Mireille Serlie, MD, PhD - Nourishing the Brain: The Interplay of Nutrients, Obesity, and the Brain’s Dopamine and Serotonin Systems in Humans

March 07, 2024

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00:00I'm going to introduce our next speaker,
00:02So Doctor Murray Cirilli earned
00:04her MD and PhD from the University
00:07of Amsterdam, the Netherlands,
00:09and is an endocrinologist at the
00:12Amsterdam University Medical Center.
00:13In 2019 she became the Professor of Medicine,
00:17Nutrition and Energy Metabolism
00:18at the University of Amsterdam,
00:20and in 2023 she moved to Yale University,
00:24while she was promoted to Professor of
00:26Medicine in the section of Endocrinology.
00:28Her research interests lie in the
00:31metabolic consequences of obesity and
00:32the role of the brain in weight gain.
00:35Doctor Sohaili,
00:45thank you Anya and for
00:47organizing this great initiative.
00:49So I'm going to talk mostly
00:51data in humans and data on
00:55the on the human brain. So,
00:59so the the, the prevalence of of
01:04obesity really parallels the the
01:08increase in availability of food.
01:11So apparently when there's
01:13a lot of food around,
01:14people eat more than they actually need.
01:18So the question really is why do
01:21we eat beyond homeostatic need?
01:24And I think that answer mostly
01:28can be found in the brain.
01:31So to very briefly summarize the food
01:36intake regulation so that you know
01:38you understand more of what we've been
01:41doing with neuroimaging in humans,
01:43I want to just briefly guide you
01:46through this very complex regulation
01:47and this is very simplified.
01:49So there are many signals coming from
01:54the body, including the gut peptides,
01:58GOP, 1G, IPCCK, etcetera,
01:59ghrelin that inform the brain about food
02:02in the stomach and intestines or no food.
02:06But other factors like nutrients,
02:09glucose,
02:10hormones like insulin and leptin
02:12from adipose tissue also inform
02:15different areas in the brain,
02:17as you can see here.
02:18And then all these signals are put
02:20together and then that leads to a
02:23feeding or no feeding response.
02:27To make it even more simple to
02:29be able to study this in humans,
02:32we had to simplify the model even further.
02:35So we defied, and this
02:38is a little artificial,
02:39but the the food intake regulation
02:42systems in a homeostatic part and
02:44a hedonic part or reward part.
02:47Of course there's a lot of overlap
02:50between these areas and there are
02:52many neurotransmitters involved.
02:54One of the major neurotransmitters
02:56in the reward system in the brain is
02:58dopamine and one of the neurotransmitters
03:01in the homeostatic system,
03:03which lies mostly in life settlements
03:06in the brain stem is serotonin.
03:08So for the sake of time I'm just going
03:10to very briefly touch upon our findings
03:13on disturbances in the serotonin
03:14system in the brain in people with obesity.
03:17And this is by please don't read this,
03:19but this is just to show you
03:22how difficult it is to study,
03:24in this case, serotonin,
03:27serotoninergic regulation of
03:28food intake by the brain.
03:30But here you can see we just summarized
03:32all the literature showing all the
03:34brain areas and within the brain areas,
03:37the nuclei that use serotonin for
03:39signalling to modulate food intake.
03:42So you can imagine it's really hard to
03:45study and therefore we need all the the,
03:48the, the animal data.
03:49So this is just to summarize what we've
03:52been seeing in the serotonergic system.
03:54And this is small, but it doesn't matter,
03:56it's just one slide.
03:57So when we looked at postmortem hypothalamic
04:00tissue in people with a healthy
04:02weight and people with ABMI above 25,
04:05we found lower expression
04:07of serotonin transporters.
04:09And to verify that this was
04:12not a just postmortem finding,
04:14we also validate this with a
04:16SPECT scan in vivo where we found
04:19lower hypothalamic serotonin,
04:20serotonin transporter binding
04:22in people with BMI over 30.
04:26We also studied the the the response of
04:29the search energic system during fasting.
04:32So people were either fasting 12
04:34or 24 hours and then we measured
04:38hypothalamic serotonin transporter
04:39availability using the SPECT scan.
04:41And we found that in people with a
04:43healthy weight there was an increase
04:45in serotonin transporters and this was
04:47not the case in people with obesity.
