Single-cell multi-omics identify OTP and NOVA1 as regulators of leptin action in hypothalamic feeding circuits
- 1Department of Anatomy and Neurobiology, University of California Irvine School of Medicine, Irvine, CA, USA
Abstract
Leptin acts directly and indirectly on multiple neuronal populations to regulate feeding and numerous other physiologic functions. However, our understanding of how a single circulating signal coordinates diverse neuronal populations across multiple circuits is limited. To further elucidate how leptin reshapes molecular states in its direct and indirect neural targets, we combined time-resolved single-nucleus transcriptomics and chromatin accessibility profiling to map leptin-induced transcriptional and chromatin state changes across individual neurons in two key hypothalamic nuclei: the arcuate nucleus (ARC), which contains the majority of leptin receptor (LepR) neurons, and the paraventricular hypothalamic nucleus (PVH), an established downstream target of ARC LepR neurons. We found that leptin treatment of leptin-deficient ob/ob mice does not alter neuronal identity, but instead induces coordinated, cell-type-specific transcriptional and regulatory state changes that propagate hierarchically from the ARC to downstream PVH neurons. Integrating RNA velocity, cis-regulatory analysis, and cell-cell communication inference revealed that leptin modulates hypothalamic circuit architecture by selectively strengthening specific interactions while pruning broadly distributed, low-specificity signaling. Although leptin broadly activated STAT3 signaling across LepR neuronal subtypes, integrated multi-omic analyses revealed that activation of STAT3 engages distinct downstream regulatory programs in different neuronal populations, often with opposing physiological functions. Functional analyses identified the homeobox transcription factor OTP, a leptin-responsive regulator selectively induced in AGRP neurons, as a critical mediator of leptin-mediated inhibition of hunger-promoting AGRP neuronal activity and feeding. In parallel, unbiased analysis of PVH neuronal state transitions shows that NOVA1, an RNA-binding protein primarily expressed in inhibitory neurons, is regulated by leptin and alterations of NOVA1 expression bidirectionally control food intake and body weight. Together, these findings define a multi-layered regulatory framework through which leptin regulates hypothalamic feeding circuits to control energy balance.
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BibTeX
@misc{tan2026singlecell,
title = {{Single-cell multi-omics identify OTP and NOVA1 as regulators of leptin action in hypothalamic feeding circuits}},
author = {H. L. Tan and Y. Tan and J. Ruiz-Ortiz and M. Paul and Z. Han and L. Kelly and A. Toci and K. Plucinska and Y. Tajima and R. Shiao and B. Lee and A. Ilanges and R. B. Darnell and P. Cohen and J. M. Friedman},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.04.764326},
url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764326v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Single-cell multi-omics identify OTP and NOVA1 as regulators of leptin action in hypothalamic feeding circuits
AU - H. L. Tan
AU - Y. Tan
AU - J. Ruiz-Ortiz
AU - M. Paul
AU - Z. Han
AU - L. Kelly
AU - A. Toci
AU - K. Plucinska
AU - Y. Tajima
AU - R. Shiao
AU - B. Lee
AU - A. Ilanges
AU - R. B. Darnell
AU - P. Cohen
AU - J. M. Friedman
PY - 2026
DA - 2026/11/04
PB - bioRxiv
DO - 10.64898/2026.11.04.764326
UR - https://www.biorxiv.org/content/10.64898/2026.11.04.764326v1
AB - Leptin acts directly and indirectly on multiple neuronal populations to regulate feeding and numerous other physiologic functions. However, our understanding of how a single circulating signal coordinates diverse neuronal populations across multiple circuits is limited. To further elucidate how leptin reshapes molecular states in its direct and indirect neural targets, we combined time-resolved single-nucleus transcriptomics and chromatin accessibility profiling to map leptin-induced transcriptional and chromatin state changes across individual neurons in two key hypothalamic nuclei: the arcuate nucleus (ARC), which contains the majority of leptin receptor (LepR) neurons, and the paraventricular hypothalamic nucleus (PVH), an established downstream target of ARC LepR neurons. We found that leptin treatment of leptin-deficient ob/ob mice does not alter neuronal identity, but instead induces coordinated, cell-type-specific transcriptional and regulatory state changes that propagate hierarchically from the ARC to downstream PVH neurons. Integrating RNA velocity, cis-regulatory analysis, and cell-cell communication inference revealed that leptin modulates hypothalamic circuit architecture by selectively strengthening specific interactions while pruning broadly distributed, low-specificity signaling. Although leptin broadly activated STAT3 signaling across LepR neuronal subtypes, integrated multi-omic analyses revealed that activation of STAT3 engages distinct downstream regulatory programs in different neuronal populations, often with opposing physiological functions. Functional analyses identified the homeobox transcription factor OTP, a leptin-responsive regulator selectively induced in AGRP neurons, as a critical mediator of leptin-mediated inhibition of hunger-promoting AGRP neuronal activity and feeding. In parallel, unbiased analysis of PVH neuronal state transitions shows that NOVA1, an RNA-binding protein primarily expressed in inhibitory neurons, is regulated by leptin and alterations of NOVA1 expression bidirectionally control food intake and body weight. Together, these findings define a multi-layered regulatory framework through which leptin regulates hypothalamic feeding circuits to control energy balance.
ER -