Good afternoon everyone. As part of our Emery
Pharma seminar uh speaker series I'm honored to present to you an accomplished speaker whose
work really has had a significant mark on our comprehension of nutrition and well-being and sort
of the intricate connections that bind them. Today it's my privilege to introduce Dr Robert Lustig
to our Emery Pharma speaker series. Many of us are very familiar with some of Dr. Lustig's work,
particularly on The Perils of excessive sugar consumption and its implications for health. His
viral lecture, sugar the bitter truth has actually gained millions of views I've seen that myself
and sparked worldwide discourse on the detrimental impacts of sugar particularly on human health
as an accomplished author Dr Lustig has also penned several influential books including fat
chance, beating the odds against sugar processed food obesity and disease uh it's actually a book
that my wife's company actually has for all of their Physicians but really delves into again the
scientific inquiries behind or intricacies excuse me behind the Obesity epidemic, but beyond these
scholarly and you know advocacy Pursuits Dr Lustig holds the position of a Emeritus Professor for
the division of Endocrinology, the department of pediatrics at UCSF University of California San
Francisco um and today he's going to delve into some of the connections that intertwine food
metabolism and psychiatric disease. So please join me in welcoming a a warm welcome, Emery
Pharma welcome for Dr Lustig. Thank you Ryan, thank you Ron, thank you Ana, thank you all, you
know again I'm kind of like part of the extended family so I've talked to you about metabolism and
systemic health Health in the past and today we're going to talk about metabolism and brain health
mental health and what the connection and what the role of food is in metabolic health of the brain
and I will make the argument during the course of the hour that in fact mental health is metabolic
health of the brain okay that the two are actually indistinguishable and the same processes that are
going on perect Al to cause disease are going on centrally to cause disease and the treatments
guess what are the same real food we're gonna we're going to go there and you'll see why okay
so again I always have to start with disclosures okay so I did write these books for the general
public and metabolical has a lot of what I'm talking about today uh I'm chief medical officer
for these four companies and I'm a paid advisor to the these other and uh I'm specifically I'm an
adviser to the UC Davis Innovation Institute for food and health who's looking at all of these very
specifically okay and I'm also the chief science officer of a nonprofit here in the Bay Area called
eat re uh whose mission is to get real food into kada2 nationally okay all right starts here starts
with 1920 okay when physicians at John's Hopkins University realized that patients who were in
diabetic keto acidosis who also had concominant seizure disorders stopped seizing when they were
in keto acidosis okay and so people said well why is that and so they started experimenting with
the ketogenic diet and they found lo and behold getting people to be ketogenic that is is lowering
their insulin and inducing fat mobilization and oxidation via ketones because ketones are the
breakdown products of fat led to a cessation in seizure frequency and seizure severity in these
patients and so then people started experimenting with ketogenic diets in other things and then of
course we had the Atkins diet and then of course you know moving on and now of course everybody
is just flagrantly keto all over the world for all sorts of reasons including our colleague
here Mark who has lost 30 pounds and had his alt go from 80 down to 24 right do I get it right
yeah okay so this is a good thing and the question is you know do you have to be that extreme and
is does it work for everybody and why does it work in the first place so that's that's where
we're going so it's possible that the ketogenic diet could prevent seizures through metabolic
effects that are direct at the brain or it could be through gut microbiota effects because it
changes the microbiome the ketogenic diet changes the microbiome because it provides different
nutrients than were there before so you expect different bacteria to glom onto that differently
and so there's the possibility of changing your amino acid profile therefore changing what might
be excitatory at the level of the CNS all of these things could potentially lead to changes in
seizure susceptibility well then people said well could the ketogenic diet help with other types
of brain problems aside from seizures now my colleague and now good friend Christopher pmer
at Harvard Medical School was the first person to recognize this possibility he was presented
with a guy who had severe manic depression who had tried everything that was refractory to
all medical therapy he also happened to be 300 lb and the guy wanted both help for his bi
bipolar and also help for his weight and Palmer didn't know what to tell him but he said you
I've heard about this ketogenic diet you know maybe that'll help your weight and turn turned out
not only did it help his weight but his bipolar resolved and since then he's gone on to treat
numerous patients and have developed K series and now is doing clinical trials with you know
uh randomized control trials to determine whether or not the ketogenic diet will actually fix
manic depression schizophrenia and multiple other CNS brain SL mental health problems and
in fact now there's actually a literature on the ketogenic diet in Psychiatry now this talk is
not about the ketogenic diet this talk is about food okay in general and how it might impact
but it gives us a a a window into this issue and this problem and the reason is because the
ketones don't need insulin to work they don't need insulin to enter cells and they don't need
insulin to stimulate energy uptake they just get in there's no transporter for ketones they
just get in so if you've got lots of ketones in your blood they're going to get to your brain
okay and don't need any help there's no key un loock here they just go and so that might be a
reason why it might be better but it also might be because the insulin went down and that might
be better we don't know yet so the question that Christopher asked is could food or even fasting
be a psychopharmacologic therapy and that's where we're going today now many investigators many
clinicians many scientists many pundits have postulated a relationship between metabolic and
mental health and that they might actually be the same and here are a bunch of different books we've
talked about some of them today at lunchtime so David pearlmutter wrote brain maker uh Fel Jacka
down in Australia wrote brain changer a lot of brains here okay uh my colleague Bill Wilson in L
Massachusetts wrote brain drain and then em Meyer who's at UCLA and does microbiome uh work uh
wrote The Mind gut connection and you know and Christopher Palmer's new book Brain energy which
uh is actually perhaps the best of the bunch and this hasn't escaped um shall we say the cognic
you know in academic medicine because this is from Lancet okay and here's this is a very
important quote the emerging and compelling evidence for nutrition as a crucial factor in
the high prevalence and incidence of mental disorders suggests that diet is as important as
Psychiatry as it is to Cardiology endocrinology and gastron neurology I couldn't agree more
and it's nice that somebody at Lancet figured that out because i' be honest with you they
