Sabrina Diano Brings Brain Research Focus to Institute of Human Nutrition

Last year, nutrition and brain researcher Sabrina Diano, PhD, and colleagues discovered mechanisms by which mice fed a high-fat diet developed brain inflammation in just three days—even before they began to show signs of obesity.

The findings offer new clues about how fundamental processes in ancient parts of the brain may help explain the relationship between behaviors, like eating, and human disease. Diano is hoping the insights from her work will lead to improvements in human nutrition that may prevent or even reverse obesity and diabetes—and neurodegenerative diseases linked to these metabolic disorders.

The CUIMC Newsroom spoke with Diano about her research and her new role as director of the Institute of Human Nutrition at Columbia University Vagelos College of Physicians and Surgeons.

Why are you studying diet and the brain?

The brain plays a fundamental role in regulating behavior, including feeding behavior. This is the main interest of my laboratory. 

We know that different diets induce different feeding responses and metabolic outcomes in animals. For example, a diet rich in fats and carbohydrates—like fast food—in the long run leads to the development of obesity and diabetes. Interestingly, the first thing that happens before body weight increases and the animal becomes obese, leptin resistant, insulin resistant, and diabetic is that the brain develops inflammation. So we investigated the cause of this inflammation.

In a paper published last year, we showed that in animals fed this rich diet, the combination of fat and carbohydrate caused changes in specific cells within the brain in as little as a few days, causing inflammation of the hypothalamus that eventually expanded further in the brain. This has important implications not only for the metabolic outcome, but possibly for the development of brain disorders. 

How might brain inflammation caused by diet be linked to brain disorders?

Studies have shown a strong association between metabolic disorders such as obesity and diabetes and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Similar to obesity and diabetes, neurodegenerative disorders are also accompanied by a strong central inflammation. In the brain, the cells that cause inflammation when activated are called microglia. However, it is unclear whether the activation of these cells in neurodegenerative disorders is the cause or the consequence of the disease. Thus, the neuroinflammation that is triggered by the high-fat diet may represent the link between neurodegenerative disorders and metabolic disorders. 

We’ve been interested in understanding the intracellular mechanisms that induce brain inflammation and why these microglia cells are getting activated when we eat a calorie-dense diet. We found that the combination of nutrients in this diet (high in fats and carbs) activates a mechanism, which is related to mitochondria—the powerhouse of the cell that generates ATP (energy) necessary for cells to function. When we interfere with this mitochondrial mechanism in the microglia, we can prevent the development of a metabolic disorder. Basically, we can prevent the increase in body weight and obesity in animals exposed to that same diet.

Now we are trying to see if interfering with the same mechanism in an Alzheimer’s mouse model can delay the onset or have an effect on the development of this disorder. This would help explain why metabolic disorders are associated with the development of neurodegenerative disorders. 

How did you become interested in areas of the brain linked to depression?

Major depressive disorder is highly associated with decreased appetite and loss of body weight, but we don’t know why. So we became interested in looking at an area of the brain within the brainstem called the dorsal raphe nucleus, which has been shown to be an important regulator of mood. 

In our latest study, we found that inhibiting a metabolic signaling pathway in this area of the brain in mice resulted in decreased food intake and an increase in anxiety levels and depression-like behavior. This is very exciting for us, because it could explain the link between depression and a lack of interest in feeding associated with this psychiatric disorder. 

Why research the brain when trying to understand obesity or related conditions like diabetes?

Understanding the brain mechanisms that drive feeding could offer clues about how to combat metabolic disorders linked to overeating, like obesity and diabetes.

Our lab is interested in identifying the different neuronal populations in the brain that help regulate feeding, the signals that control these neurons, and then, eventually, the behavioral outcome, such as increasing or stopping feeding. The field has been focused on a very specific part of the brain, the hypothalamus, which was described almost a century ago as playing a role in feeding regulation. 

There’s always been this concept that high brain function, directed by the cerebral cortex, works to control our behavior. We should also look at how very basic brain structures, like the hypothalamus, which is highly conserved in mammals and has such a fundamental role in our survival and reproduction, must have great influence in parts of the brain that evolved later. So instead of looking top down, we are looking bottom up, to see how these brain regions influence high brain function.

We’re realizing that eating behaviors don’t only involve the hypothalamus; there are many other brain areas and circuits involved in feeding behavior.

Will we find a way to control these brain circuits so that people can lose weight?

In order to survive, eating has to be dominant, and from an evolutionary perspective, it is important to maintain this drive’s dominance. And that’s one of the reasons why it’s difficult to lose weight and keep the pounds off for a long time. It is also important to consider that the brain is a very complex organ. We can’t compartmentalize different parts of the brain and their functional effects because many brain regions communicate with each other. There is a lot of crosstalk between brain regions that control different functions. And this is why it’s very difficult to aim at one brain function without affecting another. For example, many medications that are used to treat depression or epilepsy also affect feeding and body weight. Thus, it is difficult to develop medications that address obesity and related metabolic disorders without having secondary side effects.

Why continue studying the brain if we can’t target specific circuits/areas to reduce obesity and related diseases?

By studying the brain and diets, we now understand that healthy eating is important not only for the overall health of the body but also for the health of the brain itself. It is simple: A healthy and balanced diet prevents deleterious outcomes, not only for the overall health of the body (preventing/curing obesity and diabetes), but also for the health of the brain and perhaps the ability to prevent neurodegenerative disorders. 

How does this approach fit into the overall mission of the IHN?

I’d like to highlight the importance of nutrition not only in preventing metabolic disorders, but also in other areas of medicine. As a basic scientist, I’m interested in understanding how different nutrients affect the brain and our whole-body metabolism and behavior and possibly contribute to the development of diseases. For example, how does nutrition play a role in cancer development? This is why nutrition is a very important topic to consider not only from a research perspective but also from an educational point of view.