Abstract
The arcuate nucleus of the hypothalamus plays a central role in sensing and integrating nutritional, hormonal, and neural signals that regulate feeding, energy homeostasis, growth, and reproduction, all of which show pronounced sex differences. However, the cellular mechanisms underlying these responses remain poorly understood. We performed snRNA-seq of the mediobasal hypothalamus, focusing on the arcuate nucleus, in female and male mice under different nutritional states. Analysis of 42 cell types revealed that Agrp neurons were most sensitive to nutritional changes, dopaminergic neurons showed strong sex-specific differences, and KNDy neurons were highly responsive to both sex and nutrition. Pomc neurons displayed moderate nutritional sensitivity. Most glial populations were stable, although microglia and oligodendrocytes showed moderate variation. Cell–cell communication analysis identified neurotrophic factor signaling as a key pathway regulated by sex and nutrition. This study represents a major effort to comprehensively characterize sex-specific differences in arcuate nucleus response across nutritional conditions.
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Data availability
The fully processed snRNA-seq dataset generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under accession code GSE282955. Source data are provided as a Source Data file. Source data are provided with this paper.
Code availability
Detailed analysis codes used in this study are available on the Github repository 663 (https://github.com/jbeanphd/ARH_Sex_by_Nutr) https://doi.org/10.5281/zenodo.18276251.
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Acknowledgements
H.L. discloses support for the research of this work from the CPRIT Scholar in Cancer Research [RR200063], NIH/NIA [U01AG086143], NIH [DP2AT013275], the Longevity Impetus Grant, the Ted Nash Long Life Foundation, and the Welch Foundation. Y.X. discloses support for the research of this work from the Silver Endowment. X.F. discloses support for the research of this work from NIDDK [1F32DK138685-01A1]. M.W. discloses support for the research of this work from NIMHD [1F32HD112123-01A1].
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J.C.B., H.L., and Y.X. co-conceptualized the study. J.C.B. and J.J. performed the experiments and analyses, with assistance from T.C.L., H.L., K.M.M., D.A.T., S.V.J., M.E.B., J.C., Y.D., X.F., X.G., J.H., Y.L., H.L., Q.L., Y.L., Y.S., L.T., M.W., X.X., Y.Y., M.Y., X.L., M.S., F.W., O.Z.G., Y.Y., Y.H., C.W., and Y.Q., H.L., and Y.X. supervised the study.
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Bean, J.C., Jian, J., Lu, TC. et al. Sex-specific differences in mediobasal hypothalamus in response to nutritional states. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69239-w
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DOI: https://doi.org/10.1038/s41467-026-69239-w
