Summary: Researchers at Hiroshima University report that NPGL, a recently discovered hypothalamic protein, increases appetite during fasting and reduces it after overeating, suggesting a role in maintaining body weight and energy balance.
Source: Hiroshima University.
Why food seems more appealing when you diet
Scientists have identified a small hypothalamic protein called neurosecretory protein GL (NPGL) that appears to adjust appetite depending on energy status. According to research led by Professor Kazuyoshi Ukena of Hiroshima University, NPGL elevates hunger during periods of calorie restriction and suppresses appetite after short-term overconsumption, acting as part of the brain’s system for preserving body mass.
This discovery adds an important layer to our understanding of appetite regulation and energy homeostasis. Previously, two hormones were central to the popular model: leptin, produced by fat cells, which reduces food intake, and ghrelin, produced by the stomach, which stimulates hunger. Both influence neuronal circuits in the hypothalamus, the brain region that controls energy balance. The identification of NPGL shows these regulatory networks are more complex and introduces a new neuropeptide that directly affects feeding behavior.
Professor Ukena first detected NPGL in birds, observing that young chickens exhibited increased growth regardless of dietary changes. This prompted a search for NPGL across species; database analysis revealed that NPGL is conserved across vertebrates, including mammals and humans. To study its function in mammals, Ukena’s team examined NPGL expression and effects in mice under different dietary conditions.
Three groups of mice were used: one fasted for 24 hours, a second fed a high-fat diet for five weeks, and a third given a high-fat diet for 13 weeks. The fasting mice showed a substantial rise in NPGL expression in the hypothalamus, while the five-week high-fat group showed a marked decrease. Interestingly, NPGL expression returned to baseline in mice exposed to the high-fat diet for the longer 13-week period, suggesting adaptive changes over prolonged energy excess.
Anatomical mapping revealed that NPGL-producing neurons and their projections are located in the mediobasal hypothalamus, in the lateroposterior part of the arcuate nucleus—regions already known to interact with appetite-suppressing and appetite-stimulating systems. NPGL-immunoreactive fibers are found near pro-opiomelanocortin (POMC) neurons, which are key mediators of satiety signaling.
Functional tests support NPGL’s role in promoting feeding: mice given intracerebroventricular injections of mature NPGL displayed increased food intake. Based on these findings, the research team proposes that NPGL acts as an appetite promoter when energy reserves are low, functioning in opposition to leptin’s suppressive action. When energy intake is high for short periods, NPGL expression falls, which could help limit further intake.
The return of NPGL levels to normal after prolonged high-fat feeding is consistent with the development of leptin resistance during chronic overnutrition. In such a state, leptin’s ability to suppress appetite diminishes, so even normal NPGL levels may contribute to continued weight gain and the progression toward obesity. This suggests that NPGL participates in the same homeostatic circuitry that can become dysregulated in metabolic disease.
Professor Ukena emphasizes that further research is needed to define how NPGL interacts with established appetite-regulating signals and to determine the broader implications for energy balance and metabolic disorders. Understanding NPGL’s modes of action may open new avenues for addressing conditions such as obesity or cachexia, but translating these findings into therapies will require more detailed study of its receptors, pathways, and long-term effects.
For now, the discovery helps explain why dieting is often so challenging: molecular systems like NPGL are designed to defend body weight, increasing hunger when calories are scarce and adapting under prolonged overnutrition. These innate mechanisms illustrate the evolutionary pressure to maintain energy stores and survive fluctuating food availability.
Funding: Research supported by JSPS Fellows and the Program for Promotion of Basic and Applied Sciences.
Source details: Norifumi Miyokawa, Hiroshima University. Image credit: Kazuyoshi Ukena.
Original research: Daichi Matsuura, Kenshiro Shikano, Takaya Saito, Eiko Iwakoshi-Ukena, Megumi Furumitsu, Yuta Ochi, Manami Sato, George E. Bentley, Lance J. Kriegsfeld, and Kazuyoshi Ukena. Title: “Neurosecretory protein GL, a hypothalamic small secretory protein, participates in energy homeostasis in male mice.” Endocrinology. Published online March 17, 2017. DOI: 10.1210/en.2017-00064.
Abstract (summary)
Neurosecretory protein GL (NPGL) is a small secreted protein first identified in the avian hypothalamus. In chicks it promotes weight gain. This study identified the NPGL precursor in the mouse hypothalamus and localized NPGL-expressing neurons to the lateroposterior arcuate nucleus. NPGL fibers make anatomical contact with pro-opiomelanocortin neurons. NPGL mRNA increases after 24-hour fasting and decreases after five weeks of high-fat feeding, and central administration of mature NPGL stimulates food intake. These results indicate that NPGL is a conserved hypothalamic peptide that participates in mammalian energy homeostasis.
Please cite the original research article for full experimental details and methodology. This summary aims to convey the main findings and their potential implications for appetite regulation and energy balance.