Tamas Horvath, DVM, PhD - Obesity and the Brain: New Research with Semaglutide and Other Nutrient-Stimulated Hormones-Based Pharmacotherapeutics

March 07, 2024

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00:00And next we're going to move to our speaker,
00:04Doctor Tamash Horvath. And Dr.
00:06Horvath is the Jane and David West
00:09Wallace Professor and chair of the
00:11Department of Comparative Medicine.
00:12He's also Professor of Neurosciences and
00:16OBGYN and Reproductive Sciences here at Yale.
00:19He was the founding director of the
00:21Yale Program and Integrative Cell
00:23Signaling and Neurobiology of Metabolism,
00:26which was the predecessor for
00:28the current Yale Center for
00:30Molecular and Systems Metabolism.
00:32He received a doctorate of veterinary
00:35medicine from the Faculty of
00:38Veterinary Sciences in Budapest,
00:39Hungary, and and a PhD degree from
00:42the University of Saged in Hungary.
00:45His research has been focusing on
00:48the body brain communication that
00:50support physiological and pathological
00:52homeostatic conditions as well as
00:55aging and higher brain functions.
00:57And with that,
00:58Doctor Horvath,
01:04thank you, Anya. Thank you,
01:06Nancy, for the introduction.
01:07It's, it's it's a little bit
01:09of a tall task to follow this
01:12really remarkable talk of Anya.
01:14So I I'll give you more of a conceptual
01:17framework and and philosophical take
01:19on this coming from the research
01:21that started at Yale in 1990 and
01:23just going to repeat some of the
01:25slides that probably are redundant.
01:27And that is how obesity and diabetes
01:30have been growing and will be growing
01:32in the in the coming decades unless
01:34these medications really pan out and
01:36then we can end this trajectory.
01:38And of course diabetes is to great
01:42extent supported by increased
01:44body weight to obesity,
01:46which is also increasing
01:48over the last decades.
01:50If you look at the longevity of
01:52individuals with different BMI,
01:53you can see that BMI has some
01:55predictive factor of how long we live.
01:57And obviously all these various
02:00metabolic impairments have impacts on
02:03all tissues we have in our in our body.
02:07And as Anya pointed out,
02:08they have been medications over
02:11the last almost 100 years.
02:13They've been tried and some
02:14of them successfully treated,
02:17obviously including the one in 1933,
02:19which is a mitochondria on coupler.
02:21You really were beautiful losing weight,
02:23but you ended up in the cough
02:24and then you died.
02:25So eventually that had to be
02:27stopped and and we are trying
02:28to go away from from those.
02:30But many of those issues that I
02:32will refer to actually relates
02:34to these conceptual frameworks.
02:36What it is to lose hunger and what
02:38it is to lose hunger and live with
02:41that for a prolonged period of time.
02:44But definitely what happened in the
02:46last few years made a huge splash
02:48in in in every level, every medium.
02:51We do agree with the many of
02:53us agree with the science.
02:55Last issue of science that this was a
02:59breakthrough that occurred in 2023.
03:02So what's for me?
03:04Again,
03:04it's going to be my perspective on this.
03:06What's for me it's remarkable
03:08because these signaling molecules
03:09that that Anya referred to and I
03:11will come back to for a second,
03:13they usually function for a couple
03:14of minutes in our body when we
03:16eat and they do not sustain their
03:18functionality for the problem period
03:19of time that the medication is taken.
03:22And and I will come back to what
03:25how the how our understanding of
03:27the control of feeding and and
03:29obesity evolved in the last 30 years.
03:32But how?
03:32Actually these drugs may not
03:34be coming from an evolution,
03:36but actually coming from a revolution
03:39of quasi serendipitous pharmacology.
03:42And I say that because when Dan
03:43Drucker was here a few weeks ago
03:45who gave a wonderful talk about GRP
03:47one and what came since mid 80s,
03:49when I asked him could you please
03:51tell me how these medications
03:53relate to Physiology, he said none,
03:55not at all,
03:56zero.