04:49So apparently the fasting response
04:51in terms of certainergic fasting
04:53response in the brain is different in
04:56people with obesity and this might be
04:59related to differences in circulating
05:01factors like free fatty acids and insulin.
05:04And finally we also did a study where
05:06we did an overfeeding study where
05:08we fed people with a healthy weight
05:11snacks in between meals and they
05:14gained like 5 or 6 kilos and they
05:18were totally fit leaned man in this
05:20case and we were able to replicate
05:23the findings in people with obesity.
05:25So we think that overfeeding leads to
05:28a decrease in serotonin transporters
05:30and serotonin signalling and that
05:33might contribute to overeating and
05:36obesity but moving on to to dopamine.
05:44So dopamine is a really the
05:45whole dopamine system is very,
05:47very important in reward learning,
05:50reward processing and hedonic part and
05:54the motivational part of food intake.
05:57So we are able to image dopamine receptor
06:00bind or receptors by using a radio
06:03tracer and in this case we used SPECT.
06:06In the future we're probably
06:08together with nuclear medicine.
06:10We will use PET scan because
06:12it has a better sensitivity.
06:14But in any case,
06:15we found that in people with obesity,
06:17these were all women,
06:19but there were lower dopamine receptor,
06:22there was a lower dopamine receptor binding.
06:24We don't know at this point whether
06:26there was a lower dopamine receptor
06:29expression or more dopamine release.
06:32But in any case,
06:33we found lower dopamine receptor
06:34binding in people with obesity.
06:35So there seems to be something
06:37wrong in the dopamine system.
06:39So we were wondering is this
06:41reversed by weight loss?
06:42So the same women with obesity underwent
06:46beartic surgery and six weeks after
06:48Bretic surgery where they already
06:50were in a negative energy balance
06:52for a couple of weeks or six weeks.
06:55We found no reversibility,
06:57so there was no increase in
07:00dopamine receptor binding.
07:02We then studied them again about a
07:04year and a half or two years after
07:06bretic surgery and there we found that
07:08there was a slight but significant
07:10increase in dopamine receptor binding.
07:11So we think it might be partially reversible.
07:15It was still lower as you can see
07:18here compared to the lean controls,
07:20but BMI was also still higher.
07:22But having said that,
07:24we of course correlated,
07:25We wanted to know what are the
07:27determinants of an increase in dopamine
07:29receptor binding in these women.
07:31And this was not correlated
07:33to the decrease in BMI.
07:36And actually when we put data together
07:40from published trials in humans,
07:43we found that indeed there is no
07:46linear correlation between BMI
07:48and dopamine receptor binding
07:50using patents, SPECT scans.
07:52And it seems to be that there first
07:54is an increase followed by a decrease.
07:57And this is also what we found in
07:58our own studies.
07:59This is still unpublished.
08:03So we were thinking what other
08:05determinants then of lower dopamine
08:07receptor binding and we think part
08:09of it might be explained by eating
08:12patterns and timing of food intake.
08:14And as you know,
08:15a lot of people get a lot of calories,
08:18their daily calories from snacking.
08:23So there was a very elegant study.
08:25As you know, there is a lot of interest
08:27in intermittent fasting and time
08:29restricted eating to lose weight.
08:32And this is a very nice study
08:33where they looked at total energy
08:35expenditure in people that would
08:37eat most of their calories in the
08:39morning or later in the day during a
08:42hypocaloric diet and they found no
08:45difference in total energy expenditure.
08:47But what they did find is that there was,
08:50there were reduced feelings of
08:52hunger in the people that ate most
08:55of their calories in the morning.
08:58And that fits really nicely with a study
09:02that we did earlier in Man with Obesity
09:06that we put on a timed hypocaloric diet.
09:10And So what we did is they got a pretty
09:13strict I have to say hypocaloric
09:15diet and they would eat most of
09:18their most of their calories in the
09:21morning or in the OR in the evening.
09:24And while the calories at lunch
09:25were the same,
09:26So first we looked at so the per study
09:29design they lost the same amount of weight.
09:32And 1st we looked at metabolic
09:34outcomes and it really didn't matter
09:36whether they would eat most of the
09:38calories in the morning or evening
09:40in terms of improvement in insulin
09:42sensitivity in the liver or in muscle.
09:45And also liver fat was was really
09:49decreased in both conditions.
