The Hungry Brain: Outsmarting the Instincts That Make Us Overeat

by Stephan Guyenet

Yet when Levin’s team made the rats switch diets, they found that the rats seemed to defend dramatically different body weights depending on which diet they were currently eating. For example, when they were switched from Ensure to ordinary pellets, their food intake dropped impressively and they rapidly lost weight, until they approximated the weight of animals that had been eating pellets the whole time. When these same animals were switched back to Ensure, they gorged and quickly bounced back up to the weight of animals that had been eating Ensure the whole time. Again, it seemed as if the diets were not just passively causing weight gain but actually changing the set point of the lipostat...

Levin ascribed much of this effect to the diet’s palatability, in part because the rats would only overeat and gain weight on chocolate-fla...

:0 i need to include this in my presentation.

Five years after the machine-feeding studies, Michel Cabanac, a physiology researcher at Laval University in Canada, published another study that supported and expanded upon these findings. Cabanac’s team had a group of volunteers eat an unrestricted bland liquid diet for three weeks, which caused them to spontaneously eat fewer calories and lose just under seven pounds. Then the researchers had a second group of volunteers lose the same amount of weight over the same period of time by deliberately restricting the portion size of their normal diet. Cabanac found that the portion control group developed the expected hunger response to weight loss—but the bland diet group didn’t. He reported that the bland diet volunteers “reduced their intake voluntarily and were always in good spirits,” while the portion control group “had to continually fight off their hunger and would spend the night dreaming of food.” On the bland diet, the starvation response never kicked in. Cabanac concluded that diet palatability influences the set point of the lipostat in humans.

Cabanac found that the portion control group developed the expected hunger response to weight loss—but the bland diet group didn’t. He reported that the bland diet volunteers “reduced their intake voluntarily and were always in good spirits,” while the portion control group “had to continually fight off their hunger and would spend the night dreaming of food.” On the bland diet, the starvation response never kicked in. Cabanac concluded that diet palatability influences the set point of the lipostat in humans.

this seemslike a straghtforward evidence for reducing food palatability instead of portion control as a diet strategy.

The truth is that there are many ways to lose weight, but all else being equal, a diet that’s lower in reward value will control appetite and reduce adiposity more effectively than one that’s high in reward value.

calorie-dense, highly rewarding food may favor overeating and weight gain not just because we passively overeat it but also because it turns up the set point of the lipostat.

Researchers have often noted that people who exercise more frequently gain less weight over time. There’s a seemingly straightforward explanation for this: They’re burning more calories, so they remain in energy balance. This is probably at least partially correct, but there may be more to the story, as Barry Levin’s research suggests. His findings show, not surprisingly, that exercise attenuates weight gain in rats when they’re offered a fattening diet.107 Yet Levin’s data also reveal that fit rats aren’t just leaner—they actively defend a lower adiposity set point than sedentary rats on the same diet. This is actually quite consistent with human studies, in which physically fit people are better able to resist fat gain in the face of overeating. It appears that exercise helps keep the lipostat happy at a lower set point.

when we only consider studies in which volunteers had to regularly report to a research gym and exercise under supervision—ensuring compliance—a different picture emerges. In these studies, fat loss is often substantial, and it increases with the intensity and duration of the exercise regimen. So it appears that many of us in the research world, including myself at one time, may have misjudged exercise: It really does cause fat loss.

Another fact that’s often overlooked is the difference between weight loss and fat loss. When someone tries to slim down, the goal is not usually to lose weight—it’s specifically to lose fat. It turns out that exercise helps preserve muscle mass during weight loss. Although slow progress on the scale may be frustrating, changes in the mirror and in health as a result of exercise can be better than what the scale suggests.108

for me looking in the mirror isnt a good indicator of my weight because i vary in my attitude depending on clothing, how nice my hair looks, and how full i feel.

