested in
03:34negative energy balance and how
03:36to induce negative energy balance
03:38and what that does to Physiology.
03:40And as Tomas had mentioned,
03:43one of the key interventions that
03:45was discovered almost 100 years
03:48ago that extends lifespan and
03:50health span is caloric restriction.
03:52And so as you know obesity is a
03:57fundamental disorder of thermodynamics.
03:59So you have energy intake and you
04:01have energy out energy expenditure.
04:03We heard a lot about everything
04:05that's currently is known about
04:07obesity interventions,
04:08pharmacologic interventions are
04:09all on energy intake which is
04:12inhibiting your food intake.
04:13And we are very much interested to see
04:15what's the other side of the axis,
04:17Is there a way to expend energy?
04:20Anyway,
04:20I'm not going to go into the details of this,
04:22but we know that when the host
04:24is in negative energy balance,
04:26you get lifespan extension.
04:27Actually you have less diseases,
04:29except there's a dirty little secret here,
04:32which is as we get this longevity,
04:35this longevity dividend comes at
04:39with the risks of these trade-offs.
04:44So animal models that live long,
04:47all of them, they live,
04:48they do live long, but they have,
04:50they're growth ******** they do not breed.
04:53If you take them out from a specific
04:55pathogen free facility, they fall dead.
04:58And we've been studying
04:59this for almost 100 years.
05:00And the question has been if this
05:02intervention that extends lifespan
05:04has this multiple health benefits.
05:06If are we going to ever harness any of
05:08the so-called Pella restriction mimetics?
05:10Is it actually relevant to human Physiology?
05:13And this is what we have been trying
05:15to do over the past 15 years or so.
05:17I'm not going to go into the
05:18details of model organisms.
05:20Both Tomas and I are failed veterinarians.
05:21It's very nice to give a
05:23talk right after him. So.
05:26But the idea here is that the
05:30dietary interventions,
05:31especially things like caloric restriction,
05:33if you do in animals, you know,
05:36animal in a cage does not sign consent forms.
05:39It doesn't know if you're going to,
05:41you know, give 40% less calories.
05:43Animal doesn't know what's going to happen.
05:45So the idea is to actually do a
05:47randomized controlled study in people,
05:48see if it is relevant to human Physiology in
05:50in terms of inducing negative energy balance,
05:53most importantly without
05:54inducing these trade-offs.
05:56And many of these trade-offs
05:57actually come from stress signaling.
05:59All right.
05:59And see if that is actually relevant.
06:01Can we harness those endogenous factors
06:04assigned causality using the animal models?
06:06And this was a trial that was funded
06:08by the National Institute on Aging.
06:10It's now complete.
06:11This trial was initiated while I
06:14was starting my faculty position
06:16in Pennington in Louisiana.
06:17And the idea that NIH wanted was
06:19that we take healthy people, OK?
06:21See,
06:22if we restrict the calories
06:24by 25% for two years,
06:26would that delay the trajectory
06:29of reducing the risk of disease
06:31and slowing the process of aging?
06:35It was a really an ambitious goal
06:37because there is no way to know after
06:39two years how you have actually traject
06:40changed the trajectory of aging.
06:42You know there are no markers,
06:43there are no biomarkers or
06:44or any of those things.
06:46Anyway,
06:48what we have been interested in is to see if
06:50it is indeed relevant to human Physiology.
06:53Can we harness some of
06:55those endogenous factors?
06:56So this is what happens when people
06:58undergo caloric restriction.
07:00So actually humans in free living
07:02condition can only undergo about
07:0414% or 15% caloric restriction.
07:05The reason why we have obesity
07:07epidemic is because exercise and
07:09reducing food intake doesn't work.
07:10That's why we have pharmacology.
07:12The key point here is that,
07:13so this is transcriptional data
07:15from adipose transcriptome,
07:17data from adipose tissue.
07:18These are individuals at the baseline.
07:20These are individuals
07:21after caloric restriction.
07:22And you can see the remarkable change in
07:24the transcriptome of the adipose tissue.
07:26And I recall that when we were doing
07:28this analysis, my collaborator,
07:29Washu Mike Sardomoff says,
07:30oh, you know,
07:31your mice look amazing.
07:33These are not inbred 99.9%
07:35genetically identical animals.
07:36As far as I know.
07:37They're all human beings.
07:39Yeah. So I'm not going to
07:40go into the detail of that,
07:42but share some really new data
07:45in next 5 minutes or so that is I
07:48think is quite serendipitous in,
07:50in many ways that we have found
07:52suggesting that there are several
07:53other pathways that could be really
07:55interesting and important for weight loss.