09:50But when we then looked at the
09:52brain there were some differences.
09:54So the man that ate most of the calories
09:58in the morning during weight loss had an
10:02increase an increase dopamine transporters.
10:06Sorry,
10:06a dopamine transporter availability
10:08in the street and using SPECT
10:11scans while the people,
10:13the man in the dinner group that
10:15ate most of the calories at dinner,
10:17they they had a decrease and this
10:20differential response was significant.
10:23So there.
10:23So timing of food intake seems
10:25to affect the dopamine system.
10:28And also,
10:28and this is still unpublished,
10:30when we put them in the in the
10:32MRI and scanned them and showed
10:34them pictures of food,
10:35we found that the man that ate
10:37most of the calories that during
10:39or later during the day at dinner
10:41that they reacted more strongly
10:43to high caloric visual food cues.
10:46And we do know that that reaction
10:48really predicts weight gain,
10:49it predicts the ability to lose weight
10:52and it also predicts food intake.
10:57So timing of food intake matters.
10:59So we were also interested in in
11:03nutrient sensing and so how does the
11:05brain know that there is food around?
11:08Well, that's by tasting and
11:10smelling and seeing food.
11:12But there is also an interaction
11:14between nutrients in the gut or the gut
11:16and the brain and the communication
11:18goes through a vagal efferents,
11:20through gut hormones and serotonin
11:24and of course also circulating
11:27nutrients and hormones.
11:28So we wanted to study,
11:29is there something wrong in this
11:31communication between the gut and
11:33the brain in people with obesity.
11:38So what we did, we infused directly into
11:41the stomach using a nasogastric tube,
11:44either glucose or lipid or
11:47water control over volume.
11:49And it was the same in
11:51in volume and calories,
11:53in people with a healthy weight
11:55and also in people with obesity.
11:57And then we did Mris and SPECT scans,
12:00and the people with obesity then
12:02underwent A hypocaloric diet intervention
12:04and they lost 10% in 12 weeks.
12:08And then we rescanned them.
12:11So this is just to show you this is,
12:13this is the scan after the intragastric
12:17infusion of either lipid or glucose
12:19in people with a healthy weight.
12:20So there were so glucose gave more
12:24like immediate effect to lipid.
12:25It took a while,
12:26but we saw a decrease in many,
12:28many brain regions,
12:30a decrease in brain activity,
12:32and those included striatal
12:35structures and limbic structures.
12:38So you could say this is the physiological
12:41response to food in the stomach.
12:43When we did the same,
12:45this whole brain analysis,
12:47we found no effects whatsoever
12:50measurable in people with obesity.
12:53So somehow the brain doesn't sense that
12:56there's 500 kilocalories in the stomach.
12:59When we then zoomed in on specific regions,
13:01doing a region of interest analysis,
13:03we found that in glucose and lipid condition,
13:05there was a decrease in brain
13:07activity in the nucleus accumbens,
13:09which is the ventral striatum,
13:10which is really really important
13:13for reward and reward learning.
13:15And this this decrease in in activity makes
13:19sense because if there's food in the stomach,
13:21there's no need to go and
13:23search for more food,
13:24there's no need to be
13:25motivated to go and eat food.
13:27But this,
13:28this reaction was not present in people
13:31with obesity and and more importantly
13:33this didn't change after these people
13:37with obesity lost 10% of their body weight.
13:40This was the same in the dorsal stratum.
13:44Then we looked at,
13:45OK,
13:45what are the determinants?
13:46And of course we think it's it's
13:48it's got brain communication,
13:50something we cannot easily measure in
13:53people but we can of course in rotor models.
13:56But we found that GOP one seems to predict
14:00some of the response in the dorsal stratum.
14:03So lipid sensing might need GOP
14:07one signalling.
14:08I'm going to go over this because of time.
14:11We also looked at functional connectivity.
14:14Now functional connectivity really is
14:16looking at brain areas that change in
14:19synchrony and we think if they change
14:21in synchrony that they directly or
14:23indirectly communicate with each other.
14:25So this is more brain network response
14:28to intragastric nutrients and overall
14:30and we're still working on these data.
14:32We found that lipid had most effects
14:35on functional connectivity between
14:36the accumbens and some brain areas.
14:38Areas well glucose had more effect on
14:41functional connectivity between the
14:43dorsal stratum and and other areas.