03:56This is all pure pharmacology and
03:58I think it's a very important conclusion.
04:00It's a very important thing to consider
04:03because it seems that in this case
04:05and potentially many other diseases
04:07that are undissolved for the moment,
04:09the meticulous way of understanding
04:13the physiological mechanism
04:14may not lead to solutions.
04:16However, such pharmacology as we've
04:18been discussing or we'll be discussing
04:20today may lead to solutions of disease.
04:23And I think it may apply again for many,
04:25many diseases for the future,
04:27including neurological disorders.
04:28So an evolution which was
04:31actually beautiful was insulin.
04:33When insulin was discovered,
04:34that really led to a fundamental change
04:37in how millions of people saved,
04:39millions of people's lives have been
04:41saved and continuously being saved.
04:43So that was a great example of how
04:45there is an evolution of science that
04:47leads to a medical intervention.
04:49I'm going to tell you a little bit about
04:52the evolution of our understanding of
04:54metabolism and obesity regulation from
04:56from the perspective of the brain.
04:59And indeed this is known by most,
05:01that the main reason why we gain weight
05:04is because we eat more and eating is
05:07primarily governed by by the brain and
05:10very specifically physiologically is
05:12governed by by the by the hypothalamus.
05:14And I was lucky enough to be involved
05:16in one of the first studies here in
05:19a year when I came to you in 1990
05:21that described relationship between 2
05:22subsets of neurons in the hypothalamus,
05:24one for using MPY or now we know
05:27AGRP and the other one that was
05:30producing pro opioid metacortin
05:31peptide including beta endorphins.
05:33And in 1992 we suggested that
05:35this interplay between these two
05:37subsets of neurons might be relevant
05:40for the control of hunger.
05:42And in fact with the subsequent
05:44discovery of leptin by Jeff Friedman's
05:47positional cloning of of leptin did
05:50lead to the conclusion that indeed
05:52this hormone that is secreted by the
05:55adipose tissue in the year of your body
05:57mass signals to the hypothalamus to to
06:00these two specific subset of neurons
06:02to control eating to promote satiety.
06:06Few years later,
06:07Matthias Chirp and eventually in
06:09collaboration with Matthias Chirp,
06:11we showed the ghrelin,
06:11A hormone that is sick,
06:13secreting from the gut that is elevated
06:15when you have less fuel available that
06:17comes to the brain that's come to the
06:20hypothalamus and again functions in
06:22the same subset of neurons to control,
06:25in this case hunger.
06:26And the idea was that with these
06:28two subsets of hormones,
06:30ghelin and leptin,
06:31eventually we would be able to control
06:34obesity and find medications to obesity.
06:37This was further supported by the by
06:40the findings and discoveries of three
06:42very talented individuals in Cambridge,
06:45Sadaf, Farooqi,
06:46Jazeo and and Steve O'Reilly,
06:49who identified single mutations in
06:51this pathway of the hypothalamus
06:54that underlie obesity.
06:55Now these are few cases in the maximum,
06:59if you Add all these together may
07:01represent 1010% of of obesity.
07:03But nevertheless they suggested
07:05that genetic underpinning is the
07:07cause of obesity and perhaps finding
07:10the way to interfere with these
07:12pathways would help us deal
07:14with the with this,
07:15with the with the disease.
07:17Just to summarize the circuitry again,
07:19it's a very simple one.
07:20In this case I indicate
07:22you're the peripheral stomach,
07:23you have low energy availability.
07:24You have signals such as ghrelin
07:26coming to the hypothalamus and in this
07:29part of the brain you have these T2
07:31subsets of neurons that HGRP the MP1
07:33neurons when activated they promote
07:35hunger and then you eat they they
07:37get turned off and those neurons
07:39that produce menacordin active are
07:41activated and acting through the
07:43menacordin 4 receptor promote satiety.
07:45So there are interesting aspects of this
07:48these these anatomy and that is that
07:50the the default circuitry promotes hunger.
