Obesity and the brain

For a long time, scientists have looked at obesity as a disease of the body: the relationship between obesity and conditions like heart disease, high blood pressure, and diabetes has been well established. But in recent years, more and more research programs have focused on how obesity is linked to losses in brain function, including severe or accelerated cognitive decline.

“It's about time we acknowledge obesity is a disease with direct impact on the brain,” says neuroscientist (Biomedical and Molecular Sciences; Psychiatry).

The relationship between obesity and cognitive decline is clearer with each study – her work has demonstrated, for example, that animals with obesity have fewer brain nerve cells than those with a healthy weight. But the exact mechanisms through which the two conditions influence each other are still being unraveled.

A member of the and expert in Alzheimer’s disease, Dr. De Felice has been investigating the role of different hormones associated with obesity, including insulin, in cognitive decline. She’s seeking to uncover what could potentially protect patients’ brains from the negative impacts of obesity and comorbidities like diabetes. In 2019, she and her team demonstrated that irisin, a hormone boosted by physical activity, can slow down Alzheimer’s progression.

Dr. Fernanda De Felice (Biomedical and Molecular Sciences; Psychiatry).

The team’s new research paper, , focuses on another hormone, leptin, involved both in food intake and neurodevelopment. A genetic mutation that affects leptin signaling is often the cause of morbid obesity in young patients. Leptin resistance – like insulin resistance – can also be acquired throughout life and makes individuals feel hungrier and eat more. Both genetic and acquired changes in leptin signaling eventually lead to lower brain mass in comparison to individuals at a healthy weight.

The pre-clinical study led by Dr. De Felice investigated neurodevelopment in mice models genetically modified to suppress the expression of leptin-receptors – in these animals, the leptin signaling was “turned off.” But the research team was able to turn the gene back on, bolstering neurogenesis (the formation of new neurons in the brain) and therefore reversing some of the negative effects caused by leptin resistance in the central nervous system, including brain atrophy and cognitive deficit. In addition, the mice who received treatment also lost weight.

“Our study reinforces how important hormones are for both weight control and cognitive functions, including memory,” says Dr. De Felice. “Our results suggest that, if we can restore leptin signaling in obese patients, we might be able to reverse both excessive weight and brain damage.”

In the future, these results open new treatment pathways, for example, with CRISPR gene editing. But, while scientists work on these solutions, Dr. De Felice stresses that lifestyle interventions such as increasing physical activity and eating a healthy diet can also play an important role in decreasing leptin resistance.