How a high-fat diet makes that stick of celery seem less rewarding

By shooting the gut fatty messenger, apparently.


Do brains dream of delectable treats? Source:

A longstanding debate in obesity research is whether compulsory eating is an “addiction”. The A word certainly brings baggage to the table – by calling overeating an addiction we’re essentially labelling the obese as mentally ill. Negative connotations aside, there certainly are strong parallels: just like drugs of abuse, rewarding foods stimulate the same brain circuits (most natural rewards do), triggering dopamine release in the striatum, which signals reward and motivates feeding behaviour.

It’s a great system optimized to keep us alive. But it tragically breaks down when we take gustatory decadence to the extreme. Chronic consumption of high fat & sugar goodies overwhelms the system, so that the individual becomes less sensitive to reward signals. One idea is that people then overeat to compensate for the lack of a fat/sugar high – just like addicts striving for the next hit, despite being fully aware of the health and social consequences.

While it seems like a good theory, one link is missing: excess food consumption happens in the intestinal tract, while dopamine rush occurs in the brain. What’s happening in between?

Luis A. Tellez et al. 2013. A gut lipid messenger links excess dietary fat to dopamine deficiency. Science 341: 800-802.

The messenger might be oleoylthanolamine (OEA, say it out loud I dare you), an appetite-suppressing lipid synthesized in the gut following food intake. Why point the crosshairs at OEA? The authors didn’t really say, but did note that OEA is one of the few factors that DECREASES in response to a high-fat diet (as opposed to leptin, insulin and glucose which all increase in the obese), and that supplementing OEA reduces body weight in obese mice.

The authors put 216 mice on either a very high-fat (60% fat, 20% protein and 20% carbs) or low-fat (10% fat, 20% protein and 70% carbs) diet and let them eat to their little hearts’ content. 15 weeks later, compared to low-fat fed mice, high-fat mice indeed had significantly lower levels of OEA in their small intestines. The mice also responded to fatty foods differently. As you can see below, when researchers delivered a “fat shot” (a flavorless fatty solution, ew) directly into the mice’s intestines, high-fat fed mice (HF, white line) showed a muted dopamine response compared to low-fat fed ones (LF, black line).

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However, when high-fat fed mice were given external OEA before the gut fatty infusion (blue arrow below), they once again experienced a dopamine rush (white line in graph B) – just like low-fat fed mice (A). OEA acts through a protein called PPARalpha, and transmits information through the vagus nerve, part of the peripheral nervous system, to the brain. OEA is certainly acting in the gut; if you directly give OEA into the brain, it looses its effect. Thus, the gut itself can sense the presence of rewarding fatty foods – even in the absence of taste and mouth feel – and that dopamine response to fat in the gut is muted in rats raised on a high-fat diet.

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A: low-fat fed mice; B: high-fat fed mice. In high-fat fed mice, administering OEA before fat infusion restores dopamine bump. (From Fig 1)

Sure, but do high-fat mice BEHAVE differently? The authors first wanted to see if a fatty diet alters feeding motivation. Intra-gastric feeding is a dopamine-dependent behaviour; dopamine is often associated with motivation. As you can see in the graph below, although high-fat mice (right) ATE the same amount of yummy fatty food as low-fat fed (left) mice, they showed far less interest in administering flavourless fats into their guts (compare the two black lines). When given an extra dose of OEA (shadowed areas and white lines), low-fat fed mice seemed to lose their appetite, self-administering far less high-fat solution than usual (left). This makes sense, as OEA is naturally produced in the gut to signal fullness and satisfaction.

Screen Shot 2013-08-24 at 1.18.51 PMHowever, high-fat mice perked up after OEA and pumped MORE fatty solution into their guts (right graph above, shadowed area and white line). Interestingly, the same dose of OEA caused both types of mice to infuse themselves with the same number of calories. In other words, OEA may create a “set-point” of calorie intake and once that level is reached, call out to the brain to either drive the mice to get more or less calories through dopamine signalling. In high-fat fed mice who hesitate to self-administer fatty liquids into their guts, OEA thus restored their deficient dopamine-dependent motivational circuits.

