Hunger Switch: The Tiny Nucleus In the Brain That Decides Whether You Eat More Or Less

Researchers have discovered a new group of neurons in the brain that help control hunger and body weight. These neurons are influenced by a hormone called leptin, which is produced by body fat. When this hormone does not act correctly in these neurons, a person feels hungrier and can gain weight. This discovery could pave the way for new treatments for obesity.

Obesity and overeating are serious public health problems worldwide, and more effective treatments are still needed. To achieve this, it is essential to better understand how the body controls appetite and food consumption.

One of the most important hormones in this process is leptin. It is produced by the body's fat cells and acts as a signal to the brain about the amount of fat stored. The more fat we have, the more leptin is released, helping to regulate appetite and energy expenditure.

When there is a deficiency of leptin or when the brain does not respond properly to it, the person feels hungrier and burns fewer calories, which can lead to severe obesity. This process has been observed in both animals and humans.

Leptin acts primarily in the brain, especially in a region called the arcuate nucleus of the hypothalamus (ARC). Within this area, there are groups of neurons that have opposing roles: some reduce appetite (such as POMC neurons), while others increase hunger (such as AgRP and NPY neurons).

However, research shows that leptin does not exert such significant direct control over neurons that reduce appetite in adults. And while the absence of the leptin receptor (LEPR) in AgRP-type hunger-increasing neurons causes moderate obesity in young animals, the same manipulation in adults results in more significant weight gain.

This shows that neurons other than hunger-increasing neurons are also involved in this appetite control system.

Recently, scientists at the Max Planck Institute for Metabolism Research in Germany have identified a new group of neurons in the arcuate nucleus of the hypothalamus that may be behind this process: neurons that express a substance called prepronociceptin (PNOC).

These neurons are GABAergic (i.e., they use the neurotransmitter GABA) and help promote weight gain in mice fed high-fat diets. In addition, they directly inhibit appetite-suppressing neurons that would normally help reduce appetite.

These PNOC neurons have also been found to respond to glucose and, in some cases, are inhibited by leptin, indicating their importance in regulating eating behavior.

This image shows how reactivating the leptin receptor (Lepr) in a specific group of neurons called PNOCs can help control body weight. In panel (A), scientists genetically engineered mice so that only the PNOC neurons had the leptin receptor reactivated. Panel (B) shows the visual difference between the groups: the mice with Lepr knocked out (left) are much larger than the mice with Lepr restored in the PNOC neurons (middle) and the healthy controls (right). Graph (C) shows that the mice without Lepr gained much more weight over time, while the mice with Lepr reactivated were in between, and the controls were the lightest. Graphs (D) and (E) confirm this with measurements of total weight and amount of body fat. Panels (F) and (G) show images of the brain highlighting a protein (pSTAT3) that indicates that the neurons are responding to leptin. Mice with Lepr in their PNOC neurons showed more of this protein than those without the receptor, indicating that leptin was partially functioning again in these brains. In short, this shows that activating the leptin receptor in these specific neurons can help reduce obesity.

In this study, the researchers showed that an important part of leptin’s action in controlling hunger and body weight occurs through PNOC neurons. When the scientists removed the leptin receptors from these neurons, the animals developed obesity due to increased food intake, even though the neurons still produced PNOC.

Using a genetic sequencing technique, the scientists observed that the absence of the leptin receptor in these neurons caused them to produce more neuropeptide Y (NPY), a potent appetite stimulant. Interestingly, these neurons that increased NPY were not the classic hunger-inducing neurons, but rather a new population of PNOC neurons that express neuropeptide Y but not Agrp.

These new PNOC/NPY neurons also express the leptin receptor, and when they were artificially activated, they caused a marked increase in food intake. Furthermore, this same type of neuron has also been identified in the human brain, which suggests that the results may be relevant for future treatments.

Increased expression of NPY in PNOC neurons of mutant mice, but not in AgRP neurons. Using a technique called "in situ hybridization" to identify which genes were being activated in these neurons, three of them were marked with different colors: Pnoc (green), Npy (cyan/light blue) and Agrp (magenta). The images shown compare two groups of mice, a normal group and another with a genetic modification in the neurons that express Pnoc (PNOCΔLEPR), in two situations: (A) after fasting for 16 hours and (B) after having been fed for 1 hour. The scales in the image indicate the size of the cells. In the graphs (C and D), the researchers count how many cells were active with the NPY and AgRP genes in both conditions (fasting and after feeding). This helps to understand how these neurons respond to hunger and feeding, especially when leptin (the hormone that regulates hunger) is absent in these neurons.

Finally, when the scientists forced these neurons to produce more neuropeptide Y, the animals ate more and became obese, but this only happened when the change was made to the PNOC neurons, not the AgRP neurons.

In short, this study reveals that a specific group of neurons in the brain, called PNOC/NPY, is critical to leptin’s action in controlling appetite. These neurons offer a promising new route to developing more effective treatments for obesity.

READ MORE:

Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis 

Marie H. Solheim, Sima Stroganov, Weiyi Chen, P. Sicilia Subagia, Corinna A. Bauder, Daria Wnuk-Lipinski, Almudena Del Río-Martín, Tamara Sotelo-Hitschfeld, Cait A. Beddows, Paul Klemm, Garron T. Dodd, Sofia Lundh, Anna Secher, F. Thomas Wunderlich, Lukas Steuernagel, and Jens C. Brüning

Cell. 23 April 2025

DOI: 10.1016/j.cell.2025.04.001

Abstract:

Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin’s anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.