In the hypothalamus, neuropeptide Y (NPY) neuron circuits control feeding and energy homeostasis. Non-hypothalamic neurons can also produce NPY, but the role of these neurons in feeding is unclear. Research in Cell Metabolism now uncovers a previously unknown NPY neuron system that is activated by the combination of stress and calorie-dense food.
“Although it is known that stress and consumption of high-calorie food can cause obesity, the actual mechanism on how central pathways mediate this effect was unclear,” explains corresponding author Herbert Herzog. “Using a NPY–GFP reporter mouse line, we noticed that while under stress conditions the expression of GFP is mainly found upregulated in the arcuate nucleus of the hypothalamus; the expression of NPY was also strongly enhanced in the central amygdala (CeA) when stress was combined with a high-fat diet (HFD).”
As previously shown, mice that were fed a HFD and subjected to stress conditions (HFDS) showed a significant obese phenotype compared with control mice. Notably, mice deficient in Npy in the CeA showed attenuated obesity in response to HFDS. Moreover, overexpression of NPY in the CeA increased the obese phenotype associated with HFDS. In addition, DREADD (designer receptors exclusively activated by designer drugs) technology was used to show that activation of NPY neurons in the CeA caused mice to consume more food.
Interestingly, HFDS-induced obesity was associated with impaired insulin inhibitory effects on NPY neurons located in the CeA. Mice with CeA NPY neurons that were engineered to be deficient in Insr showed increased HFDS-induced obesity, suggesting that insulin has an important role in regulating stress-induced food intake.
mice deficient in Npy in the CeA showed attenuated obesity
“We have now uncovered a previously unknown feeding stimulatory pathway that is specifically activated under conditions of chronic stress combined with high-caloric food,” concludes Herzog. “One of the main aims of future research is to determine the downstream neuronal network (or networks) and the involved control mechanisms that might be potential targets for intervention to prevent accelerated obesity development.”
Ip, C. K. et al. Amygdala NPY circuits promote the development of accelerated obesity under chronic stress conditions. Cell Metab. https://doi.org/10.1016/j.cmet.2019.04.001 (2019)
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Starling, S. Stress fuels obesity. Nat Rev Endocrinol 15, 376 (2019). https://doi.org/10.1038/s41574-019-0211-9