(This is part 2 of “The science of feeling peckish”, promised way back in April. Thanks for the encouragement/prodding in the original comments thread about finishing the series.)
I hope you’ll stick with me for this rather technically dense post. As always, I will gladly accept all error corrections and pointers to research that disputes or usefully refines the information below.
Regurgitating (sorry) Part 1
As we join our story already in progress, we recall that the 1976 article “The Physiological Psychology of Hunger: A Physiological Perspective” made the following points in reviewing energy metabolism:
The various parts of the body are largely source-agnostic when it comes to getting energy from the diet: carbs, fat, and protein are broken down into their constituent parts and used all over the place. (A couple of small exceptions become important later on.)
The brain is always fed first and steadily; you’d pretty much have to be on a desert island surrounded by a fishless sea for many days before making a dent in your brain’s energy supply. And in fact, all your tissues get an adequate supply pretty much all the time, despite the fact that you don’t graze constantly.
A few cautions before we proceed: First, we’re talking physiological hunger here, not emotional bingeing, or missing lunch because you’ve got a deadline. Second, the research used to support the discussion in the article is mostly about laboratory rats. There are precise parallels when it comes to energy metabolism among the higher mammals, however, so don’t be offended if I use the word “you” below…
Hunger Hypotheses on the (Dinner) Table
The Friedman-Stricker article addresses two popular hypotheses for explaining what triggers hunger. They both posit a special role for the central nervous system:
The glucostatic hypothesis: The brain responds to blood-borne signals about your level of blood sugar, making you eat when it dips (mmm, dip) and lay off the food when it’s sufficiently high.
The lipostatic hypothesis: The brain responds, instead, to signals about your level of body fat. You could think of this as a “fat set point”.
Ultimately the authors present an alternative view, which I’ll get to in due time.
“Brain and Brain. What is Brain?”*
Much of the research examined in the article involves making lesions in the brains of rats, specifically damaging either the ventromedial hypothalamus (VMH) or the lateral hypothalamus (LH), and seeing what happens to weight, hunger, and feeding in various conditions (like shaving their fur off to make them cold, or even administering the dreaded “tail pinch”). A moment of silence, please, for these poor rats.
In general, it’s known that VMH lesions stimulate hunger and lead to weight gain, and LH lesions do the reverse. This is called the “dual hypothalamic model” (and initially led to speculations that the VMH is the “satiety center” and the LH the “hunger center” of the brain, but things got a little more sophisticated in the next iteration). Here’s how the two hypotheses predict these effects.
Glucostatic: There are “glucoreceptors” located in the VMH, and they detect when blood sugar is low or when available blood sugar isn’t getting properly used.
Lipostatic: Damaging the VMH either messes with a brain “hunger center”, taking off its controls and making you way hungrier than normal, or it turns up the dial on your “fat set point” so that you feel compelled to meet the higher requirement.
A Taste of the Arguments Against
The gross effects of messing with rat brains do seem generally supportive of one of these choices. But dig a little deeper (no, not murine-cerebrally) and the evidence doesn’t look as great. The article goes into a lot of technical depth; here is my best attempt at a summary of the “con” positions.
The idea that there are glucoreceptors in the VMH was already weakening at the time the article was written. For starters, originally it was noticed that small dips in blood sugar are indeed associated with hunger, so this formed the core of the hypothesis. But since diabetes involves both higher blood sugar and greater hunger, the hypothesis had to be refined to say that the brain is suffering from less-efficient use of the blood sugar you’ve got. However, it turns out this refinement doesn’t help; more on this below.
In addition, feeding behavior in the presence of lesions, lab conditions such as excess cold, and treatment with substances like insulin tends to float in surprising directions.
Finally, as Taubes adds in GCBC, this hypothesis doesn’t explain things like weight gain back to normal levels after an illness.
It’s a funny thing: Rats with VMH lesions add body fat even before they begin eating, even if they’re prevented from eating for many hours. So if the rats’ brains are telling them to eat, the eating doesn’t seem to be the first effect in line. And it’s known that the lesion immediately causes higher levels of circulating insulin (geez, why didn’t they say so before?), with effects similar to seasonal obesity in animals who migrate or hibernate (and, hmm, similar to other effects I’ve discussed in the past).
And in any case, positing a lipostat in the brain simply doesn’t get you very far. In particular, Taubes notes, it doesn’t explain why the very obese have an elevated set point. It’s all a bit circular:
Saying that we’re all endowed with a lipostat that monitors our adiposity and then regulates hunger appropriately is just another way of saying that our weight remains remarkably stable, whether we’re lean or obese, and then assigning the cause to a mysterious mechanism in the brain whose function is to achieve this stability. [GCBC p. 428]
Sugar Sugar, Ah, Honey Honey
It’s worth looking more closely at the diabetes problem for the glucostatic hypothesis. It reveals a metabolic story that goes way beyond a simple blood sugar level.