His team was able to show that injecting insulin into the brains of rats reduces the production of NPY in the hypothalamus and also reduces food intake. This was the first time anyone had been able to draw a biological road map from food intake, to a circulating hormone, to a brain circuit, and back to food intake.

Leptin reduced hunger-promoting NPY levels exactly as predicted, supporting the idea that leptin controls food intake (in part) by reducing NPY levels in the brain.

another group of proteins, called melanocortins, play the opposite role of NPY in the brain: When injected into the brains of rodents, melanocortins powerfully suppressed food intake.111 Like NPY, melanocortins are located in distinct neurons of the arcuate nucleus, which were named POMC neurons, after the POMC protein that is the precursor of melanocortins.

What emerged from these studies was a remarkably logical explanation for how leptin regulates the lipostat: It turns off neurons that drive eating, and it turns on neurons that inhibit eating. And, by implication, when leptin levels decline, neurons that drive eating turn on and neurons that inhibit eating turn off, increasing the drive to eat. This “push-pull” system is redundant and extremely robust, and only disrupting major nodes in the signaling pathway can derail it. Disrupting a major node is precisely what Albert Hetherington and Stephen Ranson did by damaging the VMN “satiety center” in the rat studies we encountered early in the last chapter. The VMN contains neurons that stimulate POMC neurons, and when it’s destroyed, POMC neurons become less active and cease to restrain appetite. As Hetherington and Ranson showed, this makes rats overeat tremendously and grow to impressive proportions. But it doesn’t require brain damage to disrupt a major node in the signaling pathway. Getting rid of leptin is another way to do so, and as we’ve seen, the result is the same.

His group was the first to specifically stimulate NPY neurons in awake, normally behaving mice.114 When they turn on NPY neurons, mice eat. A lot. I’ve replicated this experiment myself, and it’s quite impressive. With the flick of a switch, a mouse will stuff its face with whatever food is around—eating up to ten times what it would normally eat in the same period of time.

Furthermore, Sternson’s work shows that the way NPY neurons compel a mouse to seek food is by making the mouse feel bad until it eats.115 Like humans, mice don’t like to feel hungry, and relieving that hunger state by eating—or, in Sternson’s case, by turning off NPY neurons directly—is itself a reward.

wow. this is very interesting.

What this suggests is that the primary reason obese animals overeat and become tremendously fat is that their NPY neurons are in constant overdrive because there isn’t any leptin around to keep them in check. Get rid of the NPY neurons, and the animals slim down, even without a trace of leptin. This has a second, even more remarkable implication: The hunger, the obsession with food—many of the physiological and psychological effects that we see in people who are dieting, starving, or born without leptin—could be largely due to a population of hyperactive NPY neurons that is small enough to fit on the head of a pin.

As far as we currently know, NPY and POMC neurons are the most important convergence points between the adiposity-regulating inputs and outputs of the brain, and as such, they have attracted a disproportionate amount of attention from the scientific community.

In many ways, we’ve already reached the next level Schwartz is referring to. In fact, we’ve cured obesity countless times—in rodents. We now have the ability to take genes from almost any species, manipulate them to make them do what we want, insert them into the mouse genome so that they are expressed in specific cell populations of the brain, and use them to influence food intake, adiposity, and many other things. We can precisely activate, silence, or even kill specific populations of neurons in the mouse brain, controlling appetite and adiposity as if the mouse were a marionette. Modern neuroscience has achieved feats that would have seemed like science fiction to researchers only a few decades ago.

really? i havent heard of any circuit-level manipulations that specifically reset the mtabolic setpoint.

With time, we could undoubtedly adapt the techniques I described for use in ourselves. So what’s holding us back from curing human obesity? In a word, ethics. While we already have the technical ability to genetically engineer humans, and probably directly manipulate the brain circuits that control eating, we don’t currently consider it ethical.

table flipping emoticon.

on an unrelated note, how does Panera's bread slicer manage to cleave the bread so perfectly and crumblessly without heating the blade element? is it really just a matter of heavy blade falling at great speed, like a guillotine? i don't know why i am so amazed by this technology.

