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

Lepr+/Glp1r+ hypothalamic neurons retain leptin sensitivity and limit hyperphagia and weight gain in diet-induced obesity, despite widespread leptin resistance.

• Why it matters: Understanding which neural pathways remain responsive to leptin in obesity is crucial for developing targeted treatments to control overeating and weight gain, as most hypothalamic neurons lose leptin responsiveness.
• What they did: Using spatial transcriptomics and single-nucleus RNA sequencing in mice with diet-induced obesity, the study identified a Lepr+/Glp1r+ neuron subpopulation that maintains leptin sensitivity and projects to inhibit orexigenic Agrp neurons; Lepr was deleted from these neurons to assess their role.
• The result: Loss of Lepr in Lepr+/Glp1r+ neurons abolished leptin’s anorectic effects, increased hyperphagia and obesity, and unexpectedly reduced hypothalamic microglial activation, highlighting this population’s role in restraining overeating during obesity.