Neural Mechanisms of Emotional Eating: The Role of Lateral Hypothalamic Proenkephalin Neurons


Emotional eating, characterized by the excessive consumption of comfort foods in response to negative emotional valence rather than physical hunger, has been a subject of scientific inquiry due to its impact on individuals exposed to life-threatening events. This phenomenon provides relief from distress and tension, allowing individuals to regain a sense of control.

Despite previous studies indicating the involvement of feeding-related neural circuits and neuroendocrine systems in stress-induced maladaptive responses, the specific neural circuits and hormonal dynamics remain unclear.

The Lateral Hypothalamus (LH) as a Nexus of Behavior:

The LH, a significant component of the hypothalamus, houses genetically distinct cell populations associated with various primitive behaviors such as feeding, emotion, and stress responses. Hypocretin-expressing LH neurons have been linked to the hypothalamic-pituitary-adrenal (HPA) axis, influencing stress responses. Leptin receptor-expressing LH circuits play a role in the regulation of palatable food consumption. However, the key LH neuronal populations involved in threat-triggered emotional eating remain poorly characterized.

Proenkephalin’s Role in Emotional Processes:

Proenkephalin (Penk), a precursor of endogenous opioid peptides, is expressed in multiple brain regions, modulating neuropeptidergic systems that control physiological and emotional processes. While the roles of Penk in various brain regions have been explored, its function in LH circuitry concerning emotional eating remains unexplored.

Stress Hormones and Corticosterone:

Stress hormones, particularly corticosterone (CORT), can stimulate appetite. Threat-induced transient elevations of CORT may interact with specific hypothalamic neurons, sensitizing responses to palatable foods. The role of CORT in long-term changes in LH neuronal properties related to emotional eating is not well-understood.

Research Findings:

The study investigated the role of LHPenk neurons in emotional eating in mice exposed to a threatening predator-scent stimulus (PSS) with cat odor. Mice exhibited a negative emotional state and overconsumption of a high-fat diet (HFD) 24 hours after PSS exposure. Microendoscopic calcium imaging of LHPenk neurons revealed heightened sensitivity to HFD, displaying potentiated activity during HFD eating bouts.

Chemogenetic/optogenetic activation of LHPenk neurons replicated HFD overconsumption and the negative emotional state, while silencing these neurons abolished these behaviors. Disruption of enkephalin in the LH reversed the sensitized responses of LHPenk neurons to HFD. MOR activity in the lateral periaqueductal gray (LPAG), a downstream structure of LHPenk neurons, was necessary for PSS-induced HFD overconsumption.

PSS elevated serum CORT levels, and LHPenk neurons likely responded to PSS-induced CORT due to their predominant expression of glucocorticoid receptors (GR). Pretreatment with CORT mimicked the effects of PSS, increasing HFD intake and LHPenk neuronal reactivity to HFD. Pharmacological inhibition of GRs in the LH attenuated PSS-induced HFD overconsumption, suggesting a role in suppressing negative emotional valence.


Perceptions of threats can elicit both immediate and delayed stress responses, impacting individuals beyond the threatening situation. While immediate responses help actively avoid threats, maladaptive reactions, such as cravings for palatable foods, may persist, contributing to problematic eating habits. Understanding post-stress factors influencing vulnerability to overconsumption is crucial for therapeutic development.

LHPenk Neurons and Emotional Overeating:

This study highlights the critical role of LHPenk neurons in eliciting emotional overeating in mice exposed to a naturally threatening stimulus (PSS), particularly under high-fat diet (HFD) conditions. The identification of LHPenk neurons as a key component unveils a mechanism through which threat-induced stress responses influence hypothalamic neuropeptidergic systems, distinct from homeostatic eating.

The LH’s cellular heterogeneity is evident as Penk-expressing neurons differ from other populations. LHPenk neurons, responsive to PSS, represent a unique subset regulating feeding behaviors. The study suggests LH enkephalin as a crucial endogenous opioid source, modulating PSS-induced maladaptive responses at both neuronal and behavioral levels.

Potential Mechanisms:

The intricate interplay between LHPenk neurons, the paraventricular nucleus (PVN), and downstream structures like the lateral periaqueductal gray (LPAG) is explored. Glutamatergic inputs from the PVN and possible retrograde transmissions involving GABAergic or glutamatergic inputs are speculated, indicating a complex network influencing LHPenk neuronal reactivity.

MORs in the LPAG are implicated as possible mediators of PSS-induced HFD overconsumption. However, alternative downstream targets are suggested, including connections with the ventral tegmental area (VTA), a region linked to motivated behaviors. Further investigation into endogenous enkephalinergic system effects on LHPenk circuit organizations may elucidate discrete effects on disordered eating behaviors.

Negative Emotional Valence and LHPenk Neurons:

While many studies focus on positive emotional valence associated with food consumption, this research emphasizes the role of LHPenk neurons in driving food-seeking behaviors linked to negative emotional valence. The study’s findings suggest that LHPenk neuron activation encodes negative emotional valence, driving palatable food consumption.

Hormonal Regulation and Time-Dependent Effects:

The study delves into the time-dependent regulation of appetite after stress, emphasizing the role of the HPA axis and glucocorticoid hormones. Corticosterone (CORT) administration induces delayed-onset emotional overeating, implicating genomic processes and AMPAR-mediated synaptic transmissions in LHPenk neurons. The link between elevated CORT signaling, endogenous enkephalinergic LH circuits, and delayed-onset emotional overeating is proposed.

Implications and Therapeutic Interventions:

In conclusion, this research provides insights into the mechanisms underlying emotionally triggered HFD overconsumption after threatening events. The proposed interactions between CORT signaling and endogenous enkephalinergic LH circuits offer potential therapeutic targets. The suppression of endogenous enkephalinergic LH circuit activity or glucocorticoid receptor (GR) antagonism emerges as potential interventions for emotional overeating following life-threatening events, opening avenues for further studies and therapeutic developments. Understanding these intricate neural mechanisms may pave the way for targeted interventions to mitigate the adverse effects of emotional eating.

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