Stress and high fat diet reconfigure the active translatome of CeA-NPY neurons

TL;DR

Stress and high-fat diets change how CeA-NPY neurons translate RNA, linking appetite and emotional responses.

Contribution

The study reveals how stress and high-fat diets jointly affect the active translatome of CeA-NPY neurons.

Findings

CeA-NPY neurons show orexigenic traits and connect to brain regions involved in feeding and emotion.

Stress combined with high-fat diets alters lipid-sensing and synaptic pathways in these neurons.

NPY expression is downregulated by high-fat diets but accelerated by chronic stress.

Abstract

The interplay between calorie-dense food and chronic stress significantly accelerates obesity development, with neural circuits expressing Neuropeptide Y (NPY) in the central amygdala (CeA) emerging as the key mediator of this process. While these circuits are known to enhance hedonic feeding behavior and promote weight gain, the precise molecular mechanisms regulating NPY neuron activity at the translational level under the combined influence of high fat diet and stress conditions have remained poorly understood.

We employed translational ribosome affinity purification coupled with Next-Generation Sequencing (TRAPseq), allowing us to specifically identify RNA transcripts actively undergoing protein translation in NPY neurons under high fat diet (HFD) or high fat diet combined with stress conditions (HFDS).

Our molecular profiling demonstrates that NPY neurons specifically co-express with genes marking the orexigenic (appetite-stimulating) population, while showing minimal overlap with anorexigenic (appetite-suppressing) markers. Gene ontology analysis identified distinct clusters involved in fatty acid metabolic processes, stress response pathways, and the production of feeding-related neuropeptides specifically under HFDS. Immunohistochemical investigations revealed in addition to local CeA (CeAm) NPY connection pathways, long-range projections, to the lateral habenula (LHb), the periaqueductal gray (PAG) and parvicellular reticular formation (PCRt). These projections suggest a specific role for CeA NPY neurons in coordinating feeding and emotional responses.

Collectively, our findings identify specific lipid-sensing mechanisms and synaptic modulating pathways as principal targets of stress within the CeA-NPY circuit, revealing novel molecular mechanisms through which NPY neurons integrate and process both dietary and stress signals.

•Central amygdala NPY neurons are of orexigenic nature.•High fat diet downregulates NPY expression in the CeA.•Chronic stress in combination with HFD accelerates NPY expression and action.•CeA NPY neurons coordinate feeding and emotional responses.•HFD combined with stress modulates lipid-sensing mechanisms and synaptic pathways in CeA-NPY neurons.

Central amygdala NPY neurons are of orexigenic nature.

High fat diet downregulates NPY expression in the CeA.

Chronic stress in combination with HFD accelerates NPY expression and action.

CeA NPY neurons coordinate feeding and emotional responses.

HFD combined with stress modulates lipid-sensing mechanisms and synaptic pathways in CeA-NPY neurons.

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