haven't figured out much of anything else so food what can you do to food to either make
it good or bad okay Real Food Works but clearly we're not eating real food 73% of the items in
the grocery store are not real food they are ultr processed food and is that Ultra processed
food actually impacting our brains in a negative fashion that's the question so what are they
doing to food well you can add something you can add vitamins and Omega-3s you can subtract
something like artificial colors or allergens these are all out of you know ultr processed
food to make the food better you could change the macronutrient composition or the timing so
you could go vegan you could do Tim restricted eating you know or intermittent fasting you
could alter the microbiome which I think is a great way to do this and the easiest way to do
that is not with a probiotic but rather with a Prebiotic because a Prebiotic will allow the right
bacteria to grow a probiotic won't that's why you have to keep taking a probiotic because after all
if a probiotic worked you'd only have to take it once it's a live culture why doesn't it just set
up shop the first time the reason is because the internal mil of the intestine is so inhospitable
that's why those bacteria are not there in the first place that's how they got killed off that's
why you need the probiotic except that you haven't fixed the mil so like why would you expect it to
work because it won't take so fix that first and that's called fiber okay and then of course all
the above and you can do that with a ketogenic diet now why would these work why could these food
manipulations have beneficial effects in terms of psychopharmacology CNS is central nervous system
it could alter CNS energy metabolism that is making the mitochondria work better to make more
ATP it could alter CNS neurotransmission we're going to talk about the glutamate Gaba cycle in a
minute it could alter trophic factors in the CNS like for instance leptin and bdnf brain derived
neurotrophic factor which cause neuronal outgrowth and in some cases neurogenesis it could alter CNS
exposures like toxins and infections one of the big ones is strep and I think you all know this
because all you have to do is go back to 1791 when syum demonstrated that a strep infection caused
severe choreoathetosis called cims Korea due to rheumatic fever okay like why would a bacteria
cause a change in your central nervous system well you know we've known that for a long time and of
course all the above and the ketogenic diet does all those okay so the ketogenic diet again it's
our window into the problem it's not the only issue but it's a window okay could potentially
have lots of different effects it could change energy consumption because the mitochondria don't
need insulin and it gets in so it's you know if if you have a you know Ketone level in your blood
it will make it into the brain and potentially you can have more efficient ATP production okay
or it could change neurotransmitters over here so it could change the Gaba to glutamate balance
you know a lot of people forget that glutamate is the precursor to Gaba okay and so there's a
glutamate to Gaba cycle and that is under the control of different enzymes that are manipulable
and glutamate is excitatory and Gaba is inhibitory and so if you have a problem converting one to
the other guess what you might go freaking crazy and in indeed people do okay gurg transmission
changing glutamate transport Ang which could lead to angiolytic effects Etc okay everybody
got it in addition maybe more cholesterol and cholesterol can be converted to pregnanolone which
can then be converted to Alo pregnanolone an Alo pregnanolone binds to the progestin receptor and
can cause reduction in CNS output so it's a smile sedative okay and maybe even improve immune
function too all of these plus there are fats that matter in this story so there are Omega-3s
like EPA and DHA ioso pentenoic acids and DOA hexenoic acid the EPA DH a and you get these from
where you get these from wild fish not farmed fish okay and these are necessary for normal neuronal
membranes and normal neural transmission and I will show you in a minute that these are very
important in terms of uh emotional well-being and mental health on the other side you have omega
sixes and Omega sixes all come from this guy over here linolic acid which is in seed oils and this
is pro-inflammatory because it is the precursor to arachadonic acid and arachadonic acid is
the precursor to prostaglandins thromboxanes and lucrin all pro-inflammatory so we know that
inflammation of the brain leads to mental health disorders and so keeping that inflammation
down is necessary so you need a Omega 6 to omega3 ratio that basically allows for normal
neural connectivity and transmission and doesn't allow for inflammation well that Omega 6 to
Omega-3 ratio optimally should be about 1: one maybe even up to 3:1 4:1 our current Omega
6 to Omega-3 ratio is 20:1 and the question is does that have detrimental effects well we
know that poor psychiatric health is linked to persistently low Omega-3s in fact significant
depression and schizophrenia too all with low Omega-3s now is that an epif phenomenon is that
a primary phenomenon is it correlation is it causation obviously you can't tell from this kind
of study the only way to know that is by doing the clinical trials and seeing whether you can do
that I'm going to show you some so this leaves us to the question of what is is going on in the
brain what makes a difference is it the ketones is it the type of fat is it the elimination
of carbohydrate or all the above and is very specifically because it's my interest what is
Sugar's role in this and is the reason that any of this works just because you're getting rid of
sugar which is possible I'll show you why so we know that if you do any of these things you will
improve insulin sensitivity well that will lower the amount of insulin at the level of the neuron
which is good because insulin makes the neuron do other things other than what you want it to do
okay actually basically drives energy metabolism in the wrong direction because you're in storage
mode not burning mode and your brain wants to be in burning mode not storage mode and it turns out
beta hydroxy butyrate which is the primary Ketone it's not the only one AC acetoacetate is another
one but beta hydroxy butter is the primary one from fat metabolism turns out it's a signaling
molecule it stimulates the cell to make cerin in particular S 2 and two which is a primary
driver of mitochondrial biogenesis so you're making more mitochondria which is good okay so
is it the Improvement in instant sensitivity or is it the reduction in Sugar consumption itself
we don't know because no one's ever tested just sugar reduction against carbohydrate reduction
to find that out out so these are still open questions and every time I go to a talk or a
symposium about metabolic Psychiatry this is the question I ask and no one can answer it yet
okay and I'm going to be the biggest gadfly in the world asking which of these or both is is the
important issue in why this matters don't know yet is it the carb reduction or the sugar reduction
that matters and through what mechanism I care I think you all care too okay so when we talk about
sugar reduction what are we talking about well we're talking about two molecules right dietary
sugar I.E sucrose is two molecules one glucose one fructose bound together with an glycidic linkage
linking the two high fructose corn syrup is one glucose one fructose not bound together okay now
the enzyme in your intestine SU C Cleaves this Oly AIC linkage in a nanc you absorb both molecules
