Rebel Neurons Fuel Appetite in Obesity

Our appetites should normally be linked to the levels of energy stored in our body, increasing when we need additional fuel. Nevertheless, excessive eating behavior fuels obesity. Researchers have identified a subset of brain cells that intensify appetite when an extended energy surplus is present in the body – for example, high levels of body fat in obesity. The findings, published in the journal Cell Metabolism by a team from the Garvan Institute of Medical Research, offer a fresh perspective on obesity and could pave the way for innovative anti-obesity treatments.

Over one in ten adults globally are obese. This figure is drastically increased in Western countries – as of 2020, over four in ten adult Americans were obese. This is a significant health concern due to obesity’s links with long-term health conditions like diabetes and heart disease. The origins of obesity are complex, but the condition primarily stems from an excessive accumulation of fat tissue in the body and is influenced by dietary habits and exercise levels.

How the brain regulates body weight

Our appetite is a complex system regulated by a network of different molecules throughout the brain and body. The current study focused on one of these molecules, NPY (neuropeptide Y). "Our brain has intricate mechanisms that sense how much energy is stored in our body and adjust our appetite accordingly. One way it does this is through the molecule NPY," explained

Professor Herbert Herzog, a visiting scientist at the Garvan Institute and the study’s senior author. “When the energy we consume falls short of the energy we spend, our brain produces higher levels of NPY. When our energy intake exceeds our expenditure, NPY levels drop and we feel less hungry. However, when there is a prolonged energy surplus, such as excess body fat in obesity, NPY continues to drive appetite even at low levels. We wanted to understand why,” Herzog added.

Herzog and his colleagues investigated cells in the brains of mice that release NPY. A significant chunk of these neurons – around one in six of the population – did not shut down NPY production even under obese conditions.

This chunk of rebel neurons was sufficient to drive appetite and even resulted in further changes in brain biology. “These cells did not only produce NPY, but also sensitized other parts of the brain to produce additional receptors or 'docking stations' for the molecule – supercharging appetite even further," Herzog said.

A “vicious cycle”

Herzog called this process a “vicious cycle” where the body’s careful metabolic balance between its energy input and stores is knocked out of balance, influencing the development of obesity.

“Our brain is wired to resist energy deficiency or weight loss, as it sees this as a threat to our survival and kickstarts mechanisms that increase our appetite so that we seek out food.  As we found now, this even occurs when we have excess energy stored in the body,” Herzog added.

The researchers hope to use this initial finding as a launchpad for exploring interventions for obesity that might be able to block the hypersensitive NPY receptors.

“Our study addresses a long-standing question about how appetite is controlled in obesity and has the potential to take the development of therapy into a new direction,” Herzog concluded.

Reference: Qi Y, Lee NJ, Ip CK, et al. Agrp-negative arcuate NPY neurons drive feeding under positive energy balance via altering leptin responsiveness in POMC neurons. Cell Metabolism. 2023;0(0). doi:10.1016/j.cmet.2023.04.020

This article is a rework of a press release issued by the Garvan Institute of Medical Research. Material has been edited for length and content.