Key result
High fat diet plus stress upregulates metabolic and stress genes in CeA-NPY neurons versus diet alone.
Why the study?
The molecular mechanisms regulating NPY neuron activity at the translational level under combined high-fat diet and stress conditions were poorly understood.
Combined stress and high-fat diet reconfigure the active translatome of CeA-NPY neurons, highlighting specific lipid-sensing and synaptic modulating pathways.
Rodent data implicate CeA-NPY neurons in diet-stress feeding; hypothesis-generating for human obesity mechanisms.
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. To address this, 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 (CeA m ) 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.
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Ip et al. (2025) studied Obesity and chronic stress. High fat diet combined with stress conditions (HFDS) vs. High fat diet (HFD) alone was evaluated on Active translatome of NPY neurons. High fat diet combined with stress altered the active translatome of CeA-NPY neurons, upregulating genes involved in fatty acid metabolism, stress response, and feeding-related neuropeptides.
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