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

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

SUBMITTER: Dylan Belmont-Rausch 

PROVIDER: S-SCDT-10_1038-S44318-026-00914-W | biostudies-other |

REPOSITORIES: biostudies-other