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Is the gut or the brain more important in regulating appetite and metabolism?
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The gut provides crucial information regarding what we eat and when we eat it; however, without the brain, there is nothing to interpret that information.
I do not deny the importance of the gut, which clearly plays a very important role in regulating appetite and metabolism. However, while hormones secreted by the gut provide useful information about what we’ve eaten, the actual translation of that information, which influences our appetitive behavior and interaction with foods, must be done by the brain. Receptors in the brain sense these signals that come from the gut and interpret the signals.
Additionally, the gut provides only part of the information our brain requires to fully regulate appetite. The gut provides short-term information — what you have just eaten — but the brain also needs to know how much fat you have, your long-term stores, in order to fully regulate appetite.
Undoubtedly, for treating metabolic diseases like type 2 diabetes, the microbiome is very exciting. For appetite regulation, the gut is going to be a huge target, because the gut produces signals that might be possible drug targets. Researchers, in effect, are hoping to “Trojan horse” a treatment, mimicking gut hormones that will, in turn, find their way to the brain and deliver different signals. Still, all of this has to go through the brain to make any difference whatsoever in terms of food regulation. We know, for example, from mouse studies and from naturally occurring human studies, that when the hypothalamus is damaged, either accidentally or through a tumor, you wind up tremendously obese. All these people have a fully functioning gut. What they do not have is the ability of the brain to interpret the signals from the gut.
When we look at the genetics of body size, we now know through genome-wide association studies that there are more than 200 genes that influence BMI. The vast majority of those genes are expressed in the brain — none of them in the gut. Even from a genetic perspective, when looking at body weight, all genes point to the brain as the main source of regulation.
Giles Yeo, PhD, is a principal research associate at the MRC Metabolic Diseases Unit at the University of Cambridge, U.K. Disclosure: Yeo reports no relevant financial disclosures.
The gut and the skin are the major access routes for us to have direct contact with our environment. Therefore, it stands to reason that the way we interact with our food has to come through the gut, and the gut must play a central role in regulating what happens when we receive those nutrients.
We have an endocrine system that has evolved to capture not only what type of calories are coming in, but what type of micro- and macronutrients are coming in — proteins, carbohydrates or fat. If we do not take in sufficient calories or the correct type of calories, the gut will send signals that will make the brain do certain things. As we put food into the gut, the gut will make the brain feel satisfied. If we do not put calories in, the gut will make the brain feel hungry. Those also turn out to be symptoms of obesity. People with obesity have excess hunger or reduction in satiety, both regulated by the gut.
I would absolutely agree that the brain makes the calls, but the gut influences those calls. However, research dating back several decades in decerebrate rats demonstrated that when the cortical and subcortical areas of the brain are disconnected, the rats’ feeding patterns remain intact. The gut can function without the brain, but the brain cannot function without the gut. We also know from scenarios where a person is declared brain dead that the gut is still functioning and can keep the body going, provided sufficient nutrients are placed inside the gut.
The brain is not one thing. When talking about the endocrine control of obesity as a disease, we are focusing on the subcortical areas of the brain. The gut is sending signals to the subcortical areas of the brain — not the parts of the brain that we use for philosophy or mathematics.
If we want to understand how our treatments for obesity can become better, and we now understand that obesity is a disease, then we can stop blaming people for their disease or think the patient has a lack of moral fiber. We can stop focusing our treatments on motivation; but if we understand that obesity is a disease of the subcortical areas of the brain, then we can consider how we can enhance how the gut is communicating with those areas. This will greatly enhance our therapeutic strategies. Now, you target a diet to make the person feel more satisfied or less hungry, or medications, such as gut hormone treatments, to make the person feel less hungry, or even using surgery to enhance satiety.
If I had to create a hierarchy, I would probably have to say the subcortical area of the brain is the most important, but this debate allows us to recognize that the gut plays a critical role, because it allows us to understand the disease of obesity and how to treat it.
Carel Le Roux, PhD, MSc, MBChB, FRCP, FRCPath, is a reader in investigative science at Imperial College London. Disclosure: Le Roux reports he has served on advisory boards for GI Dynamics and Novo Nordisk, received grants from AnaBio and Johnson & Johnson and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Johnson & Johnson and Sanofi.