Why Do We Crave Sugar? | Dr. Charles Zuker & Dr. Andrew Huberman
00:00:00.000 | Let me tell you about the gut-brain axis and our insatiable appetite for sugar and fat.
00:00:17.560 | Insatiable for sugar and quenchable for fat.
00:00:23.040 | And this is a story about the fundamental difference between liking and wanting.
00:00:35.080 | Liking sugar is the function of the taste system.
00:00:43.000 | And it's not really liking sugar, it's liking sweet.
00:00:49.740 | Liking sugar, our never-ending appetite for sugar, is the story of the gut-brain axis.
00:01:01.880 | Liking versus wanting.
00:01:03.720 | And this work is work of my own laboratory that began long ago when we discovered the
00:01:11.020 | sweet receptors, and you can now engineer mice that lack these receptors.
00:01:20.040 | So in essence, these animals will be unable to taste sweet.
00:01:24.920 | A life without sweetness, how horrible.
00:01:30.680 | And if you give a normal mouse a bottle containing sweet, and we're going to put either sugar
00:01:37.520 | or an artificial sweetener, alright, they both are sweet.
00:01:41.360 | They have slightly different tastes, but that's simply because artificial sweeteners have
00:01:48.800 | some off-tastes.
00:01:51.080 | But as far as the sweet receptor is concerned, they both activate the same receptor, trigger
00:01:56.640 | the same signal, and if you give an animal an option of a bottle containing sugar or
00:02:02.440 | a sweetener versus water, this animal will drink 10 to 1 from the bottle containing sweet.
00:02:10.600 | That's the taste system.
00:02:12.760 | Animal goes, samples each one, licks a couple of licks, and then says, "Uh-uh, that's the
00:02:16.520 | one I want because it's appetitive and because I love it."
00:02:20.280 | So it prefers sugar to artificial sweetener.
00:02:23.000 | No, no, no.
00:02:24.000 | No, no.
00:02:25.000 | Equally artificial sweetener.
00:02:26.000 | In this experiment, I'm going to put only sweet in one bottle, and it could be either
00:02:31.280 | sugar or artificial sweetener, it doesn't matter which one.
00:02:34.040 | Okay, we're going to do the next experiment where we separate those two.
00:02:37.880 | For now, it's sweet versus water.
00:02:41.800 | And sweet means sweet, not sugar.
00:02:44.840 | Sweet means anything that tastes sweet, alright?
00:02:48.280 | And sugar is one example, and Splenda is another example.
00:02:52.760 | Aspartame, monk fruit, stevia, doesn't matter.
00:02:55.760 | Yeah, I mean, there's some that only humans can taste, mice cannot taste, because their
00:03:02.000 | receptors between humans and mice are different.
00:03:06.080 | But we have put the human receptor into mice.
00:03:10.440 | We engineer mice, and we completely humanize this mouse's taste world, alright?
00:03:19.420 | But for the purpose of this conversation, we're only comparing sweet versus water.
00:03:25.840 | An option, my goodness, they will leak to know, from the sweet side, 10 to 1 at least
00:03:33.040 | versus the water.
00:03:35.200 | Make sense?
00:03:36.200 | Alright.
00:03:37.200 | Now, we're going to take the mice, and we're going to genetically engineer it to remove
00:03:41.680 | the sweet receptors.
00:03:44.220 | So these mice no longer have in their oral cavity any sensors that can detect sweetness,
00:03:50.260 | be it a sugar molecule, be it an artificial sweetener, be it anything else that tastes
00:03:54.980 | sweet.
00:03:55.980 | And if you give these mice an option between sweet versus water, sugar versus water, artificial
00:04:03.300 | sweetener versus water, it will drink equally well from both because it cannot tell them
00:04:07.900 | apart, because it doesn't have the receptors for sweet, so that sweet bottle tastes just
00:04:12.540 | like water.
00:04:15.220 | Make sense?
00:04:16.220 | Makes sense.
00:04:17.220 | Very good.
00:04:18.220 | Now, we're going to do the experiment with sugar.
00:04:20.700 | From now on, let's focus on sugar.
00:04:22.620 | So I'm going to give a mouse now sugar versus water.
