By shooting the gut fatty messenger, apparently.
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).
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.
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.
However, 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.
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