Obesity as a disorder of the brain

The biology behind energy homeostasis

I studied obesity in grad school (in classes and in research), and during that time I grew to appreciate the importance of biological factors in weight maintenance. That’s not to diminish the role of other things—like the environment, psychology, and personal choices—in regulating weight. Those things are important, but I do think that the role of the brain has been largely overlooked in the public discourse...

That is until the advent of Ozempic, approved for weight loss in 2021. Suddenly targeting the brain became actionable weight loss advice. Ozempic and its related class of drugs do help some people (but not all) lose weight. Perhaps equally important is that the success of this drug has brought awareness to the fact that obesity is not a personal failing. I have seen people share online that after taking this drug, for once, their lives didn’t revolve around food. For once, they felt normal. 

So, I am a bit late to the party talking about this, but I do have some things to say, so here goes:

The part of the brain implicated in maintaining energy balance is called the hypothalamus. The hypothalamus gets signals from all over the body—from fat cells, the digestive system, the pancreas, the thyroid, other parts of the brain—to make an executive decision: are you hungry or are you full?

For most people, the hypothalamus works fine. Perhaps such people may groan and fiddle with their diet before a wedding ceremony or after a particularly busy holiday season. But they can mostly rely on their body’s hunger cues to maintain their weight. 

For others, listening to their body’s hunger cues will lead them to gain weight, sometimes rapidly. Less commonly, these cues may be misbalanced to lead to weight loss. For example with hyperthyroidism. Hyper- like hypothyroidism does also affect energy expenditure but the weight changes seen in these conditions is due to energy intake not being adjusted to match the new energy output.

People in this position can’t rely on their hypothalamus to maintain their body weight. If they wish to move their weight in a different direction than their body’s hunger cues, they must, basically, offload the task to their prefrontal cortex. This may involve consciously monitoring what they're eating, tracking calories with pen and paper, and adjusting their plan based on which direction the scale is moving. Whatever the case, deliberately monitoring energy intake not only requires time, attention, and mental energy. But also going against what their body wants them to do puts people in a position of physiological discomfort. It’s not pleasant to be hungry.

You might say, wait now—isn’t it that we have too much high energy density food that’s driving the obesity epidemic? All that refined sugar and processed food? All that sitting around? This is true. The global rise in obesity has undeniably been due to a change in our environment. However, my conceptualization of obesity (and this is not an uncommon one) is that some people are more predisposed to overeating in this new environment than others.¹

Bringing it back to something that we can see in our every day lives: the fact that obesity is a brain disorder can most easily be seen in toddlers. Toddlers do not really understand the relationship between food and weight, nor do most of them care. Toddlers aren’t glutinous if heavy, and toddlers aren’t self-disciplined if thin. They just eat what’s available to them when they’re hungry, and they stop when they’re full. Importantly, it’s also not the fault of the parents if toddlers are heavier—it’s extraordinarily difficult to deny a hungry child food even if you know they’ve already had too much to eat.

Same with pets. Some pets will overeat unless their diets are closely monitored and meals doled out on a regular schedule. Other pets are extraordinarily picky and will only eat some foods and only in small amounts. Yet other pets seem to maintain a relatively healthy weight without much intervention on the part of the owner. I have cared for all three kinds. 

A little more about the science

So, how do we know that the hypothalamus plays a role in energy regulation? Originally, we know this from animal studies in which the hypothalamus was in various ways manipulated resulting in either weight gain or weight loss in the animal. We rely mostly on the concept of homology (the conservation of function between species due to common ancestry) to infer the hypothalamus’s equivalent role in humans. We can’t willy nilly manipulate the hypothalamus in humans to see what happens (and frankly, it’s debatable whether we should be doing it to animals), but there has been some solid human genetics done to confirm the hypothalamus’s role in energy homeostasis in humans. Mainly, three monogenetic disorders that  cause severe obesity in humans affect proteins that do their job in the hypothalamus.

The hypothalamus, as I said earlier, interprets signals from all over the body. Below is an incomplete list of some of the signals that inform it:

• Ghrelin: the first hunger hormone discovered. It is released by the stomach.

• Leptin: a signal of satiety released by fat cells. The more fat that is stored, the more leptin that should be in bloodstream reducing desire to eat.

