Researchers pinpoint brain cells and circuitry that drive appetite in obesity

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"A team ... has discovered a group of brain cells that boosts appetite when there is a prolonged surplus of energy in the body, such as excess fat accumulation in obesity.

The researchers discovered that these cells not only produced the appetite-stimulating molecule NPY, but they in fact made the brain more sensitive to the molecule, boosting appetite even more. ...

In mouse models of obesity, the researchers investigated cells in the brain called neurons that produced NPY and discovered that surprisingly, 15% of them were different – they did not shut down NPY production during obesity.

“We found that under obese conditions, appetite was mostly driven by NPY produced by this subset of neurons. These cells did not only produce NPY, but also sensitised other parts of the brain to produce additional receptors or ‘docking stations’ for the molecule – supercharging appetite even further,” ...

“What we have uncovered is a vicious cycle that disrupts the body’s ability to balance its energy input with energy storage and enhances obesity development.” ...
The researchers say their discovery opens the possibility of blocking the additional, more sensitised receptors for NPY as a new approach to developing anti-obesity medication. ..."

From the abstract:

"Neuropeptide Y (NPY) in the arcuate nucleus (ARC) is known as one of the most critical regulators of feeding. However, how NPY promotes feeding under obese conditions is unclear. Here, we show that positive energy balance, induced by high-fat diet (HFD) or in genetically obese leptin-receptor-deficient mice, leads to elevated Npy2r expression especially on proopiomelanocortin (POMC) neurons, which also alters leptin responsiveness. Circuit mapping identified a subset of ARC agouti-related peptide (Agrp)-negative NPY neurons that control these Npy2r expressing POMC neurons. Chemogenetic activation of this newly discovered circuitry strongly drives feeding, while optogenetic inhibition reduces feeding. Consistent with that, lack of Npy2r on POMC neurons leads to reduced food intake and fat mass. This suggests that under energy surplus conditions, when ARC NPY levels generally drop, high-affinity NPY2R on POMC neurons is still able to drive food intake and enhance obesity development via NPY released predominantly from Agrp-negative NPY neurons."

Researchers pinpoint brain cells that drive appetite in obesity | Garvan Institute of Medical Research A group of brain cells discovered by Garvan Institute researchers reveals a potential new approach to anti-obesity treatment.

Agrp-negative arcuate NPY neurons drive feeding under positive energy balance via altering leptin responsiveness in POMC neurons (partial public access)

Graphical abstract