As far as his second goal, Schwartz hopes that our greater understanding of the lipostat will soon fulfill its promise to prevent and reverse obesity in humans. For me, this goal doesn’t seem very far off, but, as Schwartz cautions, “that’s what I thought when they discovered NPY.”

lol

all of this makes me think that working on intracranial infusion technology and advocating for transhumanism may be the most effective form of altruism.

Velloso wanted an answer to a simple question: What are the cells of the hypothalamus doing when an animal becomes obese? To do so, he used an RNA microarray to compare gene expression in the hypothalami of lean rats versus rats made obese by diet.

When Velloso’s team analyzed the data, a striking trend emerged: Many of the genes that were more active in obese mice were related to the immune system, and particularly a type of immune system activation called inflammation.

As Velloso noted in his 2005 paper, this makes perfect sense. Previous research had already implicated chronic inflammation in insulin resistance—a condition in which tissues like liver and muscle have a harder time responding to the glucose-controlling hormone insulin—and this process had already been linked to increased diabetes risk. It wasn’t a major leap to suppose that inflammation in the hypothalamus might ...

To further test this idea, Velloso’s team blocked a major inflammatory pathway in the brains of obese rats.117 They reasoned that if inflammation in the hypothalamus is really causing obesity, then blocking this inflammation should reduce food intake and body weight. And that’s exactly what they observed. Since Velloso’s discovery, other researchers have followed up on the finding, confirming that i...

this is an important section.

In a healthy brain, astrocytes are small cells that send out a web of thin filaments to monitor surrounding cells, and these filaments don’t overlap with the filaments of neighboring astrocytes. In an injured brain, astrocytes multiply and grow in size, and their filaments enlarge and overlap those of neighboring astrocytes

i did notknow this! is this a robust way of identifying gliosis in slies?

And we found it: Astrocytes in the hypothalami of obese rats and mice were enlarged, and their filaments were tangled together in a thick mat. Microglia had also enlarged and multiplied. Both changes were specifically located in the same area as NPY and POMC neurons (the arcuate nucleus), but not elsewhere. Our results suggest that obese rodents suffer from a mild form of brain injury in an area of the brain that’s critical for regulating food intake and adiposity. Not only that, but the injury response and inflammation that developed when animals were placed on a fattening diet preceded the development of obesity, suggesting that this brain injury could have played a role in the fattening process.

To see if humans with obesity show evidence of injury in the hypothalamus, we called on our colleague Ellen Schur, an obesity researcher at the University of Washington. She specializes in a technique called magnetic resonance imaging (MRI), which allows researchers and doctors to observe the structure of live tissues without harming them, sort of like an X-ray that can see soft tissues in great detail. One of the conditions doctors use MRI to diagnose is brain damage resulting from a past injury, such as stroke or physical trauma. This is because when the brain is injured, astrocytes go into overdrive to support the healing process, and they eventually form a scar that is visible on an MRI scan for a long time after the injury. This is analogous to how your skin grows scar tissue as it heals a cut.

Although we weren’t expecting to see stroke-like changes in the hypothalami of people with obesity, we thought it was worth looking for a subtler version of the same scarring—similar to what we found in rats and mice. And that’s exactly what we saw. Schur’s analysis showed that the more signs of damage we found in a person’s hypothalamus, the more likely he was to have obesity. What’s more, this effect was once again located in the part of the hypothalamus that harbors NPY and POMC neurons. “The scariest implication,” explains Schur, “is that the food we eat may cause damage in areas of the brain that we need to regulate our body weight and our appetite, as well as our blood sugar and, to some degree, our reproductive health.”

Just as a tumor in Elisa Moser’s hypothalamus caused her to develop obesity, a milder form of brain damage could be contributing to our own expanding waistlines.

the logic is more than sound, it's qualia.

the real question is whether there is any remaining adaptive advantage to astrogliosis and microglial activation in modern times. is it like the nonsensically exaggerated stress response arising from the lack of parasites in our bodies.