07:53So this is one of the culprit of of
07:55our our our life and that is our brain.
07:57We always try to make an attempt to
07:59drive us to eat and it's sensible
08:01because if he was the other way around
08:03then you would die soon after birth.
08:05So you have to have the drive drive to eat.
08:08However,
08:09when you live in society such as we do,
08:11and you have easily available
08:13color dense foods,
08:14then obviously this scenario
08:16becomes becomes a burden.
08:19And many,
08:19many things that are associated with
08:22this circuitry indicates that it's
08:23enormously flexible and it will keep on
08:26trying to make you eat more because again,
08:29you don't know.
08:29We we evolved in a way that we don't
08:31know whether we have food tomorrow.
08:33So it's better to put it in today to
08:36make sure that tomorrow we survive.
08:38And perhaps because of this
08:40complicated flexibility of the system,
08:42despite all the advances that we had on
08:44on the circuitry on the physiological
08:47regulation of of of metabolism,
08:49we could not develop really
08:51pharmacological treatments to obesity.
08:53It's a few exceptional MC4 receptor
08:56agonies but but I believe that those
08:58are also not at the at the league of
09:01of of these incretin based approaches.
09:03So it seems at least in this case the
09:07science and medicine may be less connected.
09:10It's a question that that we ask and
09:13then serendipitous sheer luck may
09:15have more to do with the success of
09:18of of development of medical advances.
09:20And I believe and it's again it's my
09:22personal view that to some degree
09:24what we are dealing here with today
09:26on obesity medication,
09:27there is that potential relevance here.
09:31But it's also yes and no because
09:33obviously this system has been there.
09:35So those those peptide family that
09:37includes Glucagon,
09:38GRP one and *** one that Anya talked
09:41about had been known to be playing
09:44a role in systemic metabolism.
09:46*** One for example is a is an important
09:49controller of insulin release and
09:50it's all happening in in the gut.
09:52If you look at the relationship
09:55between *** one and *** One,
09:57they all have their own individual
09:59impacts on various tissues.
10:01And if you look at how they work,
10:02they they promote insulin secretion.
10:05Some of them *** 1 suppresses
10:08Glucagon release,
10:09*** promotes Glucagon and Glucagon
10:11is one of those entities that were
10:14sort of dismissed in this area for
10:16a while as not something that you
10:18want to pursue in order to deal
10:20with the metabolism and to deal
10:22with the with obesity specifically.
10:24And the classical view was then during
10:27hyperglycemia from the artha cells
10:29you have the release of Glucagon and
10:32that promotes gluconalogenesis by
10:34delivery and that's how you sort of
10:37survive in the under those conditions.
10:40However, today we understand little more
10:43about the about the Glucagon system.
10:46So there are important roles of fatty acids,
10:50metabolites, product in endocrine signals,
10:53uterinal signals and the overall
10:55effect of Glucagon.
10:56It goes beyond gluconeogenesis,
10:59It also promotes life policies,
11:01fatty acid oxidation, ketogenesis,
11:04promotes satiety and thermogenesis
11:06and energy expenditure.
11:07So the newest version of these
11:09drugs are actually a combination of
11:12all these three peptide GLP one,
11:14*** one and and and Glucagon mimics.
11:18And this is going to be potentially the
11:20next generation of of of these drugs,
11:23semaglutide still being one of
11:25the most successful one.
11:27And then you have the combination
11:28of Glucagon, *** one, *** one,
11:31*** one and the triple triple agonist.
11:34And it's assumed that it probably will
11:37be the case that you will accomplish
11:39significant weight loss with the
11:41combination of of these drugs.
11:43Now he questions remain and these
11:45are the questions that I'm very
11:46much interested in and my laboratory
11:48is very much interested in.
11:49Many of us in a comparative medicine
11:52department are very much interested in.
11:54So first of all despite of the fact
11:56that this is a very fundamental
11:58successful pharmacology,
11:59we should really understand the mechanism
12:02action and and how long term impact
12:04of Physiology and pathophysiology
12:06are affected by these actions.
