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Peer-reviewedCC BY 4.0The EMBO Journal

Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity

  • Dylan M Belmont-Rausch1,2,3
  • Benedicte Schultz Kapel1
  • Abigail J Tomlinson4,5
  • Chao Ding6,7
  • Allison M Duensing4,5
  • Bernd Coester1
  • Cecilie Vad Mathiesen1
  • Leonie Cabot6,7
  • Jenny M Brown1
  • Charlotte Høy Kruse1,2
  • Shad Hassan1,2
  • Elizabeth Heaton4,5
5 more authors
  • Christoffer Clemmensen1
  • Michael W Schwartz8
  • Henning Fenselau6,7,9
  • Martin G Myers4,5
  • Tune H Pers1,2
9 affiliations
  1. 1Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
  2. 2Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA USA
  3. 3Present Address: Research and Development, Novo Nordisk A/S, Måløv, Denmark
  4. 4Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI USA
  5. 5Department of Internal Medicine, University of Michigan, Ann Arbor, MI USA
  6. 6Research Group Synaptic Transmission in Energy Homeostasis, Max Planck Institute for Metabolism Research, Cologne, Germany
  7. 7Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  8. 8Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington at South Lake Union, Seattle, WA USA
  9. 9Policlinic for Endocrinology, Diabetes, and Preventive Medicine (PEDP), University Hospital Cologne, Cologne, Germany
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Abstract

Despite loss of responsiveness to exogenous leptin in obesity, endogenous leptin continues to restrain feeding, although the neural substrates that remain sensitive and mediate this effect remain unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we here show that while most hypothalamic leptin receptor (Lepr)-positive neurons minimally respond to elevated leptin, a single subpopulation defined by glucagon-like peptide-1 receptor (Glp1r) co-expression retains robust leptin sensitivity. These Lepr+/Glp1r+ neurons project onto and inhibit orexigenic Agrp neurons. Lepr deletion from Lepr+/Glp1r+ neurons blocks the anorectic effect of exogenous leptin, reinstates hyperphagic responses normally suppressed in DIO, amplifies the obesogenic response to palatable diet, and unexpectedly attenuates hypothalamic microglial activation – a hallmark of DIO previously attributed to diet rather than leptin signaling. Hence, preserved leptin responses by a single neuronal population in the hypothalamus limit hyperphagia and weight gain, among other responses, during obesity.

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Cite

BibTeXRIS
BibTeX
@article{belmontrausch2026leptinsensitive,
  title = {{Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity}},
  author = {Dylan M Belmont-Rausch and Benedicte Schultz Kapel and Abigail J Tomlinson and Chao Ding and Allison M Duensing and Bernd Coester and Cecilie Vad Mathiesen and Leonie Cabot and Jenny M Brown and Charlotte Høy Kruse and Shad Hassan and Elizabeth Heaton and Christoffer Clemmensen and Michael W Schwartz and Henning Fenselau and Martin G Myers and Tune H Pers},
  journal = {The EMBO Journal},
  year = {2026},
  month = oct,
  doi = {10.1038/s44318-026-00914-w},
  url = {https://doi.org/10.1038/s44318-026-00914-w},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Leptin-sensitive hypothalamic Lepr+/Glp1r+ neurons limit hyperphagia and weight gain in diet-induced obesity
AU  - Dylan M Belmont-Rausch
AU  - Benedicte Schultz Kapel
AU  - Abigail J Tomlinson
AU  - Chao Ding
AU  - Allison M Duensing
AU  - Bernd Coester
AU  - Cecilie Vad Mathiesen
AU  - Leonie Cabot
AU  - Jenny M Brown
AU  - Charlotte Høy Kruse
AU  - Shad Hassan
AU  - Elizabeth Heaton
AU  - Christoffer Clemmensen
AU  - Michael W Schwartz
AU  - Henning Fenselau
AU  - Martin G Myers
AU  - Tune H Pers
PY  - 2026
DA  - 2026/10/01
JO  - The EMBO Journal
DO  - 10.1038/s44318-026-00914-w
UR  - https://doi.org/10.1038/s44318-026-00914-w
AB  - Despite loss of responsiveness to exogenous leptin in obesity, endogenous leptin continues to restrain feeding, although the neural substrates that remain sensitive and mediate this effect remain unknown. Combining spatial transcriptomics with single-nucleus RNA sequencing in mice with diet-induced obesity (DIO), we here show that while most hypothalamic leptin receptor (Lepr)-positive neurons minimally respond to elevated leptin, a single subpopulation defined by glucagon-like peptide-1 receptor (Glp1r) co-expression retains robust leptin sensitivity. These Lepr+/Glp1r+ neurons project onto and inhibit orexigenic Agrp neurons. Lepr deletion from Lepr+/Glp1r+ neurons blocks the anorectic effect of exogenous leptin, reinstates hyperphagic responses normally suppressed in DIO, amplifies the obesogenic response to palatable diet, and unexpectedly attenuates hypothalamic microglial activation – a hallmark of DIO previously attributed to diet rather than leptin signaling. Hence, preserved leptin responses by a single neuronal population in the hypothalamus limit hyperphagia and weight gain, among other responses, during obesity.
SN  - 0261-4189
SN  - 1460-2075
ER  -