separately and they do their own thing glucose is the energy of Life fructose is consumable poison
it's that simple well if you consume high fructose corn syrup you're getting the same thing so this
whole concept of sucrose versus high fructose corn syrup is you know just a tempest in a teapot it
is just garbage okay they're both equally bad okay but of course the sugar industry thinks will
tell you it's the high fructose corn syrup and the high fructose corn syrup industry will tell you
it's the sugar and you know because they're all competing for market share all right now what is
going on in the brain well you got to measure so if you inject glucose or fructose or both into
somebody's vein and then do magnetic resonance spectroscopy of their brain here's what the
glucose reference looks like here's what the fructose reference looks like here's what the
combination looks like it's basically those two put together and this is a human being okay
who's just eating and you see they're both there okay they're both there and the reason is because
the human brain turns glucose into fructose this is work from Rick Johnson at the University of
Colorado and you can actually measure this as well so this is pregnant women pregnant women here's
the CSF to plasma ratio for glucose that makes sense because the CSF glucose level is always
half of what the blood level is that's normal here's for fructose okay why is there fructose in
the brain and why is there more because the brain converts glucose to fructose now why that's
a complicated story and Rick would tell that story much better but there's actually adaptive
advantages to that and of course Sorbitol is the way you get from glucose to fructose this is the
polyol pathway so basically Aldos reductase makes sorbitol and then it goes to um uh fructose and
fructose has its own potential effects all right so there's fructose in your brain whether
you like it or not whether you ate it or not all right it's just a question of how much
and what's it doing well what's it doing it's changing your mitochondrial metabolism is what
it's doing all right so impaired mitochondrial function and psychiatric disorders so this is not
like my you know you know imagination it's not my you know craziness you know other people have
been looking at this and so here's mitochondrial function right here in the center and you can
see there are a whole lot of things affecting that okay there's bcl2 which is a anag gene that
causes cell division mitochondrial DNA mutations glucocorticoid receptor translocation changes
in calcium influx okay that all Impact uh oh and most importantly reactive oxygen species
we're going to come back to that in a minute okay all impacting on mitochondrial function
in fact we have a paper that we've got uh uh sent out uh for review right now on the role of
active oxygen species in the toxic effects of food okay and why it drives obesity not why it drives
psychiatric disease but it's the same thing okay and when your mitochondria don't work right you're
going to have problems with synaptic plasticity neurite outgrowth ATP production apotosis calcium
homostasis okay are which are all going to have behavioral effects now remember the ketones get
get into the brain without insulin right so here's the liver making ketones beta hydroxy butyrate
right here entering the brain right here okay and basically going to both the asite and the neuron
the beta hydroxy berate ends up going from the asite feeding the neuron and you end up into the
kreb cycle so that you can burn it but you don't need insulin to do that whereas every other cell
you know if it's glucose you do need insulin to do that right so that's one of the reasons why
the ketogenic diet might work is because you don't need insulin so ketones can substitute as a
CNS energy source even when the mitochondria are dysfunctional even when they're not working right
they will work better on ketones than they will on glucose because getting from glucose to AAL COA is
its own process which can be affected negatively whereas ketones bypass that and go straight to the
CB cycle okay and you'll get less oxidative stress less reactive oxygen species when you're burning
ketones over when you're burning glucose and it's been shown that the ketogenic diet can improve
cognitive parameters in Alzheimer's disease maybe every patient with Alzheimer's should be
on a ketogenic diet well Dale breson who wrote the end of Alzheimer's thinks that that's true
okay now hasn't been tested in a formal fashion needs to be okay but in his case series which he
has just published that's one of the things that allowed for survival of Alzheimer's was going on
a ketogenic diet now why is this a problem I mean what's going on to alter the mitochondria well
that's in this slide here and I think I've shown this slide at you at Emery Pharma before I love
this slide it's one of my favorite slides okay here's glucose here's fructose they are not the
same okay the food industry will tell you calories a calories sugars a sugar garbage total complete
trash okay they say that on purpose because that's how they assuage their culpability for putting
all the fructose in the food in the first place they are not the same and this slide shows that
they're not the same glucose actually stimulates mitochondrial function so you'll notice beta
oxidation up arrow in green hooray that's good glucose increases mitochondrial function how
does it do it activates two enzymes right here activates am kinas adenosine monophosphate kinas
this is the fuel gauge on the liver cell when your cell uses up ATP it makes am right because the
phosphate bonds get broken and that's where the uh energy is is in those phosphate bonds that's
what the electron transfer support chain in your mitochondria do is they basically release the uh
uh energy and you turn n into nadh and then go back and forth Etc you know that's that the whole
oxida phosphorilation that powers cells everybody familiar with the concept right okay well amp kyes
okay if you have more amp it fits into the active site and what that does is that tells the cell not
enough energy we're energy depleted because I'm in I've got instead of ATP and so we need to make
more mitochondria so it increases mitochondrial biogenesis which is good for burning more energy
in addition it increases this enzyme here called HH hydroxy Asal COA dehydrogenase which is also
involved in increasing the rate at which two carbon fragments get converted into energy thus
beta oxidation go going up so glucose for lack of a better word is good fructose on the other
hand is another story fructose does the opposite fructose inhibits three enzymes that are necessary
for normal mitochondrial function it inhibits ayase it inhibits this one down here called aad L
ailoa dehydrogenase long chain which is necessary to cut up those two carbon fragments and it also
through uric acid inhibits this over here cpt1a carnitine pido transferase 1A this is the enzyme
that regenerates carnitine and carnitine is the shuttle mechanism by which the fatty acids get
from the outside into the mitochondria for burning in the first place the sum total of which is that
beta oxidation goes down glucose beta oxidation goes up fructose beta oxidation goes down they
are not the same clearly Ron Khan CEO of Joslin who was the senior author on this paper famously
said about this paper the most important takeaway of this study is that high fructose in the diet
is bad it's not bad because it's more calories but because it has effects on liver metabolism to
make it worse at burning fat as a result adding fructose to the diet makes the liver store more