07:57So one of the things that we have
07:59been very interested to see is
08:00also the changes in metabolism
08:01that that occurs when individuals
08:03undergo caloric restriction.
08:04So when we did the metabolomics,
08:05the the pathway that really lit up
08:08was the pathway that is associated
08:11with taurine and cysteine metabolism,
08:13which led me into this area that
08:15we had never thought about,
08:17which is the transalphuration path.
08:19Please don't hate me.
08:20This is not meant for you to kind of
08:22really look into it in any details.
08:24We've we've all suffered through TCA cycle.
08:25OK.
08:26The key point here is I want
08:28you to focus on cysteine, OK.
08:30This is a fundamental pathway that is really,
08:33really critical for us in terms of
08:35maintenance of sulfur amino acid metabolism.
08:38OK.
08:38Why is this metabolism showing up
08:40in this calorie restriction we had?
08:42This is not what we predicted and
08:44that's the beauty of science in many ways.
08:46So this is the enzyme just quickly.
08:49So cysteine is made from this
08:52enzyme here cystathione gamma lyase.
08:54And when we checked our transcriptional data,
08:56indeed this enzyme is very
08:58critical and it gets up regulated
09:00upon caloric restriction.
09:02So prediction would be that
09:04you have more cysteine,
09:05well actually just before that
09:08and this increase of this enzyme
09:10while we were doing these studies,
09:11this paper came out from vitamin
09:13Gladyshave's lab that this enzyme is
09:15also increase in multiple intervention
09:17that in in in mice that extend lifespan.
09:20So we thought that OK,
09:21we are probably on the right trajectory,
09:23right.
09:23And and this is the kind of a
09:26snapshot of how cysteine metabolism
09:28and transulphuration looks like.
09:30So this is the methionine cycle.
09:32All of you know that cysteine is
09:34dietary non essential and I'm going to
09:36show you that it's actually really essential.
09:38It may be dietary is not essential,
09:40it's really essential for Physiology.
09:42So this enzyme increases by caloric
09:44restriction and what it does is it
09:47converts histathionine into cysteine.
09:48And as you know cysteine is a very
09:50important substrate for multiple
09:52things including glutathione.
09:53And the key part of cysteine is,
09:55is this very critical modification
09:59here thiol group.
10:00It's the only amino acid that
10:03has a thiol group in it, OK.
10:04And that is absolutely essential
10:06for its function.
10:07But you know,
10:08prediction would be that if the
10:10cysteine levels are high, oh, sorry,
10:12the if the Cth levels are high,
10:14then the cysteine levels are going
10:15to be higher in calorie restriction,
10:17but it's actually the opposite.
10:19So what happens is in individuals
10:21that undergo calorie restriction,
10:22if you measure cysteine levels in the
10:24adipose tissue, it's actually lower.
10:26So Cth is in terms of going up to
10:29kind of maintain the cysteine levels.
10:31So what we decided to do was to see if
10:34we can target CDH and create a artificial
10:37condition of regulating cysteine.
10:39And the way you do that because
10:40if you just restrict cysteine,
10:41it's not going to make any difference because
10:43body is going to make cysteine from CDH.
10:45So what we did was create this mouse.
10:47This work was done by my
10:49former PhD student Eileen Lee.
10:51So she created these animals that
10:53lack Cth enzyme and then restricted
10:55cysteine in the diet.
10:56And what it does is that in this
10:58case there is no cysteine being
11:00made or is either being consumed.
11:02The mice are normal.
11:04Most of these mice in in when
11:06they're in the cysteine.
11:08When you give cysteine in the diet,
11:09they're totally fine.
11:10But notice what happens to the knockouts
11:13when you remove cysteine in the diet,
11:16they undergo massive,
11:17massive weight loss.
11:19And this weight loss,
11:20weight loss is really specific to cysteine.
11:23So if we so this is the weight loss
11:25here with restricting cysteine.
11:27If you put cysteine back in the diet
11:29they gain weight back up and you know
11:32we did this for three cycles just for fun.
11:35These animals don't have disease,
11:37OK,
11:38they don't have malaise.
11:40So these are the knockouts on
11:41cysteine free diet.
11:42They are pretty they are pretty healthy.
11:44So the question is what are these
11:46mice dying of or what is actually
11:48happening in terms of weight loss
11:50because we know that weight loss
11:51can be healthy and UN unhealthy.
11:53What was really striking in
11:55these animals was that when we
11:58depleted cysteine from the system,
12:00what it did was it completely
12:02changed the white adipose tissue
12:05into brown adipose tissue and it
12:07was not like a minor response,
12:08it was total conversion of
12:10the adipose tissue,
12:11both subcutaneous as well as visceral.
