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

Authors

Dylan M Belmont-Rausch, Benedicte Schultz Kapel, Abigail J Tomlinson, Chao Ding, Allison M Duensing, Bernd Coester, Cecilie Vad Mathiesen, Leonie Cabot, Jenny M Brown, Charlotte Høy Kruse, Shad Hassan, Elizabeth Heaton, Christoffer Clemmensen, Michael W Schwartz, Henning Fenselau, Martin G Myers, Tune H Pers

Published in

The EMBO journal. Oct 02, 2026. Epub Oct 02, 2026.

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.

PMID:
42827204
Bibliographic data and abstract were imported from PubMed on 03 Oct 2026.

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