fat and this is bad for the liver and bad for whole body metabolism and that's just the molecule
itself never mind what it did to the insulin right well that's one problem there's another
problem okay and it's on this slide and I've shown this slide here as well you're all familiar
with this concept now here are five pictures of food they all share one thing in common what
is it they're all delicious brown brown yes but they're all brown they are delicious and the
reason they're delicious is because they're brown okay that's the caramelization or the uh Browning
or the myard reaction the myard reaction this is of course what causes hemoglobin A1c okay so the
way to think about this is you can roast your meat at 375 degrees for an hour or you can roast
your meat at 98.6 de for 75 years the answer is the same your Browning and if you don't believe
me here's newborn rib cartilage nice and white and here's 88-year-old rib cartilage is nice and
brown okay you are Browning as we speak and if you had orange juice this morning you are Browning
seven times faster and that Browning reaction is the Aging reaction it is what causes wrinkles
it is what causes cataracts it might even be what causes Alzheimer's disease might how does it work
well as you know glucose has a ring form and a linear form this is the linear form when glucose
is in the linear form it has an alahh at one end at position one and that alahi will bind to an
Epsilon amino group of Lysine at position one of the hemoglobin molecule forming a shift base
which will spontaneously decomposed to this Cove valent linkage which then has to be cleared by
the spleen and that takes three months and that's why measuring your hemoglobin A1c basically
tells you about your glucose burden over the previous 3 months that that's why diabetics can
use it to monitor their efficacy okay everybody with me so far okay well not only does it occur
in glucose and every by the way every time that reaction occurs it releases a little reactive
oxygen species a little oxidative stress which has to be quenched by an antioxidant or it will do
damage it will cause lipid peroxidation or protein denaturation ultimately causing cell dysfunction
ultimately cell death ultimately organ death and ultimately human death okay just does it over
a long period of time like one cigarette won't kill you okay 100 cigarettes in one day won't kill
you but you know what 10 cigarettes over 20 years will most definitely kill you okay takes a while
but nonetheless it's still toxic even if it's not an acute toxin it's a chronic toxin same idea here
okay this is a buildup slowly of damage and turns out that glucose will do it and you can't stop
it it will happen if you're alive it's going on but you can slow it down and fructose does it
too and it does it seven times faster and you can actually measure this in not just the body but
in the food because when you heat Ultra processed food the fructose in the food binds to the Epsilon
amino group groups of Lysine in the food to create Advanced glycation end products in the food itself
and there's a receptor for the advanced glycation end products called rage receptor for advanced
glycation end products and when you stimulate that Rage with an advanced glycation end product
you generate reactive oxygen species all by itself so eating food that has been uh that has add
sugar in it and bound is also problematic okay and it correlates with cardiovascular disease in
patients with obesity now why does this happen and why is fructose particularly egregious for having
this happen that's here and this is our paper from uh our kids study okay this is the important term
right here delate now you've h a lactate lactate is what your muscles make right when you exercise
right lactic acid that's L lactate this is delate the isomer right the epimer okay Del lactate only
has one source and it's not exercise I will show you so there are a lot of different things
that affect that amp kinas right it is the master regulator of all of these Pathways and
it promotes all these good things and it also inhibits all of these bad things so turning on
your kyes is a good thing that's why metformin is now being utilized for type two diabetics and
possibly even as a longevity promoting agent near barsel is you know running this metformin trial
out of Albert Einstein to see whether or not metformin can promote longevity by increasing amp
kyes by increasing mitochondrial function okay so there's a a a a a theme here if you will okay so
MP kindness is pretty important and I agree it is so let's look at amp kyes a little closer three
subunits Alpha Beta gamma that gamma subunit is the B where the active site is that's where the
fits in to the pocket okay and that pocket over here okay has three arginines three arginines
three places where something could bind and form that myard reaction Well turns out a compound
that is made from an intermediary metabolite of fructose called methylglyoxal methylglyoxal it
is the breakdown product of dihydroxy acetone phosphate okay can fit in that active site and
it is an alahh and what happens when an alahh and an amino group find each other right so here's
the myard reaction if if if glucose is uh if the rate of the glucose at the myard reaction is one
fructose is at seven methy glaxal is at 250 so meth oxil is a bad guy okay because it is binding
to proteins whether you like it or not okay and it fits in the active site so it fits in that AR you
know finds one of those arginines in that active site so the methylglyoxal gets made from dihydroxy
aone phosphate from fructose fits inside there and then you turn off your kyes irreversibly you have
basically killed your amp kyes so your MP kindness goes down what does that mean for mitochondrial
biogenesis means it's in the sewer means you have decreased your mitochondrial function and if you
decrease your mitochondrial function what does that mean for your cell means your cell starving
and is that going to have any behavioral effects if it's in your brain you bet it will everybody
got the idea okay now methylglyoxal has a way of being Det toxified to deact remember I told you
deact was important this is the source of deact is methylglyoxal detoxification by an enzyme called
glyoxalase one glyoxalase one is in all your cells but different people have different levels of
the glyoxalase one it's genetically determined so some people will be able to get rid of their
MGO and some people won't so we measured deact in our obese patients and guess what it's 52% higher
okay and in our kids study where we got rid of the fructose and substituted glucose deact went down
by 38% in 10 days so the fructose gets converted to MGO the MGO basically takes the am kyes out and
so now you've got denova lipogenesis glucogenesis cholesterol synthesis all bad and all the good
things are all inhibited because amp kyes has gone down the tubes not good all because of fructose
and methylglyoxal okay so that's how mitochondria might be affected so far so good we got three more
to go loads of fun now we'll do neurotransmitters remember I told you glutamate to Gaba the link
is the intermediate glutamine glutamate goes to glutamine glutamine goes to Gaba but it's a
little more complicated than that because there are different cells and there are different
stoppage points on the way my colleague and good friend Monica Duce at University of Michigan
studies all this in fruit flies and showed that if you take fruit flies from a controlled diet and
put them on a sucrose diet it changes their entire brain structure entire brain structure just