00:04:27.860 | Normal mouse will drink from the sugar, sugar, sugar, sugar, very little from the water.
00:04:34.540 | Knock out the sweet receptors, eliminate them, mouse can no longer tell them apart, and it
00:04:39.700 | will drink from both.
00:04:42.740 | But if I keep the mouse in that cage for the next 48 hours, something extraordinary happens
00:04:50.780 | when I come 48 hours later and I see what the mouse is licking or drinking from.
00:04:57.220 | That mouse is drinking almost exclusively from the sugar bottle.
00:05:02.740 | How could this be?
00:05:04.500 | He cannot taste it.
00:05:06.980 | He doesn't have sweet receptors.
00:05:10.220 | During those 48 hours, the mouse learned that there is something in that bottle that makes
00:05:17.700 | me feel good, and that is the bottle I want to consume.
00:05:23.900 | Now, how does the mouse identify that bottle?
00:05:27.700 | It does so by using other sensory features, the smell of the bottle, the texture of the
00:05:35.620 | solution inside.
00:05:37.180 | Sugar at high concentrations is kind of goopy.
00:05:40.940 | The sideness in which the bottle is in the cage, it doesn't matter what, but the mouse
00:05:47.460 | realized there is something there that makes me feel good, and that's what I want.
00:05:54.300 | And that is the fundamental basis of our unquenchable desire and our craving for sugar, and is
00:06:04.940 | mediated by the gut-brain axis.
00:06:08.780 | The first clue is that it takes a long time to develop, immediately suggesting a post-ingestive
00:06:16.340 | effect.
00:06:19.060 | So we reason if this is true, and it's the gut-brain axis that's driving sugar preference,
00:06:28.420 | then there should be a group of neurons in the brain that are responding to post-ingestive
00:06:34.220 | sugar.
00:06:35.220 | And lo and behold, we identify a group of neurons in the brain that does this, and these
00:06:40.780 | neurons receive their input directly from the gut-brain axis.
00:06:47.740 | From other neurons.
00:06:49.260 | You got it.
00:06:52.280 | And so what's happening is that sugar is recognized normally by the tongue, activates an appetitive
00:07:00.380 | response, now you ingest it, and now it activates a selective group of cells in your intestines
00:07:08.820 | that now send a signal to the brain via the vagal ganglia that says, "I got what I need."
00:07:18.860 | The tongue doesn't know that you got what you need.
00:07:21.640 | It only knows that you tasted it.
00:07:24.840 | This knows that you got to the point that it's going to be used, which is the gut.
00:07:31.140 | And now it sends the signal to now reinforce the consumption of this thing, because this
00:07:38.420 | is the one that I needed, sugar, source of energy.
00:07:42.820 | Are these neurons in the gut?
00:07:45.460 | So these are not neurons in the gut.
00:07:46.980 | So these are gut cells that recognize the sugar molecule, send a signal, and that signal
00:07:52.660 | is received by the vagal neuron directly.
00:07:55.540 | Got it.
00:07:56.540 | And this sends a signal through the gut-brain axis to the cell bodies of these neurons in
00:08:03.100 | the vagal ganglia, and from there to the brainstem to now trigger the preference for sugar.
00:08:12.060 | Two questions.
00:08:13.060 | One, you mentioned that these cells that detect sugar within the gut are actually within the
00:08:18.300 | intestine.
00:08:19.300 | You didn't say stomach, which surprised me.
00:08:21.540 | I always think gut as stomach, but of course, intestine.
00:08:24.180 | No, no.
00:08:25.180 | They're intestine, because that's where all the absorption happens.
00:08:27.100 | So you want the signal, you see, you want the brain to know that you had successful
00:08:32.060 | ingestion and breakdown of whatever you consume into the building blocks of life.
00:08:40.060 | And you know, glucose, amino acids, fat.
00:08:43.540 | And so you want to make sure that once they are in the form that the intestines can now
00:08:48.480 | absorb them is where you get the signal back saying, this is what I want.
00:08:54.460 | Okay.
00:08:55.460 | Now, let me just take it one step further.
00:08:59.500 | And this now, sugar molecules activates this unique gut-brain circuit that now drives the
00:09:07.620 | development of our preference for sugar.