12:08And and people are working on these
12:11and and hopefully in the near future
12:13we will understand better what part
12:15of the brain are mainly affected
12:17by these various compounds.
12:19There is indication from many
12:21laboratories that that the brainstem
12:24is a main site of action,
12:25how these drugs accomplish
12:27suppression of appetite.
12:29In the same time we also understand
12:32from from studies that they also
12:34impact many other parts of the brain.
12:36So they also impact the hypothalamus,
12:38the region I was telling you about,
12:40but that's not their main action through
12:43which they accomplish suppression of eating.
12:46But those parts going to be impacted.
12:49In fact one would argue that and the
12:52entire brain is going to be impacted,
12:54not only all parts of the brain
12:55will be impacted.
12:56And and and Anya showed this interesting
12:59combination of various drugs,
13:00most of which have important action
13:02on various neurotransmitters so
13:04that the brain will be massively
13:06impacted by these interventions.
13:07And the question is to what extent
13:10those interventions and operational
13:12brain functions will have impact on
13:14behaviors and also how these brain
13:17regions eventually communicating
13:18downwards to the periphery through
13:20the autonomic nervous system and
13:23the endocrine hypothalamus will
13:24have impact
13:25on on tissue function.
13:27And I'm talking about long term.
13:28So we are talking about here using
13:31these medications not for a day,
13:32not for two days,
13:33but for decades potentially.
13:35And what will be the
13:36outcome of that eventually?
13:37I think these are very important
13:39and very intriguing questions
13:40and I think this is something
13:42that we would like to pursue.
13:43Now one interesting thing that
13:45I believe is also triggering me
13:47specifically to pursue these is if you
13:50look at the profile of these various
13:52scenarios that I show you here,
13:54color restriction which has been
13:56known and promoted to be one of
13:59the main interventions that you
14:00can propagate healthspan and
14:02lifespan incase in analogs and
14:04a situation that we all consider
14:07negative which is cachexia.
14:09So hunger is suppressed by
14:10interacting analogues as well
14:12as during cachexia and hunger is
14:15elevated during calorie restriction.
14:16Now there are many other changes here
14:19that may be similar or dissimilar
14:21between these situations but one
14:23question for me which is very
14:26intriguing is what might be the long
14:28term effect of of interfering with
14:30hunger through these interacting
14:32analogues on on longevity.
14:34And I think it's very intriguing
14:36to ask the question whether color
14:39restriction that of course comes with
14:42the lower food intake and increased appetite.
14:45But is it the decreased food intake
14:47that prolongs your life or it is
14:50the altered metabolic profile of
14:51the individual or the subject
14:53that makes you survive longer?
14:55And I think it would be cool to see
14:57whether actually it's sufficient
14:59to suppress appetite in order for
15:01you to really have a long and and
15:03and and and healthy life.
15:04And this is something we are very
15:06much interested in pursuing.
15:07We are also interested in understanding
15:10how these seemingly counter intuitive
15:12ideas such as the use of Semagrutat
15:15for example in anorexia,
15:16narrowsa setting might actually benefit
15:18certain subpopulation of of of subjects.
15:21And we've been doing that.
15:22We were working on that in
15:24my lab in in animal models.
15:26Overall,
15:26I think and I would like to finish
15:29with that that I believe that Why
15:31Weight is an amazing organization
15:33and it has an intellectual capacity
15:36and that has the ability to push
15:38forward the understanding of
15:40these upcoming challenges of this
15:42remarkable new pharmaco therapeutics.
15:44So obviously both at the pre clinical
15:47and and the clinical arena and I would
15:49like to thank you for your attention.
16:00Perfect on timing too.
16:02So questions for Doctor Horvath, Yes.
16:18So we use a model where where it's
16:21an animal model where we put the
16:23animals in a scenario where they
16:25have access to wheel and we restrict
16:27their food intake and and what you
16:29find is that most of the animals
16:31have an addiction eventually to
16:33the way running and frequently the
16:35cause of death is because of the
16:37exhaustion on on the real running.