12:14All right.
12:15And this is just the marker UCP one,
12:17which is critical for uncoupling.
12:19We all know that mice,
12:20you know they show this response
12:22typically if they're in sub thermal
12:24neutral temperature because our animal
12:25facilities are 22°C whereas you and I,
12:27we all live in thermal neutrality.
12:29So what Eileen did was did the
12:31same experiment in animals that
12:33are kept at 30°C which is thermal
12:35neutral zone and it is independent
12:37of thermal neutrality or cold.
12:39So these animals still lose weight,
12:41dramatic weight loss.
12:42And this weight loss in animals is
12:45considered lethal because they have to
12:47euthanize animals at this point of time.
12:49So idea is what is actually happening.
12:53There is increased energy expenditure
12:55in these in these animals.
12:57So they're expending more energy.
12:59They're eating the same amount of food,
13:01but they're expending more energy.
13:03So we collaborated with Famid
13:05Heider and Daniel Komen here and
13:07and Famid's lab has this fantastic
13:09technique to actually measure
13:11actual temperature in the
13:12brown adipose tissue using a probe which
13:15with with which you can actually measure
13:17the proton relaxation and the proton
13:19leak and and you can actually measure
13:21temperature that way in a very precise way.
13:24And you can see that the there's the brown
13:26adipose tissue in this case is indeed hot.
13:28So I will summarize what we have which is
13:30so this is the transalphuration pathway,
13:32this is what is happening.
13:33So when we get rid of cysteine,
13:35when you deplete cysteine,
13:37what you do is you always have this case,
13:40this loss of cysteine which is
13:42associated with loss of glutathione
13:44and then cysteine and also go into
13:47different pathways that are noted here.
13:49But what happens when you completely
13:51get rid of cysteine in this in in the
13:54animals is activation of this arm which
13:56had previously not been studied in
13:58great detail which leads to formation
14:00of this gamma glutamil peptides.
14:01I don't have time to go into that.
14:03The question you would ask is,
14:04is this dependent on UCP one?
14:05Because UCP one has been thought
14:07to be the Holy Grail of energy
14:10expenditure and the answer is no.
14:12OK, so so we created animals that
14:15lack Cth as well as UCP one,
14:18There's really no response if
14:19you if you don't have UCP one,
14:21the animals brown, they lose weight,
14:22they die.
14:25So how does it actually work?
14:27What happens is that when you deplete
14:29cysteine you get the activation
14:30of sympathetic nervous system,
14:32you get increase in norepinephrine
14:33shown here in the red bar and if
14:36you block norepinephrine receptors
14:37beta 3 adenergic receptor by this
14:41compound L70 four in the blue,
14:43you can protect the animal's
14:44death from the weight loss.
14:46I'll end by just showing you
14:48last pieces of data which is pre
14:50clinical data in animal models
14:51which is fine we're killing animals,
14:54normal animals with by disrupting
14:56this key pathway which.
14:58But the question really is whether
15:00this can be potentially be
15:01harnessed in terms of therapy.
15:03And here are animals that
15:05were fed high fat diet.
15:07These animals are fed high
15:08fat diet for eight weeks.
15:09Then we switched the high fat diet into
15:12high fat diet that only lacks cysteine,
15:15OK.
15:15And they consume same amount of calories.
15:17And what you get is again a dramatic 30%
15:20weight loss within seven days actually.
15:23All right.
15:23And this is associated again
15:26with this massive Browning
15:28of the of the adipose tissue.
15:31So what we ended up discovering in
15:34a way serendipitously through this
15:36study that was initiated in humans
15:39is that the cysteine is actually
15:42critical thermogenic checkpoint.
15:44And if you get rid of cysteine,
15:45the body tries to keep cysteine
15:47because if you get rid of it,
15:48you get this uncontrolled energy expenditure.
15:51So in a normal situation,
15:53you're consuming a cysteine in
15:55your diet and this is required
15:57for your normal energy storage.
15:58You don't really get engagement
16:00of trans sulfuration pathway.
16:02OK, because you're consuming cysteine,
16:03you don't need to make cysteine.
16:05However, if you create an artificial
16:08situation where trans alteration is required,
16:12what you get in this case is this is
16:14the methionine cycle and when the
16:16cysteine levels go down, it triggers.
16:18We don't actually know
16:19exactly how it triggers this.
16:21This loss of cysteine is sensed by
16:23the nervous system in a way that
16:25basically increases sympathetic tone,
16:26it increases Browning,
16:27there is increased proton leak and
16:30heat production in these animals.
16:32It's UCP one independent.