because you added sugar to their diet okay my colleague Bill Wilson who wrote that book Brain uh
uh drain okay he is a clinician he looks he does pattern recognition and he's taken care of like
6,000 obese patients and he stuck them all in DEA scanners so he could actually measure their body
composition and he also gave them questioning and he found 22 specific symptoms that correlated with
metabolic dysfunction and here they are read them they're all behavioral they're all behavioral
okay they're all really common maybe you have them okay and he calls this because when he puts
people on low carb diets they all get better so he calls this carbohydrate Associated reversible
brain or carb syndrome and he actually runs a Blog called carb syndrome. org which you can
you know access for free okay so I've looked at this question and in my book hacking of the
American mind suggested this model so here are the five things in the last 50 years that have
changed in our society technology process food sugar sleep deprivation drugs each of these has
been shown to increase dopamine increase reward but dopamine downregulates its own receptor
so the more dopamine the less fewer receptors therefore you need you get need more and more to
get less and less this is called tolerance okay because ligans downregulate their own receptor
now that makes you feel lousy because you can't get the reward signal like you should then throw
some stress on because the cortisol inactivates the pre frontal cortex and the two of those
together lead to addiction conversely these five also are all associated with the development
of metabolic syndrome a metabolic syndrome causes a change in the liver so that tryptophane instead
of being converted to serotonin gets converted to cyanine which is a different metabolic pathway
so you're basically depleting serotonin because you're basically fishing it out of the blood and
turning it into this non-helpful curine which actually promotes inflammation so your serotonin
goes down that makes you dymic makes you feel you know lower emotional well-being then throw some
stress on which of course cortisol decreases the serotonin 1 a receptor now you have few lians
less receptors now you got clinical depression so addiction and depression are two sides of the
same coin driven by the same toxic environmental stimuli it's just a question of Who's Who as to
which one you get maybe get both now why does this happen remember I talked about glutamate to
glutamine right well here's glutamate so glutamate becomes glutamine glutamine then and goes from
the asite to the neuron gets converted to glut back to glutamate and then goes to Gaba all right
so it's a complex Dynamic it's a complex cycle but as you can see glutamate ends up as Gaba this is a
better picture of what's going on anatomically so here's the glutamatergic neuron making glutamate
it enters the asite where this enzyme here called glutamine synthase GS will turn that glutamate
into glutamine right here then that glutamine will exit enter the gabaergic neuron and the glutamine
will get converted back to glutamate by glutamate dehydr uh glutamine dehyd glutamate dehydrogenate
sorry and then GL glutamic acid decarboxylase will turn it into Gaba so the glutamate ends up here
via glutamine and then that glutamate becomes Gaba everybody see how that works so this enzyme
here matters turns out that enzyme is inhibitable by fructose so if you incubate rack cortical
synaptosomes with glucose or with fructose you get different answers you get completely
different metabolites so look at the glutamate to Gaba ratio when you incubate with glucose
basically 3: one okay do it with fructose 50 to1 lots of glutamate very little Gap
but because you've inhibited glutamine synthes and this is true in immune cells and
therefore likely true in CNS cells because immune cells and CNS cells are very similar and you can
see here we're giving glucose or we're giving glucose and fructose sucrose glucose or sucrose
okay the difference is sucrose has fructose and glucose doesn't right and we're looking at cyto
and we're looking at so tnf Alpha we're looking at il1 beta we're looking at IL 6 okay and
you can see that in each case the fructose made those cyto much higher right and that can
be inhibited by a protein synthesis inhibitor Romy in other words this is a protein issue and
fructose is inhibiting that okay and when you put glucose into immune cells you get lactate
and lactate is okay here this is L lactate when you put fructose in it basically inhibits the
ability uh uh to metabolize it because it won't let the glutamine get turned into Gaba okay and
you end up with increased oxygen radicals so you increase your oxidative stress in immune cells
same thing happens in neurons okay number three trophic factors insulin leptin and bdnf so Ultra
processed food increased psychological distress as an indicator of depression this came out one
week ago from a Melbourne study big Melbourne study okay now this is correlation not causation
this is also correlation ultr processed food increased risk for depression why well insulin
resistance is a driver of depression and it's a driver of depression through inhibition of brain
derived neurotrophic Factor here and also glycemic disregulation here all leading to depression now
what do we know about these trophic factors leptin is a trophic Factor leptin causes new neurons
to form and causes neuron outgrowth leptin is a trophic Factor insulin inhibits leptin insulin
blocks leptin signaling we know that leptin causes neurons to branch and connect we know that
leptin regulates neural and gal protein levels we know that leptin corrects cognitive defects who
have in patients who have leptin deficiency so leptin is important it's a trophic factor and
you can actually see under the microscope the uh increase in neurite outgrowth and increase
in synaptogenesis in response to leptin we know that Sugar causes insulin resistance we know that
insulin resistance causes leptin resistance the hyperinsulinemia blocks the leptin signaling this
is part my work actually and we see it in humans as well again correlation not causation it's hard
to do causation in humans because that means you would have to take somebody's brain out okay and
they don't let you do that not too often anyway okay but this is a a correlation study out of the
white hole study in the UK sugar intake from sweet food and beverages common mental disorders and
depression perspective findings now we showed in our kids study that um uh fructose makes lots of
triglyceride makes lots of vldl when we take the fructose out of the diet and substitute glucose
nine days of isocaloric fructose restriction liver fat went down 22% turning sugar into
fat went down 46% vldl triglyceride went down 49% visceral fat went down 7% all good and most
importantly the pancreas started making insulin properly again in other words we reverse the
patient's metabolic syndrome with no change in calories no change in weight just by getting
rid of the toxin the fructose possibly through methylglyoxal possibly all on its own this has
been independently confirmed by another study done out of UC San Diego and Emory okay showing that
the control group no effect on liver fat and the treatment group where you took the sugar out Mega
reduction okay now bdnf turns out to be The Driver of improved mental functioning due to exercise
due to exercise okay so bdnf increases well sorry exercise increases bdnf increases hipocampal
volume increases memory function aging reduces bdnf lack of Serotonin reduces bdnf I already
showed you lack of Serotonin is part of metabolic syndrome okay and that's reducing hippocampal