16:39And we are interested in understanding
16:41how this addiction to the wheel might
16:43be affected by some of the and how
16:46the various metabolic profiles of
16:47these animals during those things
16:49could be affected or might be
16:50affected which may be beneficial.
16:52And also look at the long term
16:54impact of such an intervention on on
16:57stereotypic behaviors and some long
17:00longer acting negative outcomes.
17:41know you want to answer that
17:42question. How can I say if you can repeat
17:44the question because I realized I did
17:46not say my housekeeping that, yeah.
17:48So the question was how does this
17:51potentially impact, you know,
17:53insulin resistance or glucose metabolism,
17:55whether a patient has insulin resistance
17:57at baseline or potentially they have
17:59obesity and don't have diabetes.
18:00Well, I I
18:05don't have with taking these drugs.
18:09I think Anya you are the
18:10right person to answer.
18:10No, no, no, you are the clinician.
18:13I'm the clinician.
18:14OK, fine, I'm the clinician.
18:16So you know what we see is in
18:18terms of obesity treatment,
18:20what happens with these drugs
18:22is as people lose weight,
18:23the insulin levels actually come down.
18:26So, so the insulin release in terms of,
18:29you know, the to glucose response is
18:32more robust, but as they lose weight,
18:33their insulin levels actually
18:35come down long term.
18:36You know, we don't know.
18:37We have data in, you know,
18:39individuals with type 2 diabetes
18:41who take these medications.
18:42But in in obesity in and of itself,
18:44we don't have 20 years of data yet.
18:46Yeah,
18:50yeah, too much I think great
18:51point about the pharmacology.
18:53And so one of the approaches I think
18:55everybody had been thinking about
18:56was that maybe obesity is whether
18:58the cause of obesity is hyperphagia,
19:00which is only there in a few models
19:02of genetic mutations that have this.
19:05So my question is, you know,
19:07over the period of court, you know,
19:10long usage of these drugs that
19:13inhibit the hedonic pathways,
19:16they are fundamental in many ways for
19:19some multiple species like hunger.
19:21Where do you see these interactions
19:24in Physiology,
19:25in this case pharmacology
19:27impacting individuals.
19:28So I think it's a very good question
19:30and we are interested in these.
19:31The The fact of the matter is that the
19:33actual trial is going on with humans
19:35going to go on for a couple decades.
19:37But I think we can ask these questions
19:40very specifically in in in animal models,
19:42let it be mouse red,
19:43the non human primate.
19:44And I think that can inform to some degree
19:46what's going on in the human human trial.
19:48But I don't think we can really
19:52declaratively conclude that until we
19:53understand more about the human situation.
20:00Yes, John, and we'll try and
20:02repeat the question unless somebody
20:04hands you the mic, OK shout. That
20:06was a great summon to get at the
20:10question following up on this question.
20:12So if it's the hindbrain
20:15part that's driving it,
20:16those centers are associated with the kind
20:20of dangerous signal and put it forward.
20:24So is there interactivating those,
20:27those kind of tumour suppression athletes?
20:30Is there a basically sympathetic notice?
20:35Is there a difference between any?
20:38I have a question about food
20:40restriction would be hungry,
20:41which is the stress.
20:43Is the stress of that different
20:46than the stress of being told that's
20:51I think there's some great
20:52work being done right now and
20:54hopefully soon published that makes the
20:56distinction between in the hind vein,
20:58between those pathways that promote sickness
21:01type of behavior versus pure satiety,
21:04whatever that might mean.
21:05And I think that will answer your
21:07question whether that can be actually
21:09segregated with a pharmacological tool,
21:11that's a different question.
21:12But I think there is a reason to
21:14believe that you have pathways that
21:17are promoting sickness behaviour,
21:18but those are that are not
21:20promoting sickness behaviour and
21:21nevertheless suppress appetite.