Diabetes kind of looks like starvation. The body madly breaks down fat into ketone bodies (ketogenesis) for use in the periphery of the body, since those parts need insulin to make use of the glucose and there isn’t any to be had. But the body also madly makes new glucose (gluconeogenesis). The brain must think it’s in heaven since it actually gets plenty of that fine, fine stuff, but the rest of the body is out of luck — unless it can get more of the stuff it can actually use:
[T]he fat content of the usual laboratory diet can be viewed as “diluted” with carbohydrate, material of little metabolic significance during diabetes. The hyperphagia [extra feeding] of diabetic animals thus resembles the increased feeding that occurs in intact rats when food is diluted with nonnutritive bulk and may result because the decrease in utilizable metabolic fuels in the diet reduces the diet’s capacity to satiate the animal. â€¦. [D]iabetic animals maintained on a high-fat diet do not display hyperphagia despite continued impairments in glucose utilization. [TPPH:APP p. 418; citations elided; bold added]
So even the more modern version of the glucostatic hypothesis of hunger seems off.
The Mind-Body Connection
But wait, there’s more to the “con” position. The very assumption that the hunger trigger originates in the brain is suspect. All this nasty work to produce weight gain etc. in lab animals is highly unusual; as already noted, the brain lives in an energy bubble and never wants for anything whether you’re feeling peckish or not.
There’s another candidate — an organ on the periphery of the body that (a) already orchestrates fat-burning and other energy processes in our bodies and (b) is unique among its surrounding organs in that it can’t process ketone bodies but can handle fructose:
[I]t is not likely that pronounced decreases in cerebral glycolysis [energy usage in the brain] ever occur except under nonphysiological experimental conditions [rat abuse], because the brain is normally protected from such emergencies. â€¦. Our recent findings that insulin-induced feeding is abolished by infusions of fructose, but not ketone bodies, strongly implicate the liver as the origin of the hunger signal. [TPPH:APP p. 422; citations elided]
Yep, if you inject ketone bodies directly into an insulin-treated rat’s bloodstream, the rat still wants to raid the fridge — and it appears to be because its little liver is still starving.
The Friedman-Stricker article discusses a particular event in the liver that could trigger the hunger signal: a shift away from “oxidative metabolism” (the Krebs cycle for making energy out of anything) to direct production of glucose and ketone bodies (gluconeogenesis and ketogenesis — remember these from “diabetes is like starvation” above?). This seems to be the initial sign that your body is starting to “run on fumes” and needs to fill the tank again.
(The authors have continued to push the ball forward; here’s one sample of recent research to determine how the liver signals the brain that eating would be a good idea right about now.)
So after trying really really hard, scientists couldn’t quite put their finger on an actual brain center that controls levels of fat or blood sugar. And brains don’t ever want for anything, but sometimes livers do. And the totality of the energy metabolism story, not just one substance or another, is on display when each hypothesis is examined.
The simplest explanation for hunger and weight-balancing would be a homeostatic system, like so many others in the body. Taubes notes, “Life is dependent on homeostatic systems that exhibit the same relative constancy as body weight, and none of them require a set point, like the temperature setting on a thermostat, to do so.” [GCBC pp. 428]
And indeed, Friedman and Stricker show that the caloric homeostasis hypothesis fits the facts much more closely than do the others: Hunger returns when the total utilizable fuel level in your body, rather than a store of a particular kind of energy, drops below some critical level. After all, brains and bodies generally don’t distinguish between energy sources. And more insulin stimulates more frequent meals, while less insulin allows body fat to be mobilized, which appears to stave off hunger.
(If you’re a regular carbgrrl.com reader, you might think this is a blinding flash of the obvious. Please tell the diet industry.)
Taking pity if you’ve gotten this far, I’ll spare you the dry conclusion from the Friedman-Stricker article and let Taubes bring it home:
This hypothesis of eating behavior did away with set points and lipostats and relied instead on the physiological notion of hunger as a response to the availability of internal fuels and to the hormonal mechanisms of fuel partitioning. Hunger and satiety are manifestations of metabolic needs and physiological conditions at the cellular level, and so they’re driven by the body, no matter how much we like to think it’s our brains that are in control. [GCBC pp. 432-3]
Luckily, we can use our brains to understand this mechanism better — and turn it to our advantage.