00:09:12.980 | Now a key element of this circuit is that the sensors in the gut that recognize the
00:09:20.800 | sugar do not recognize artificial sweeteners at all.
00:09:26.960 | Because their nutrient value is uncoupled from the taste.
00:09:32.440 | Generically speaking, one can make that, but it's because it's a very different type of
00:09:37.020 | receptor.
00:09:38.020 | I see.
00:09:39.020 | It's not the tongue receptors being used in the gut.
00:09:42.480 | It's a completely different molecule that only recognizes the glucose molecule, not
00:09:48.000 | artificial sweeteners.
00:09:49.980 | This has a profound impact on the effect of ultimately artificial sweeteners in curbing
00:09:59.480 | our appetite, our craving, our insatiable desire for sugar.
00:10:07.200 | Since they don't activate the gut-brain axis, they'll never satisfy the craving for sugar.
00:10:15.520 | Like sugar does.
00:10:18.040 | And the reason I believe that artificial sweeteners have failed in the market to curb our appetite,
00:10:27.440 | or need our desire for sugar, is because they beautifully work on the tongue, the liking,
00:10:37.500 | to recognize sweet versus non-sweet, but they fail to activate the key sensors in the gut
00:10:47.920 | that now inform the brain, you got sugar, no need to crave anymore.
00:10:56.280 | So the issue of wanting, can we relate that to a particular set of neurochemicals upstream
00:11:04.480 | of...
00:11:05.480 | So the pathway is, so glucose is activating the cells in the gut through the vagus that's
00:11:09.920 | communicated through, presumably, the no-dose ganglion and up into the brain stem.
00:11:14.680 | Very good.
00:11:15.680 | And from there, where does it go?
00:11:16.680 | Yeah.
00:11:17.680 | Where is it going?
00:11:18.680 | What is the substrate of wanting?
00:11:19.680 | I, you know, of course, I think molecules like dopamine, craving, there's a book even
00:11:24.680 | called "The Molecule of More," et cetera, et cetera.
00:11:28.200 | Dopamine is a very diabolical molecule, as you know, because it evokes both a sense of
00:11:33.860 | pleasure-ish, but also a sense of desiring more, of craving.
00:11:38.440 | So if I understand you correctly, artificial sweeteners are, and I agree, are failing as
00:11:44.200 | a means to satisfy sugar craving at the level of nutrient sensing.
00:11:51.240 | And yet, if we trigger this true sugar evoked wanting pathway too much, and we've all experienced
00:12:00.560 | this, then we eat sugar and we find ourselves wanting more and more sugar.
00:12:04.360 | Now that could also be insulin dysregulation, but can we uncouple those?
00:12:09.160 | Yeah.
00:12:10.160 | If we have a mega problem with over-consumption of sugar and fat, you know, we're facing a
00:12:23.400 | unique time in our evolution where diseases of malnutrition are due to over-nutrition.
00:12:33.280 | I mean, how nuts is that, eh?
00:12:35.960 | I mean, historically, diseases of malnutrition have always been linked to under-nutrition.
00:12:45.440 | And so we need to come up with strategies that can meaningfully change the activation
00:12:55.040 | of these circuits that control our wanting, certainly in the populations at risk.
00:13:07.200 | And this gut-brain circuit that ultimately, you know, it's the lines of communication
00:13:16.000 | that are informing the brain, the presence of intestinal sugar in this example, it's
00:13:23.200 | a very important target in the way we think about, is there a way that we can meaningfully
00:13:29.320 | modulate these circuits?
00:13:31.500 | So I make your brain think that you got satisfied with sugar, even though I'm not giving you
00:13:39.720 | sugar.
00:13:41.000 | So that immediately raises the question, are the receptors for glucose in these gut cells
00:13:46.960 | susceptible to other things that are healthier for us?
00:13:51.360 | That's very good.
00:13:52.760 | Excellent idea.
00:13:54.720 | And I think an important goal will be to come up with a strategy and identify those very
00:14:03.560 | means that allow us to modulate the circuits in a way that certainly for all of those where
00:14:12.440 | this is a big issue, it can really have a dramatic impact in improving human health.
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