• Insulin: released by the pancreas in response to glucose in the bloodstream. Glucose itself may also directly signal the hypothalamus.

• Glucagon-like peptide 1 (GLP-1), Peptide YY (PYY), cholecystokinin (CCK): released by the intestines to promote satiety. GLP-1 is the target of weightloss drugs like Wegovy

• The circadian clock: every cell in the body keeps a circadian clock, with the master circadian clock in the suprachiasmatic nucleus located in the brain. The circadian clock determines the timing of the daily release of hormones like ghrelin. It’s why you are hungry at the same time every day. Disruption of the circadian rhythm (for example, with night shift work) associates with obesity.

• Melanocortin system: A circuit in the brain of POMC, NPY, AgRP neurons that regulate hunger/satiety in and around the hypothalamus

• Hypothalamic-pituitary-adrenal axis: Mediates the release of the stress hormones like cortisol, which plays a role in hunger/satiety.

Now, when any one of these signals break or is weakened, the other signals may hypothetically be able to make up for it (there is some redundancy in the hunger/satiety network). But also, the complexity of the network (of which we only understand a small piece of, new research is still being done) means that there are a lot of places that things can go wrong. 

For example, when leptin was discovered in 1995 as the first satiety signaling hormone, there was a lot of excitement. Both the general public and researchers thought that they may have found the cause and the treatment for obesity. However, during clinical trials, the response to leptin administration was not promising and, moreover, most people with obesity already had a lot of leptin circulating in their system. Few cases of obesity were due to lack of leptin, and those that were due to lack of leptin seemed to respond well to the treatment. Why leptin-deficiency screening is not a common practice in medicine is something I do not know. Perhaps because it is an extremely rare condition? I’m not in the know of how these findings are translated to common medical practices.

Later, we started doing population studies. This is because, since the human genome was sequenced in 2001, we now had the tools to measure genomes at scale. Studies looking at hundreds of thousands of people identified genetic variants that are more common in obese individuals than in healthy-weight individuals. (Note: BMI has been criticized as a poor measurement of obesity. This may be true on an individual basis, but BMI is still a very good proxy for obesity in population studies. It is easier and cheaper to measure than something like body fat percentage.) Over 900 variant associations have been discovered (Yengo 2018, Locke 2015, Akbari 2023). Some of these variants may more or less strongly associated with the disease. For example, a rare variant in MC4R (this association was actually discovered before population studies) almost always results in severe childhood onset obesity. Other variants may only associate with a small risk towards obesity. For example, a variant in the gene FTO confers some risk towards obesity, but that risk is mitigated by exercise—demonstrating that a genetic variant may predispose someone towards obesity in certain environments and not in others.

Most strikingly, when we look at what role the variants discovered in the population studies do in our bodies we see a clear pattern. To quote a few papers: 

“Altogether, we found that height-associated genes are significantly enriched among genes contributing to skeletal growth, cartilage and connective tissue development, while BMI-associated genes are mostly enriched among genes involved in neurogenesis and more generally involved in the development of the central nervous system.” (Yengo 2018; https://doi.org/10.1093/hmg/ddy271)

“Current results are not sufficient to isolate specific brain regions important in regulating BMI. However, we observe enrichment not only in the hypothalamus and pituitary gland—key sites of central appetite regulation—but even more strongly in the hippocampus and limbic system, tissues that have a role in learning, cognition, emotion and memory.” (Locke 2015; https://doi.org/10.1038/nature14177)

“A tissue expression analysis for BMI-associated genes in our results revealed an overrepresentation of genes that are highly and specifically expressed in the hypothalamus, a key center for the neuroendocrine regulation of energy balance.” (Akbari 2021; https://doi.org/10.1111/gean.12312)

In other words, the genes involved in regulating body weight are predominantly brain genes.

I rest my case. Also, this essays keeps getting longer the more I work on it.

If you’re interested in learning more check out this review: Loos 2022; https://doi.org/10.1038/s41576-021-00414-z. The authors discuss the recent developments in genetics research of obesity, and pull from the same body of literature I do, but write for a more technical audience. 

1. And I might add that it’s a tragedy that we have so much trouble regulating the food industry to make the environment more conducive to more people.