Wait, if supplementing OEA causes obese mice to tube-feed themselves MORE, how’s that a GOOD thing? One thing to take note is that intra-gastric feeding bypasses all the flavour and mouthfeel feedback to the brain which occurs during oral feeding, aka normal eating. While high-fat fed mice were reluctant to pump flavourless fat into their guts, they DID eagerly mow down on a delicious fatty slurpee orally, but turned their backs on a less enticing low-fat option. Mice raised on a low-fat diet, on the other hand, happily ingested both high and low-fat offerings.

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So how did OEA affect ORAL/normal eating? As you can see above, unlike intra-gastric feeding, OEA infusion caused BOTH low (left) and high (right)-fat fed mice to abhor eating more fatty food (shadowed area, white line). Especially intriguing is this: while OEA also DECREASED the amount of “diet” food low-fat fed mice ate, it seemed to INCREASE high-fat fed mice’s liking for low-fat food. The overall picture then, is that external OEA artificially boosted low-fat food’s reward value by increasing dopamine release in the brain, and rectifies motivational deviances that occur in a chronic high-fat diet.

First, I’d like to point out that the high-fat diet used in this study is actually a high-fat/moderate-sugar diet, so does not pertain to very low carb diets like the ketogenic diet. That out of the way, the authors make a good case for OEA as an intermediate link between fat consumption and dopamine response. I find it especially interesting that OEA affected feeding behaviour differently depending on the route of consumption – oral-sensory factors are definitely at play. Indeed, digestion happens long before swallowing. The sight, taste and smell of food are powerful triggers that initiate enzymatic and neurochemical responses to prepare the body for digestion. Which factors are more important in deciding the final level of motivation?

I would also love to know if in the ABSENCE of OEA, low and high-fat fed mice orally ingest fatty solutions differently. That is, whether “one piece of cream cake and lead to another” in obese mice trying to chase a heavenly fatty high. It’s interesting that high-fat fed mice were less willing to work for intra-gastric food; but what about delicious fatty food that they can taste? I also wonder if the decrease in OEA synthesis is reversible; that is, does it go back to normal after you put a high-fat fed mouse on a low-fat diet?
Tellez LA, Medina S, Han W, Ferreira JG, Licona-Limón P, Ren X, Lam TT, Schwartz GJ, & de Araujo IE (2013). A gut lipid messenger links excess dietary fat to dopamine deficiency. Science, 341 (6147), 800-2 PMID: 23950538


I gut a feeling!


Hey, we matter! Source: google “giant microbe plushies”

I bet you don’t think about the 100 trillion microbugs thriving in your gut too much. Neither did I, until I started reading up on the Human Microbiome Project (HMP) at a conference last week. Several fun facts that came out from the project:

    • For every human cell, there are 10-100 times of microbe living in your gut in harmony. Not to mention the skin, nose, mouth and foot dwellers. We’re really more bug than man.
    • People host very different types of microbug (over 1000!); but when you look at the GENES that compose each microbiome, they’re remarkably similar.
    • Along the same lines, an extremely diverse microbe composition can activate the same METABOLIC pathways to help you digest carbs and influence your metabolism – all (normal)microbug roads lead to metabolic Rome.
    • So it’s probably not surprising that aberrant microbug-ecology is involved in Type 2 Diabetes, Inflammatory Bowel Disease and MAYBE cardiovascular disease.
    • There’s tantalizing (but little) evidence that environmental bacteria may get into healthy brains and start colonizing.
    • One for the ladies: we can be “bug typed” into 5 categories, depending on our vaginal microbiome composition. Like blood type.

And finally, most interesting to me, is the emerging brain-bug connection. Microbes rapidly and densely settle in newborns as their brains are still developing. If the bad (pathogenic) ones get in, it may drastically increase a child’s chance of developing schizophrenia and autism. If the “normal” ones don’t get in – well, it seems to influence mood, anxiety and even cognition, at least in mice.

