Let’s talk sugar, and how you know if you’ve eaten enough of it. Just in time for Halloween! This is a field I’ve done drug discovery for in the past, and it’s a tricky business. But some of the signals are being worked out.
Blood glucose, as the usual circulating energy source in the body, is a good measure of whether you’ve eaten recently. If you skip a meal (or two), your body will start mobilizing fatty acids from your stored supplies, and circulate them for food. But there’s one organ that runs almost entirely on sugar, no matter what the conditions: the brain. Even if you’re fasting, your liver will make sugar from scratch for your brain to use.
And as you’d expect, brain glucose levels are one mechanism the body uses to decide whether to keep eating or not. A cascade of enzyme signals has been worked out over the years, and the current consensus seems to be that high glucose in the brain inactivates AMP kinase (AMPK). (That’s a key enzyme for monitoring the energy balance in the brain – it senses differences in concentration between ATP, the energy currency inside every cell, and its product and precursor, AMP). Losing that AMPK enzyme activity then removes the brakes on the activity of another enzyme, acetyl CoA-carboxylase (ACC). (That one’s a key regulator of fatty acid synthesis – all this stuff is hooked together wonderfully). ACC produces malonyl-CoA, and that seems to be a signal to the hypothalamus of the brain that you’re full (several signaling proteins are released at that point to spread the news).
You can observe this sort of thing in lab rats – if you infuse extra glucose into their brains, they stop eating, even under conditions when they otherwise would keep going. A few years ago, an odd result was found when this experiment was tried with fructose: instead of lowering food intake, infusing fructose into the central nervous system made the animals actually eat more. That’s not what you’d expect, since in the end, fructose ends up metabolized to the same thing as glucose does (pyruvate), and used to make ATP. So why the difference in feeding signals?
A paper in PNAS (open access PDF) from a team at Johns Hopkins and Ibaraki University in Japan now has a possible explanation. Glucose metabolism is very tightly regulated, as you’d expect for the main fuel source of virtually every living cell. But fructose is a different matter. It bypasses the rate-limiting step of the glucose pathway, and is metabolized much more quickly than glucose is. It appears that this fast (and comparatively unregulated) process actually uses up ATP in the hypothalamus – you’re basically revving up the enzyme machinery early in the pathway (ketohexokinase in particular) so much that you’re burning off the local ATP supply to run it.
Glucose, on the other hand, causes ATP levels in the brain to rise – which turns down AMPK, which turns up ACC, which allows malonyl-CoA to rise, and turns off appetite. But when ATP levels fall, AMPK is getting the message that energy supplies are low: eat, eat! Both the glucose and fructose effects on brain ATP can be seen at the ten-minute mark and are quite pronounced at twenty minutes. The paper went on to look at the activities of AMPK and ACC, the resulting levels of malonyl CoA, and everything was reversed for fructose (as opposed to glucose) right down the line. Even expression of the signaling peptides at the end of the process looks different.
The implications for human metabolism are clear: many have suspected that fructose could in fact be doing us some harm. (This New York Times piece from 2006 is a good look at the field: it's important to remember that this is very much an open question). But metabolic signaling could be altered by using fructose as an energy source over glucose. The large amount of high-fructose corn syrup produced and used in the US and other industrialized countries makes this an issue with very large political, economic, and public health implications.
This paper is compelling story – so, what are its weak points? Well, for one thing, you’d want to make sure that those fructose-metabolizing enzymes are indeed present in the key cells in the hypothalamus. And an even more important point is that fructose has to get into the brain. These studies were dropping it in directly through the skull, but that’s not how most people drink sodas. For this whole appetite-signaling hypothesis to work in the real world, fructose taken in orally would have to find its way to the hypothalamus. There’s some evidence that this is the case, but that fructose would have to find its way past the liver first.
On the other hand, it could be that this ATP-lowering effect could also be taking place in liver cells, and causing some sort of metabolic disruption there. AMPK and ACC are tremendously important enzymes, with a wide range of effects on metabolism, so there's a lot of room for things to happen. I should note, though, that activation of AMPK out in the peripheral tissues is thought to be beneficial for diabetics and others - this may be one route by which Glucophage (metformin) works. (Now some people are saying that there may be more than one ACC isoform out there, bypassing the AMPK signaling entirely, so this clearly is a tangled question).
I’m sure that a great deal of effort is now going into working out these things, so stay tuned. It's going to take a while to make sure, but if things continue along this path, there could be reasons for a large change in the industrialized human diet. There are a lot of downstream issues - how much fructose people actually consume, for one, and the problem of portion size and total caloric intake, no matter what form it's in, for another. So I'm not prepared to offer odds on a big change, but the implications are large enough to warrant a thorough check.
Update: so far, no one has been able to demonstrate endocrine or satiety differences in humans consuming high-fructose corn syrup vs. the equivalent amount of sucrose. See here, here, and here.