14:45Interestingly also areas involved
14:48in memory and cognition functional
14:51connectivity in people with obesity
14:52did not show any differences.
14:56We measured dopamine release using
14:58SPECT and while glucose was still
15:01able to elicit dopamine release in
15:03people with obesity, lipid was not.
15:05So there seems to be a reduced dopamine
15:08response upon lipid infusion and this
15:12this really lines up with with animal
15:15data that was published years ago.
15:18So why do we eat beyond homeostatic need?
15:21I think we have shown in humans using
15:24neuroimaging that there are disrupted
15:26dopamine and serotonin systems in the brain,
15:28that there is impaired nutrient
15:30sensing and obesity, which is not
15:32reversible after 10% weight loss.
15:34And this might account also for
15:37regaining weight even after
15:39treatment with GOP one agonists.
15:41So maybe we're not restoring food intake
15:44regulation and the last two minutes,
15:46if I may, it's just that my
15:48interest is also a metabolism.
15:50So we are also interested in how the
15:53brain regulates glucose metabolism
15:55and besides dopamine having a huge
15:58role in food intake regulation,
16:00we also were able to show that that dopamine
16:04is able to modulate insulin sensitivity.
16:07When we increase dopamine in people in this
16:10case they had deep brain stimulation for OCD,
16:14so obsessive compulsive disorder
16:16in an area near the striatum.
16:19And we know that when we turn
16:21the stimulator on there is a,
16:22there is dopamine release.
16:24So we studied these,
16:26these patients with the with the
16:29stimulator on or off and what we found
16:32is that when we turned the DBS on,
16:36there was an improvement
16:38in insulin sensitivity.
16:40We were also thinking,
16:41OK, if it's dopamine,
16:42if we deplete dopamine,
16:43we should see a reduction in
16:45insulin sensitivity.
16:46And that is indeed what we found
16:48in humans when we blocked dopamine
16:50synthesis blocking tyrosine hydroxylase.
16:52We found that not at the hepatic level,
16:55but we found a decrease
16:57in insulin sensitivity,
16:58showing that dopamine in the
17:01brain also regulates insulin
17:03sensitivity in the body in humans.
17:07So I think that beyond gut peptides,
17:12the striatal dopamine system in the
17:15brain really is a target for future
17:18new medication reducing food intake
17:21and improving metabolic health.
17:23And I think working on and
17:25understanding why nutrient sensing
17:27is so disturbed and whether we can
17:29restore that in the long term with the
17:31new medication is really essential.
17:33So I want to thank all these
17:36people and yourself.
17:44Thank you for that.
17:46We have time maybe for one or two
17:49very quick questions. Yes, Diana.
17:53Oh, there you go.
17:54Never mind. Do you want to just say it?
17:56I'll repeat it, I'll repeat it. For the
17:59current response in the nutrient setting,
18:01the dopamine system, would you
18:04advocate for something like a ketogenic
18:06diet or a little carbohydrate diet
18:10to kind of
18:11maintain or reset the system?
18:13Well, that's an interesting thought.
18:15We don't know.
18:16We we do know that fatty acids modulate
18:18the response in the serotonin them
18:21in people with a healthy weight.
18:24So that whether I think that the the
18:28the ketones and fatty acids that
18:30enter the brain that's more you know
18:33that that's a different route than
18:35the vagal afferens in the in the gut.
18:38Whether caloric restriction or intermittent
18:40fasting to increase ketones and and
18:43fatty acids will improve food intake,
18:46we don't know.
18:47But but in in animal models with
18:50you know prolonged intermittent
18:53fasting where where animals or would
18:55only eat for a few hours a day,
18:58they do see all kinds of improvements
19:00in in body weight and in in
19:03memory function etcetera.
19:04So who knows?
19:05Yeah,
19:07yes. One more quick question.
19:29Well, that's a really difficult
19:32question because mental health in
19:35people with obesity of course has many.
19:39You know the the, the etiology of
19:41that is very complex and I don't know
19:45whether in humans we can distangle
19:48these these different factors.
19:50Given the effects of obesity
19:52on the serotonin system,
19:53I can imagine that that might make
19:57them more prone to to depression,
20:00but I'm not sure. Yeah, great.
20:04Thank you very much. And we are going to
20:06move into our second networking break.