volume which is also leading to cognitive decline how about addiction so could one ingredient lead
to Addiction in food and the answer is well yeah I mean we already know about alcohol okay but turns
out sugar and alcohol metabolize the same way and Sugar's addictive you know National Geographic
said why we can't resist it in fact that's right and I can prove it I can't prove it anybody know
what this is anybody ever been in a normal newborn Nursery at a hospital this is called sweeties
sweedies this is a 24% super concentrated sucrose solution that you dip the p pacifier in and stick
in the normal newborn boy's mouth before the circumcision the Jews have wine everyone else has
sweeties because they do the same thing okay so I can prove it right so what's going on in the brain
well what makes a milkshake rewarding is it the fat or is it the sugar turns out it's not the fat
it's the sugar how do we know because Eric sty at Oregon Health Sciences University constructed this
great Contraption all out of plastic okay with two bottles one with fat one with sugar and when you
suck okay you get different amounts depending on a regulator that he controls as to how much fat and
how much sugar makes your milkshake okay so you can have a high sugar lowfat milkshake or a high
fat low sugar milkshake okay and he stuck people in an MRI scanner while they were sucking on the
milk shake to determine what was happening to the reward center and it turned out that the fat
did not stimulate the reward center the fat only stimulated the smata sensory cortex mouth feel
only sugar stimulated the nucle cumbent the reward center and increasing the fat did not increase the
reward so it's the sugar that actually drives the reward in a milkshake this has been repeated in
a different way from a a group in Switzerland uh vulneren okay who showed no satiety or fullness
with fructose compared to glucose and no insulin rise with fructose compared to glucose but when
they looked at the fmri the glucose basically stimulated the anterior FAA and the basil ganglia
whereas the fructose stimulated the whole lyic system how about dementia so do sugar caused
dementia well D breson would tell you yeah okay so we know obesity is associated with
dementia that's old news we know obesity has altered neural projections consistent with
dementia we know that Sugar generates insulin resistance and hyperinsulinemia old news we
know that insulin resistance and high insulin levels are associated with dementia we know that
the Western diet correlates with dementia and we know that both fat and sugar can cause obesity in
rats but only sugar causes cognitive decline fat does not that's probably because of the effect
on the mitochondria okay so here's bdnf right and synaptic plasticity okay here's diet and
exercise affecting mitochondrial function okay the mitochondria make reactive oxygen species
which can affect cognition unless something takes those reactive oxygen species and quenches
them and gets rid of them you reduce the numbers okay well it turns out insulin is a bad guy
in the story the higher the insulin the less well that happens and it turns out that insulin
and fructose induced hyperinsulinemia changes membrane characteristics and Alters what is known
as membrane fluidity which has to do with how well does a membrane bounce back when perturbed either
from biochemical changes or pressure changes a way to think about this I think I talked about this at
the first talk the 8 you have a balloon okay just a plain old you know birthday balloon you blow it
up you put a knot in it you try to put your finger through it okay bounces right back now if you try
to take a pin it will explode okay take the same balloon new new balloon same same concept blow
it up same level put it in the you know corner of your bedroom for three weeks it will slowly
but surely deflate right now undo the knot blow it up again to that same level now try to poke
a hole with your finger now it'll now it'll blow it wouldn't blow before but it will now because
the membrane has changed because of the pressure that's membrane fluidity everybody got the idea
well that happens in neurons okay and fructose and hyperinsulinemia change that membrane fluidity
but there's a way to fix that that's with Omega-3s because it contributes to neuronal structure
remember EPA and DHA and it turns out that Sugar consumption correlates with Alzheimer's
preclinical Alzheimer's in population studies how about cognition this is work from Antonio
conit at uh NYU showing that insulin resistance as measured by the quick ey score is positively
correlated with changes in hippocampal volume so more insulin lower hippocampus and also more
CSF so you've lost tissue you've lost tissue and you've got more CSF not good and that correlates
with changes in executive function and cognitive flexibility here's your few vales okay this is
an adolescence adolescence so you want to know why all the kids are doing bad in school because
the hyperemia and what's the hyperemia from the processed food okay how about Behavior I love this
I mean we're in San Francisco everybody knows what the twinkie defense is right yes who does not
know what the twinkie defense is you all know oh you don't you don't know the twinkie defense
oh my God where have you been didn't you see the movie milk milk Harvey Milk Harvey Milk all right
so as you know Harvey Milk was the first gay uh legislator right and as a Board of Supervisors of
San Francisco you know that part and you know that he and mayor George mcone were killed by another
supervisor who was a former police officer named Dan White and at his trial the uh lawyer the
attorney for Dan White tried to defend White's actions by saying he was insane because he ate
a junk food diet a lot of Twinkies and so this became known as the twinkie defense now as it
turns out the jury didn't buy it white went away for 25 years got released one later one week later
he killed himself that's the story of Dan White okay point is there might be something to this
twinkie defense because it turns out adolescents who drink more than five cans of soft drinks
per week are more likely to carry a weapon more violent with their peers family members and dates
even after controlling for all the things that might affect their behavior obviously correlation
not causation but you know makes you wonder soft drink consumption is associated with behavior
problems in 5-year-olds increased impulsivity lack of being able to sit and concentrate and
finally number four the microbiome now this gets complicated the gut microbiome may be very
specifically related to CNS development and we know this because of germ-free mice so they don't
have a microbiome and they have cognitive defects so the microbiome might actually be supplying
things to your brain now might be through the blood things that get across or might even be up
the afron vagus nerve anterograde transport like of serotonin cuz 90% of the serotonin in your body
is in your gut there's very little serotonin in your brain okay it might be getting there through
the afron Vegas through anr transport so if you change the microbiome you might be changing
your neurotransmitter levels okay we know the ketogenic diet Alters the microbiome also in some
very specific ways okay having to do with with Improvement in cognitive function we also know
that the intestine has three barriers there's the mucin layer is the physical barrier there's
the biochemical barrier the tight Junction and then finally there's the immunologic barrier the
th17 cells which make il17 which basically keeps all the pathogens out if you destroy the mucin
