A hypothalamic circuit for anticipating future changes in energy balance
Walker SJ, Lowenstein ED, Douglass AM, Thomas CMP, Madara JC, Kucukdereli H, Barbosa-Meillon EA, Tao J, Resch JM, Lowell BB. A hypothalamic circuit for anticipating future changes in energy balance. Neuron.
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Author
Walker, Samuel J.;
Lowenstein, Elijah D.;
Douglass, Amelia M.ISTA 
;
Thomas, Callum M.P.;
Madara, Joseph C.;
Kucukdereli, Hakan;
Barbosa-Meillon, Eunice A.;
Tao, Jenkang;
Resch, Jon M.;
Lowell, Bradford B.
;
Thomas, Callum M.P.;
Madara, Joseph C.;
Kucukdereli, Hakan;
Barbosa-Meillon, Eunice A.;
Tao, Jenkang;
Resch, Jon M.;
Lowell, Bradford B.Department
Abstract
AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cues can also regulate AgRP neurons since cues that predict future food intake rapidly inhibit AgRP neurons, but is the converse true: can the prediction of future fasting rapidly activate AgRP neurons? Here, we show in mice that such rapid fasting activation of AgRP neurons does occur. This rapid activation is driven by excitatory input from paraventricular hypothalamic (PVH) neurons expressing Sim2, which are bidirectionally sensitive to predictions of future energy state. Thus, cognitively processed contextual information conveyed by PVHSim2 neurons strongly activates AgRP neurons. Lastly, chronic silencing of PVHSim2 neurons causes persistent hypophagia. This PVHSim2-to-AgRP-neuron circuit, by anticipating and preventing negative energy balance, provides an important new dimension of hunger regulation.
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Publishing Year
Date Published
2026-06-03
Journal Title
Neuron
Publisher
Elsevier
Acknowledgement
We thank all members of the B.B.L. laboratory for helpful discussions. We
thank the BADERC and BNORC transgenic cores (NIH P30DK057521 and
P30DK046200) for performing embryo injections to generate knockin mouse
lines. We also thank the BIDMC Energy Balance Core (supported by NIH
S10OD028635 and the Boston Area Diabetes Endocrinology Research Centers, P30DK135043), where Marissa Cortopassi performed indirect calorimetry experiments and Alexander Banks assisted with data analysis and interpretation. Confocal imaging was performed at BIDMC’s Confocal Imaging
Core. We thank Chen Wu for assistance in designing knockin mouse lines.
This work was supported by the NIH (R01DK134427, R01DK096010, and
R01DK075632 to B.B.L.). Authors were supported by an EMBO Long-Term
Fellowship (770-2018, S.J.W.), a T32 Postdoctoral Training Fellowship
(5T32DK007516, E.D.L.), the Charles A. King Trust Postdoctoral Research
Fellowship program (A.M.D.), and a K99 Career Development Award
(K99HL144923, J.M.R.).
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Cite this
Walker SJ, Lowenstein ED, Douglass AM, et al. A hypothalamic circuit for anticipating future changes in energy balance. Neuron. doi:10.1016/j.neuron.2026.05.010
Walker, S. J., Lowenstein, E. D., Douglass, A. M., Thomas, C. M. P., Madara, J. C., Kucukdereli, H., … Lowell, B. B. (n.d.). A hypothalamic circuit for anticipating future changes in energy balance. Neuron. Elsevier. https://doi.org/10.1016/j.neuron.2026.05.010
Walker, Samuel J., Elijah D. Lowenstein, Amelia M. Douglass, Callum M.P. Thomas, Joseph C. Madara, Hakan Kucukdereli, Eunice A. Barbosa-Meillon, Jenkang Tao, Jon M. Resch, and Bradford B. Lowell. “A Hypothalamic Circuit for Anticipating Future Changes in Energy Balance.” Neuron. Elsevier, n.d. https://doi.org/10.1016/j.neuron.2026.05.010.
S. J. Walker et al., “A hypothalamic circuit for anticipating future changes in energy balance,” Neuron. Elsevier.
Walker SJ, Lowenstein ED, Douglass AM, Thomas CMP, Madara JC, Kucukdereli H, Barbosa-Meillon EA, Tao J, Resch JM, Lowell BB. A hypothalamic circuit for anticipating future changes in energy balance. Neuron.
Walker, Samuel J., et al. “A Hypothalamic Circuit for Anticipating Future Changes in Energy Balance.” Neuron, Elsevier, doi:10.1016/j.neuron.2026.05.010.
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PMID: 42235510
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