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Chronic stress fuels the consumption of palatable food and can enhance obesity development. While stress- and feeding-controlling pathways have been identified, how stress-induced feeding is orchestrated remains unknown. Here, we identify lateral habenula (LHb) Npy1r-expressing neurons as the critical node for promoting hedonic feeding under stress, since lack of Npy1r in these neurons alleviates the obesifying effects caused by combined stress and high fat feeding (HFDS) in mice. Mechanistically, this is due to a circuit originating from central amygdala NPY neurons, with the upregulation of NPY induced by HFDS initiating a dual inhibitory effect via Npy1r signaling onto LHb and lateral hypothalamus neurons, thereby reducing the homeostatic satiety effect through action on the downstream ventral tegmental area. Together, these results identify LHb-Npy1r neurons as a critical node to adapt the response to chronic stress by driving palatable food intake in an attempt to overcome the negative valence of stress.



We have clearly shown that our specific stress model combined with a HFD can accelerate obesity development through a LHb/NPY-dependent mechanism.

Taken together, our data clearly show that LHb Npy1r-expressing neurons are a critical node where homeostatic control pathways from the LH interact with the hedonic controlling circuits that target the VTA to control reward. Importantly, the LHb-NPY1R neurons are also the interaction node where stress-controlled pathways originating from the CeAM intersect to override homeostatic control of feeding and emotional behavior, which, when prolonged, can lead to accelerated obesity.

Critical role of lateral habenula circuits in the control of stress-induced palatable food consumption

Ip, C. K., Rezitis, J., Qi, Y., Bajaj, N., Koller, J., Farzi, A., Shi, Y.-C., Tasan, R., Zhang, L., & Herzog, H.

Fluctuations in daily stress levels together with varying diet choices influence energy homeostasis. While acute stress can be beneficial in dealing with unexpected situations, prolonged stress can override the balance of energy homeostatic control. When rats or mice underwent prolonged stress treatment, both showed reduced food intake and displayed an anxiety-like phenotype.1,2 Surprisingly, when given a choice of highly palatable food, rich in sugar and fat, chronic stress robustly increased feeding, adapting to the stressful condition through so called “comfort-eating.” 3,4,5 Under chronic stress conditions, not only is feeding behavior altered, but basal energy expenditure (EE) is also maintained at a lower level, contributing to the exacerbation of obesity development.6 In humans, stress also affects individuals in a similar way, with some reporting reduced food intake and loss of weight, while most report an increase in their consumption of highly palatable food independent of hypo- or hyperphagia.3,6,7,8
Classically, activation of the hypothalamic-pituitary-adrenal axis triggers the release of corticosterone in mice, or cortisol in humans, to re-adjust the energy status under acute stress.9,10,11 However, under chronic stress conditions, this activity is disrupted,6,12,13 and little is known of how the brain perceives such persistent stress signals and how energy homeostasis and food preference are regulated.14,15 Nuclei, such as the arcuate nucleus (Arc), the lateral hypothalamus (LH), and the central amygdala (CeA), have been identified to play critical roles in controlling feeding behavior and EE, as well as determining the valency of consumed diets.6,16,17,18,19 The activity of these regions is also influenced by both the type of stressor and the type of diet. For example, LH circuits have recently been demonstrated to function in a way that resists the overconsumption of palatable food.18,20,21,22 This preventive mechanism acts through the direct activation of lateral habenula (LHb) neurons. The LHb is known for exerting an anti-reward function, thereby contributing to the development of a negative emotional state.5,23,24,25 Hence, short-term high-fat-diet (HFD)-induced anxiety-like behaviors could be the result of this circuit activation to prevent weight gain.26,27

Chronic stress combined with HFD is known to accelerate the development of obesity.6,12 This is driven by the most potent orexigenic as well as anxiolytic acting neuropeptide, neuropeptide Y (NPY), from both the Arc and CeA,6,28 which leads to an increase in feeding and simultaneous reduction in EE that exaggerates obesity development. Importantly, such a robust obesogenic effect, which is not seen under short-term HFD feeding in the absence of stress, implies that normal homeostatic control is overridden to favor pleasure feeding despite the already overloaded energy state.6


Sample Size

adult mice


Mice were monitored over a 4-week period where they were exposed to our standard HFDS paradigm (Figure 5A). Interestingly, LHb-specific Npy1r-deleted mice showed a significant reduction in body weight and body weight gain (Figures 5D and 5E). Moreover, dual-energy X-ray absorptiometry analysis performed 2 weeks after the start of the HFDS paradigm revealed a significantly reduced whole-body fat mass gain (Figure 5F). Whole-body lean mass was not significantly altered by LHb Npy1r deletion (Figure 5G), while tissue analyses after 4 weeks exposure to the HFDS paradigm revealed significant reductions in the weights of various fat depots (Figure 5H), but weights for other organs were comparable to control mice


lateral habenula
palatable food intake
TRAP sequencing

Key Words

Ip, C. K., Rezitis, J., Qi, Y., Bajaj, N., Koller, J., Farzi, A., Shi, Y.-C., Tasan, R., Zhang, L., & Herzog, H. (2023). Critical role of lateral habenula circuits in the control of stress-induced palatable food consumption. Neuron, S0896627323003835.


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