Obesity as a Neurobiological Disease: Fatima Cody Stanford, MD, MPH

Despite decades of evidence pointing to the complex biology that underlies obesity, the condition is still widely perceived as a matter of willpower or personal choice. In this conversation with The American Journal of Managed Care^® (AJMC^®), Fatima Cody Stanford, MD, MPH, MPA, an obesity medicine physician at Massachusetts General Hospital and associate professor of medicine and pediatrics at Harvard Medical School, explains the brain pathways that make obesity a neurobiological disease, why that framing matters for how clinicians approach treatment, and how shifting away from blame can empower patients to engage more fully in their own care.

This transcript has been lightly edited for clarity.

AJMC: Your research reframes obesity as a neurobiological condition rather than a behavioral one. Can you walk us through the core mechanisms behind that understanding, and why the distinction matters for how we treat patients?

Stanford: It's important for us to recognize obesity as a neurobiological disease, because it really is. If we think about targets for pharmacotherapy, particularly the GLP-1 [glucagon-like peptide-1] receptor agonists, we recognize that a lot is happening within the hypothalamic regions of the brain. We can think about 2 primary pathways in the brain by which a lot of the biology is happening. We can think about the POMC [pro-opiomelanocortin] pathway in the brain, where the anorexigenic pathway is happening. This is the pathway that tells us not to eat very much. The second is the AgRP, or agouti-related peptide pathway, or the orexigenic pathway of the brain. When we're thinking about these 2 pathways, we must recognize that when we're thinking about that anorexigenic pathway, if we upregulate that pathway, it will tell us to eat less, store less, and then lead to a leaner phenotype. Of course, if we also inhibit the orexigenic or the AgRP pathway, then we are also causing a leaner phenotype by looking at that pathway.

Now if we’re talking about GLP-1 receptor agonists, their primary mechanism is to stimulate that POMC pathway and downregulate AgRP. And it's also important to recognize when we're talking about, let's say, the GLP-1 receptor agonists that we're talking about a different regulation of those brain-gut mechanics that happen within the body. As we start getting into dual agonists like the GIPs or the glucose-dependent insulinotropic polypeptides, that's also in our body. But even if we get back to some of our historic medications, like phentermine, which is still, for example, available here in the US, and we still use quite frequently. When we're looking at phentermine, which stimulates norepinephrine reuptake within the hypothalamus, or topiramate, which stimulates GABA, or gamma-aminobutyric acid, within the brain, we can hear that none of this is a matter of willpower. This is all happening within the brain, within parts of the periphery, and we can see that this is not a matter of willpower or self-control.

AJMC: Why do you think obesity has historically been framed as a behavioral problem?

Stanford: I think a lot of it is because we as humans, whether we are present here in the United States or around the world, have always wanted to believe that if we can will our way into something, eat less, exercise more, that the equation is just that simple. And it's nice to want it to be that simple. Let's think about it, if you just eat healthy, eat your vegetables, your protein, your beans, legumes, lentils, and just get out there and move your body. The mechanics sound good if we were just a vacuous object. But we are controlled by so many internal and external factors, and when you put all of those together in one individual, you recognize the heterogeneity of who we are and we are not as simple as that. I think that that’s really important for us to recognize.

AJMC: How does this neurobiological framework change the clinical encounter, especially for patients who have internalized the message that their weight is a matter of willpower?

Stanford: I think the shift in thinking about obesity as a neurobiological disease helps shift away this idea that it's about willpower and maybe empowers the patient to realize, “Maybe this isn't just my fault. Maybe this really is my biology, and maybe I can have a shared relationship with my clinician and figuring out how I can better govern my biology. So, let's talk about this with my clinician and look at different treatment modalities that may be under the umbrella of metabolic and bariatric surgery or pharmacotherapy or lifestyle or a combination thereof, and see if we can find something that treats my biology in the context of this obesogenic environment.” And I think that it helps empower them in a way that maybe they had not thought about previously, when they thought it was all their fault.