Let me explain.

Since we can’t ethically eliminate normal gut microbes in human newborns, scientists turned to germ-free (GF) mice, or mice without intestinal flora. When tested for anxiety levels, adult GF mice were much bolder than their controls, wandering into terrifying bright fields and cliff-like arms of an elevated maze. This brash behaviour disappeared if they were artificially colonized with gut flora when young, but not once they reached adulthood.

This tells us that –all else the same – gut bugs can impact behavior, depending on whether or not they were present in the “critical period” in development.

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“Conv” = gut microbe (poop) transplant. If gut flora settle down & flourish before or during the critical period, germ-free (GF) mice show normal anxiety behaviour. Otherwise they turn into brash adults. Source: below #2

But it’s not just the kids that are susceptible. Giving adult mice a mixture of ANTIbiotics and antifungals for a week reduced their anxiety-like behaviors, which went back to baseline 2 weeks after the treatment stopped. This doesn’t imply gut flora’s bad for mood – a dose of PRObiotics (L. rhamnosus) also made healthy male mice gutsier. So the absolute amount of gut flora may not matter as much as composition in this case.

So HOW are normal bugs in the gut signaling to the brain? Scientists aren’t too sure yet, but peripheral and gut nerves may be involved. Gut bugs may also be generating neurotransmitters from food, which gets delivered to the brain by blood. They could also be communicating with the brain indirectly, by changing global metabolism. Alternatively, a crazier idea is that gut bugs can change protein expression in the brain – at least during early development – and so the brain “sets up” its synapses and circuits differently, eventually changing how stress and mood is processed.

There is some evidence for this. We know that monoamines, like dopamine and serotonin, are involved in mood regulation. Surveying the brains of bug-free GF mice, scientists found increased metabolism of monoamines in the striatum, a brain area important for motivation, motion initiation and reward learning. Zooming further in, at the synapse, the levels of two proteins involved in neurotransmitter shuttling and synapse maturation were changed. So were a cluster of genes related to learning (plasticity) and depression. Remember, the only thing that differed GF and control mice is their lack of gut bugs. When scientists gave young GF mice normal gut flora from a donor (read: poop implant), several synaptic protein levels returned back to normal, as did behaviour.

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Proteins involved in anxiety and learning are expressed differently in control (SPF-left) and bug-less (GF-right) mice. For those interested, A is NGF-1A, B is BDNF

So mice microbiome tweaks mice behavior. But what about humans? In one double blind, placebo-controlled 30-day trial, healthy volunteers given probiotics (L. helveticus & B. Longum) reported less psychological distress than controls. In another similarly controlled trial, healthy volunteers were given probiotics or placebo for 3 weeks. Those who scored lowest on depressive moods showed significant improvement after probiotic supplementation compared to control. Finally, in a small pilot study with chronic fatigue syndrome patients, those who took probiotics (L. casei) daily for 2 months showed significantly fewer anxiety symptoms than did the placebo group.


The “second brain” bugs the brain. Source:

You may think that everything described above sounds a little iffy (Why look at those proteins and genes and brain area? Why use that strain of probiotic? Why do antibiotics and probiotics show similar anti-anxiety effects?). I tend to agree. The gut-brain-behavior field is still in its infancy – what we do know if that the human microbiome is important, in health and disease. Whether they’re good targets for anxiety and depression treatment though, is still an open question. So maybe it’s not yet time to drop the Prozac and pick up the probiotics.

I’ll leave you with this: since what we eat heavily affects the composition of gut flora, and gut flora affects our brains, there is some scientific truth in the old saying “you are what you eat”.

Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, Hibberd ML, Forssberg H, & Pettersson S (2011). Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences of the United States of America, 108 (7), 3047-52 PMID: 21282636

Foster JA, & McVey Neufeld KA (2013). Gut-brain axis: how the microbiome influences anxiety and depression. Trends in neurosciences, 36 (5), 305-12 PMID: 23384445