The diet Schwartz and I used in our research is a light blue pellet that has the texture of greasy cookie dough.

i bet it is.

Rodents greatly prefer this stuff to normal, unrefined, low-fat food, and when we give them unrestricted access to it, they gorge on it for the first week or so.

i have falsified this.

Some researchers believe the low fiber content of the diet precipitates inflammation and obesity by its adverse effects on bacterial populations in the gut (the gut microbiota).

omg i never considered this as an explanation of why hfd works. i wonder if the exposure to regular chow from week 3 to 4 actually makes a difference in microbiota.

in the United States, most of our annual weight gain occurs during the six-week holiday feasting period between Thanksgiving and the new year, and that this extra weight tends to stick with us after the holidays are over. Thanksgiving dinner is the definition of overeating, and Christmas Eve, Christmas Day, and New Year’s Eve aren’t far behind. Throughout that entire period, well-meaning family and friends inundate us with cookies, pies, and other tempting calorie-rich treats that tend to hang around the kitchen until we eat them.

i should obviously include thos in any essay aout the badnessof socially pressured food and eating.

The brain stem is the most ancient part of the brain, evolutionarily speaking, and it tends to govern deeply instinctual, nonconscious functions, such as digestion, breathing, and basic movement patterns (see figure 38). It is also, according to Grill’s research over the last forty years, the most important brain region for satiety.

Even more impressive, when offered food continuously, decerebrate rats would eat the same amount as intact rats normally eat during a meal and then abruptly refuse additional food. “They would take meals!” exclaims Grill, still excited by his seminal finding four decades later.

The similarity with normal rats didn’t end there. Decerebrate rats reacted to a variety of satiety-related signals in the same way as normal rats: They ate less at a meal when Grill’s team gave them a “snack” first, and they ate less in response to satiety hormones that the gut normally produces when we eat. This demonstrated, without a shadow of a doubt, that the brain stem is single-handedly capable of monitoring what’s happening in the gut and generating the satiety response that ends a meal.

di they sever the cranial nerves?

Thanks to the research of Grill and many others, we now have a reasonably clear picture of how this happens. When you eat food, it enters your stomach and stretches it. After partially digesting the food, your stomach gradually releases it into the small intestine. Here, specialized cells in the intestinal lining detect the nutrient content of what you ate, for example, the amount of carbohydrate, fat, and protein. These stretch and nutrient signals are relayed to the brain, primarily via the vagus nerve, which plays a major role in bidirectional gut-brain communication (see figure 39). At the same time, incoming nutrients cause the gut and pancreas to release a number of hormones that either activate the vagus nerve or act on the brain directly.

i need to read a review of harvey grill's researc.

These signals that encode the quantity and quality of food you just ate converge on a brain region called the nucleus tractus solitarius (NTS), which is the junction point of the vagus nerve with the brain stem. The NTS integrates the various signals ascending from the digestive tract and produces a level of satiety that’s appropriate for what you ate. These complex computations happen beyond your conscious awareness, and the only information your conscious brain receives is whether or not you feel full.

no they didnt sever all cranial berve because the vagus nerve is still intact.

Despite the fact that part of the hypothalamus was once called the satiety center, and leptin was dubbed the satiety factor, we now believe the brain stem is the primary brain region that directly regulates meal-to-meal satiety, while leptin and the hypothalamus primarily regulate long-term energy balance and adiposity.

Grill’s research shows that although decerebrate rats take normal-sized meals, if they are underfed, they are unable to compensate normally by increasing the size of subsequent meals. In other words, their satiety system works great, but their lipostat is out of the picture, once...

whoa.

A more accurate name for the hypothalamus would be the adiposity center, and leptin, the adiposity factor. Yet this distinction isn’t black and white: Grill’s research shows that the brain stem has a hand in regulating adiposity, and the hypotha...