layer which could be from emulsifiers we talked about it lunchtime okay it might be more likely
that bad guys will get through if you destroy the tight junctions like for instance celiac disease
or sugar as you'll see in a minute more likely bad guys will get through and if you destroy the
immunologic barrier same thing more bad guys get through so this looked at the microbiome in
associated with fructose consumption and I'll just read you the one sentence because this is an
awfully complicated concept that associated with fructose seem to hold more potential to induce
host metabolic disturbances compared to glucose mainly by promoting bile acid deconjugation and
torine release and compromising intestinal barrier Integrity fructose Alters intestinal barrier
integrity and how come because fructose nitrates those tight Junction proteins and makes them
unreliable so they're supposed to basically hold like this in response to Sugar they go like this
and it might be because fructose changes the ATP content of intestinal ocytes and makes them ATP
depleted because of that mitochondrial function we talked about okay got it and so that could lead to
bacteria and lipopolysaccharide translocation into the liver and now you've got hepatic inflammation
and insulin resistance and high glucose levels can activate t 17 cells in inflammation also okay and
there is a pathway between the gut microbiome and autoimmunity that runs through this IL 17 as well
because of an increase in inflammatory cyto kindes due to micro microbiota disbiosis possibly
due to short chain fatty acid reduction in association with sugar consumption I've already
shown you this go keep going okay and this might be relevant to clinical medicine because dietary
intake of sugar is associated with increased disease activity in lupus in a patient you know a
patient with an inflammatory process sugar makes the inflammatory process worse okay association
between consumption free sugars and number of complications and here might be the reason
why we know about Sim's Korea right we know about a disease called pandas anybody heard of
pandas p n D- Progressive autoimmune neuropathic disease associated with streptococus disease
related to strepto cacus synm Korea is like the early famous one but now a lot of kids
have thing this thing called pandas and as a pediatrician Pediatric and chronologist
I saw this in the hospital okay it's a big problem well might be because the strep is
growing okay and making bad stuff it makes toxins okay it makes toxins on your tooth to
eat a hole in your tooth right the strap strep mutans here okay and strep the caucus in your
intestine so here we're growing group a strep on different media 2% glucose oh sorry here's
glucose notice no effect here's sucrose huge effect here's fructose huge effect sucrose
plus glucose same effect so in each case the group a strep is preferring the fructose
as a substrate for metabolism so increasing the sugar in the diet might be increasing group a
strep colonization leading to psychiatric disease uh I'm going to pass this for time so let me just
finish what I've told you food has effects on the brain okay I mean I don't have to like convince
you of that you already know that but like what okay it's not just growth but also Behavior
food can act centrally or peripherally can act via the gut of the liver via afret mechanisms
or could act directly via the blood brain barrier to alter neuronal function food can act as
an initiating or an aggravating factor for many psychiatric diseases it can affect brain
metabolism through changes in mitochondrial function through glutamate neurotoxicity through
insulin resistance and its effect on leptin and bdnf or through microbiome dysfunction leaky
gut and autoimmunity now the ketogenic diet seems to affect many of these I'm not saying
everyone needs that but maybe certain people do okay we don't know if it's due to the sugar
restriction or the carbohydrate restriction or the insulin reduction or the ketones themselves
because of the cin effect we don't know yet but might be able to treat some of these pathologies
and this is what Christopher Palmer at Harvard is doing okay anecdotal data and case series support
the association but we need the randomized control trials they are now ongoing so we have a ways
to go not there yet but I hope what this has done this talk has given you some idea about
how important this concept of metabolic or nutritional Psychiatry is and the fact that our
current disaster debacle of mental health is not just because of the stress of our politics or even
the stress of our cell phones but actually might be because of the stress of our diet too so with
that I'll close and of course answer any questions and you know thank you for [Applause] attending
so uh Rob as we discussed obviously sucrose uh basically it's a you know molecule that contains
both glucose and fructose right and fructose is a single molecule right SU R is a combination
of two tiny little molecule right so and what you're showing is effectively glucose in many
aspects seems to be safer compared to fructose sure compared to compar toose why why aren't we
using glucose more oh cuz it's not very sweet cuz it Doesn't generate that reward system okay
okay you don't see people going around chugging kro syrup do you okay that's glucose not very
interesting okay might be good in a cookie but you know I mean that's only after you add the
fructose first okay glucose has a sweetness index of 74 sucrose has a sweetness index of
100 and fructose alone has a sweetness index of 173 okay so it might be just due to the
sweetness but more importantly it's the reward signal sorry so diet sweeteners have
a very high sweetness index they you know in the hundreds but most diet sweeteners do
not stimulate the reward signal and so let me ask you a question have you ever had
a no sugar diet sweetener only chocolate bar are they good no no no they're sweet
are they good no T do you ever want another one no why not doesn't because you didn't
stimulate the reward center just because you got the sweetness didn't mean you got the
reward okay they're not the same so it's less about the sweet and has more to do with the
reward signaling and fructose specifically drives that reward signal binds to receptors in
on the neuron itself so how do you satisfy that crave without causing metabolic disease ah
so invite me back and I will give you a talk that I'm going to give two weeks from now in
uh North Carolina called the true purpose of nutrition and the true purpose of nutrition is
metabolic health and so the question is if the true purpose of nutrition is metabolic health and
if Ultra processed food only causes metabolic D function is ultra processed food food well could
you make Ultra processed food healthy yes or no yes yes if you know what the principles that
you had to abide by are now the current you know ultr processed food industry they don't care
they don't know but any better I don't they do they actually do I know they do because they've
told me they do okay but you know it's about money it's about money they're not going to do anything
that's going to alter their gravy train okay not until they're told to have to not until there's
regulation okay and they told me so there you know that's that's their stick okay it's about the
money they're not in business to feed the world they're in business to make money and anything
that interferes with that is not is not welcome period could you make ultr processed food healthy
well yes by adhering to three principles and this is what uh we did with a uh this company in the
Middle East called Kuwaiti Danish Dairy company kdd okay and um we wrote this up and uh it was
