Summary: New research shows the brain uses two separate neural circuits to regulate carbohydrate versus fat intake. In mice, glucoprivation — a drop in blood glucose induced experimentally — engages distinct neurons in the paraventricular nucleus of the hypothalamus (PVH). AMPK-regulated corticotropin-releasing hormone (CRH) neurons drive preference for high-carbohydrate foods, while melanocortin 4 receptor (MC4R)–expressing PVH neurons bias intake toward high-fat foods.
These PVH circuits are activated by neuropeptide Y (NPY)–producing neurons in the brainstem regions nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM) in response to energy deficit. The findings explain how the brain distinguishes nutrient types when restoring energy balance and suggest new targets to address overeating and metabolic disorders.
Key Facts
- Distinct circuits: Carbohydrate and fat consumption after glucoprivation are mediated by separate PVH neuron populations.
- Brainstem trigger: NPY neurons in the NTS and VLM activate both PVH pathways following glucoprivation.
- Behavioral output: ARC NPY neurons selectively influence fat preference by inhibiting PVH MC4R neurons, while PVH AMPK–regulated CRH neurons promote carbohydrate intake.
- Clinical relevance: Identifying nutrient-specific feeding circuits opens avenues for treatments targeting obesity, binge eating, and metabolic disease.
Source: NINS
Overview: Mammalian feeding is governed by complex neural networks. While many pathways that regulate total calorie intake are well described, how the brain selects specific nutrient types — for example, carbohydrates versus fats — has been less clear. This study addresses that gap by examining neural control of food choice during glucoprivation in mice.
Under normal conditions, mice display a strong innate preference for high-fat diets (HFD). However, when glucoprivation is induced by administration of 2-deoxy-d-glucose (2DG), mice increase consumption of both a high-carbohydrate diet (HCD) and an HFD. The researchers set out to identify the neural circuits responsible for these shifts in food choice.
Using a combination of chemogenetic and optogenetic approaches to manipulate specific neuron types, they traced how different NPY neuron populations influence PVH targets. They found that PVH-projecting NPY neurons in the NTS and VLM rapidly activate AMPK-regulated CRH neurons in the PVH, driving an immediate increase in carbohydrate intake that helps recover blood glucose. In parallel, PVH-projecting NPY neurons from the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) suppress MC4R-expressing PVH neurons, which promotes fat consumption — reflecting the mice’s baseline preference for fatty foods. Notably, ARC NPY neurons had a particular role in promoting HFD selection.
Taken together, these results reveal two anatomically and functionally distinct pathways within the PVH that selectively promote HCD or HFD intake following glucoprivation. The study clarifies how upstream brainstem and hypothalamic NPY populations differentially shape nutrient-specific feeding behavior.
Key Questions Answered:
A: The hypothalamus engages distinct PVH circuits: AMPK-regulated CRH neurons promote carbohydrate intake, while MC4R-expressing neurons favor fat intake.
A: Glucoprivation triggers NPY neurons in the brainstem (NTS and VLM) to activate PVH circuits, prompting consumption of nutrient-dense foods to restore energy balance.
A: They reveal nutrient-specific control of feeding behavior in the brain, identifying candidate neuronal targets for interventions against obesity, diabetes, and binge-eating disorders.
About this neuroscience and food craving research news
Author: Hayao KIMURA
Source: NINS
Contact: Hayao KIMURA – NINS
Image: The image is credited to Neuroscience News
Original Research: Open access. “Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus” by Nawarat Rattanajearakul et al. Metabolism
Abstract
Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus
Background
While pathways that regulate overall calorie intake are well characterized, mechanisms that control selection among different macronutrients remain poorly understood. This study investigates how glucoprivation influences choice between carbohydrate- and fat-rich foods.
Methods
Male mice underwent glucoprivation via intraperitoneal 2-deoxy-d-glucose (2DG) administration and were given a diet choice between a high-carbohydrate diet (HCD) and a high-fat diet (HFD). The investigators used chemogenetic and optogenetic tools to selectively modulate AMPK-regulated CRH neurons, MC4R neurons in the PVH, and NPY neurons that project to the PVH, then measured subsequent food selection and neural activity.
Results
2DG-induced glucoprivation engaged two separate PVH pathways that drive different nutrient preferences. Activation of PVH-projecting NPY neurons in the NTS and VLM rapidly stimulated AMPK-regulated CRH neurons in the PVH, increasing HCD intake and aiding recovery from low blood glucose. At the same time, PVH-projecting NPY neurons from the NTS, VLM, and ARC inhibited PVH MC4R neurons and promoted HFD consumption, consistent with mice’s innate fat preference. ARC NPY neurons were specifically implicated in enhancing HFD selection.
Conclusion
This work uncovers a previously unrecognized, nutrient-specific organization of feeding circuits: distinct NPY inputs to the PVH separately drive carbohydrate versus fat intake during glucoprivation. These insights offer a refined framework for understanding food choice and may guide future strategies to treat metabolic and eating disorders.