16:34And this is basically,
16:35you know, how it works. So.
16:39So what I've told you is that the
16:41defense of cysteine actually is
16:42absolutely critical and I think
16:44is a thermogenic checkpoint.
16:46And this is the,
16:47as far as I know,
16:48the only study that I know in the
16:49literature where you can actually
16:51kill a mouse by lethal thermogenesis.
16:52OK, so I've shown you that cysteine
16:55starvation causes uncontrolled Browning.
16:57If you get rid of cysteine,
16:58it causes uncontrolled Browning
16:59and the trans alphuration pathway
17:02which is activated in color
17:04illustration is actually a way for
17:06the body to conserve energy.
17:07So obviously the future this is just
17:10you know really emerging work which
17:12we are very interested and excited by
17:14and will time will tell how far this
17:16goes in terms of clinical translation.
17:19All this work was done by Eileen Lee,
17:20a graduate student in the lab.
17:22This project is now being LED
17:24very ably by Lucy Urliegue and
17:25and Abby Lee in the lab and and
17:28of course all my collaborators.
17:30I'm not as organized as Tomas to finish
17:33on time. Sorry.
17:42Thank you. Wonderful questions. Please.
17:50No, it does not affect energy
17:53intake. Yeah. Marcelo,
17:58hello. My question is more general and it's
18:01I was wondering if in the in the
18:04trials with these drugs in general if
18:07there is any evidence that so we know
18:11from that there's more brown adipose
18:13tissue in humans presumably in the
18:16winter here or in cold climates versus
18:20people that live in tropical climates.
18:23So in terms of this thermogenic checkpoint,
18:26if there is any evidence that these drugs
18:29and to visit the drugs work more or
18:32less in the winter versus the summer in
18:35the tropics versus in the cold climate,
18:39if there is any, There's so many people.
18:42So if there's any evidence there,
18:44there's some interaction with
18:46the thermogenic checkpoint.
18:48Yeah, I don't know, Marcelo.
18:49I mean this is a question that you
18:51know folks that study thermogenesis
18:52have been asked several,
18:53several times that you know there
18:54are people living in Scandinavia
18:56in an Arctic and are there is
18:57the less incidence of obesity,
18:59there is some association but association
19:01is not causalities but and most of
19:03those times people are still majority
19:04of the times in thermal neutrality.
19:06You know we still are in
19:08thermal neutral condition.
19:09So they're never though these pathways
19:10are never you know kind of activated.
19:13So it's not really clear hopefully in time,
19:20right
19:22expands quite substantially in the
19:27winter. It tells us that even though
19:29we are regulating our climate,
19:30we are not absolutely determinate
19:33otherwise, you know, yeah,
19:35counter regulation for increasing.
19:37So my point is
19:39to see if the cysteine pathway
19:41is potentially affected in there
19:44in the winter. They are taking
19:46some appetite and all the, yeah
19:52are more effective like the
19:54individual that you were studying.
19:56Yeah, gender question. Yeah, potentially.
20:00Yeah, clinically we haven't seen that yet,
20:02but it's something to consider.
20:04One more quick question shot.
20:10Yeah, the bill will work.
20:11The what is what do you think primary
20:15side of action of positive restriction,
20:18whether when wrong type self or
20:20what type self or the mother? Yeah.
20:23So, so Shawn Yang is asking
20:25how does cysteine work?
20:26Where is it acting?
20:28And the answer is complex.
20:30So we have knocked it out in multiple places,
20:33including liver, adipose tissue.
20:35And if you knock it out in specific cells,
20:38there is no effect because cysteine
20:40is so important for the host that
20:44other organs compensate for it.
20:46As far as brain is concerned,
20:47this is a really a great question.
20:49We don't really know.
20:51We only have preliminary evidence
20:53as at this point of time and I
20:55think we are working with Tomasha's
20:56lab to see and Bernardo here,
20:58who's in I guess in the audience
21:00somewhere to see if cysteine
21:02is being sensed in the brain.
21:03If you get rid of cysteine in the brain,
21:04is that the one that is triggering
21:06the sympathetic nervous system
21:08outflow into the adipose tissue?
21:09But yes,
21:10one thing is very clear that that
21:13the lack of cysteine triggers
21:15the upstream sympathetic activity
21:17that basically then leads to the
21:20thermogenic major thermogenic response.
21:22And most of the thermogenic
21:24response is independent of all
21:26the known current currently known
21:28pathways that people have been
21:30publishing in terms of uncoupling.
21:32None of those are involved.
21:35Great.
21:35OK, With that we're going to go ahead and
21:37move into our break. Thank you so much.