published in frontiers of nutrition in March okay three precepts if you adhere to those three
precepts you can make Ultra processed food healthy those three precepts are and they're in the paper
protect the liver feed the gut support the brain those three why those three protect the liver how
ah how so get rid of the toxins okay so fructose is a toxin cadmium is a toxin Branch chain amino
acids are toxins to the liver okay feed the gut well what does the gut want to eat fiber and
support the brain okay well how do you support the brain short chain fatty acids which can come
from that fiber okay another way is um Omega-3s okay and few other you know uh things you know
getting rid of all the other stuff and basically preventing the inflammation so you have to stop
the leaky gut well how do you stop the leaky gut well I just showed you the three the three
barriers you got to keep those intact could Ultra processed food keep those those three intact and
the answer is yes if you know what you're doing right now that's not happening so actually Ultra
processed food could be made healthy and that's what we did for kdd and we're hoping that we can
get other food companies on you know this track to basically alter their uh products and their
fair to ultimately become metabolically healthy yeah I have a two questions um so one one of the
slides you were talking about how the membrane the separation is not tight IT wi oh the the leaky
gut okay leaky gut is that is that similarly the reason why fat might get stored in the liver
or is that it could be it could be especially for medium chain triglycerides probably not for
um uh uh kyom microns because kyom microns get made from regular uh triglyceride and you know
they're big fluffy things they probably don't make you know they're made on the other side
of the membrane anyway and they circulate via the lymphatics and go straight to the liver and
get cleared through the LDL receptor okay and so it's a slightly different um pathway for them but
medium train Trias rides could certainly do that because they go through the portal system so they
yes leaky gut could affect those and uh there was another slide where you were talking about uh how
sorry you were talking about how fructose inhibits uh your ability to retain leptin or or consume
leptin no no fructose induces insulin resistance and hyperinsulinemia and Insulin blocks leptin
signaling at the level of the brain so how how can we increase the leptin uh sensitivity sensitivity
sure yes well get rid of the thing that's causing the leptin resistance okay now most people say
obesity is the cause of leptin resistance that's not true obesity is a marker of leptin resistance
but it is not the cause the cause is what's happening at the leptin receptor itself What's
blocking leptin from signaling and obesity is not it triglycerides are triglycerides block leptin
signaling but hyperinsulinemia insulin blocks lepin signaling so and of course hyperglyceridemia
is associated with hyperinsulinemia so that makes it doubly worse thank you uh Rob uh one more thing
you talked about ketogenic diet and its potential benefit for uh potential TNS for certain patients
disorders and so forth what are the downside of extreme ketogenic diet uh ketogenic diet is
already extreme I know what is it what is the potential Downs well so if you have familial hyper
cholesterolemia you can't be on a ketogenic diet because you can't process the LDL because your
LDL is going to go up on a ketogenic diet and you need the LDL receptor to be able to internalize
and if you can't internalize now your ldls are super high and you're going to get a heart attack
and die so that's one in 500 people right right off the bat in addition there's a disorder called
type five hyper lipopro Mia which is a different disorder it's not f H it's it's type five and it
is hyper hyperchylomicronemia okay you can't clear the kyom microns and you can't be on a ketogenic
diet you have to be on a lowfat diet for both of those okay in general a ketogenic diet will
work for most people it will the problem the problem is most people who go on a ketogenic diet
don't monitor themselves what should they monitor well they have to monitor their ketones so it
can either be urine ketones which is messy it can be blood ketones which is doable or it can
be breath ketones I actually am an adviser to a company that makes a breath Ketone monitor
called Journeys metabolic okay uh used to be called readout Health they rebranded and they make
a breath Ketone monitor so you can actually it's looks like a kazoo and you can basically determine
whether you're in ketogenesis or not based on your breath and if you fall out of ketogenesis then
you have to get yourself back in so it's a method for self-reinforcement point is if you are left
to your own devices and you're just going on a ketogenic diet based on a book you read like the
Atkins Revolution okay you can start out ketogenic and within two months you will be back on your
regular diet and if you're trying to be on a ketogenic diet and you're not monitoring yourself
the likelihood is that carbs have you know invaded your diet and you didn't even know it they've
increased your insulin which have suppressed your ketones so you're not on a ketogenic diet
now you're on a high fat medium carbohydrate diet which is the actual absolute worst diet you can
be on that's the best way to get a heart attack so if you're going to do a ketogenic diet you
got to go all the way how about monitoring your cardiovascular LD you know LDL well LDL will go up
on a ketogenic diet dietary fatting increas is LDL but it's the large buoyant LDL we talked about
at the first uh meeting okay not the small Den the small Den are the problem the large buoyant
they're just cardiovascularly neutral so you have to know which LDL you're uh you're uh increasing
and if it's if it's large buoyant well so what do would your normal blood test that you do at Kaiser
or HMO tell you that no it won't tell you that but you can sort of glean it because you look at the
LDL but you also look at the triglyceride so if you have a high LDL and a low triglyceride then
those are large buoyant that's okay if you have a high LDL and a high triglyceride then those are
small dense and then that's not okay so in each case it's the triglyceride that's the big problem
not the LDL LDL has a hazard risk ratio for heart disease of 1.3 so if you have a high LDL you
have a 30% increased risk for heart attack Fair triglyceride has a hazardous ratio of 1.8 so
if you have a high triglyceride irrespective of your LDL you have an 80% increase risk for
heart attack 30% risk 80% risk which is worse the triglyceride is a bigger problem than the LDL
ever was the reason why everybody looks at the LDL why everybody thinks that's the guru of all of
this is complete and utter [ __ ] okay because because because number one triglycerides don't
mean anything if you're not fasting and a lot of people when they do their fasting lipids are not
fasting okay because a lot of people forget and then they're at the doctor's and then oh well
you know get it anyway okay so triglycerides can be all over the place if you're not fasting
that's for sure and number two we didn't have a drug for it we had a drug for LDL satins okay it
was a long time before we had a drug for hyper triglyceridemia we do it's fibrates but fibrates
are expensive and fibrates have side effects and so you know nobody wants to do that but fish
oil will work if it's wild fish wild so that's that's the uh the key any other questions
anybody any any other questions let's give another [Music]
