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

A specific hypothalamic Lepr+/Glp1r+ neuron population retains leptin sensitivity and limits hyperphagia and weight gain in diet-induced obesity.

• Why it matters: Understanding which neural circuits remain responsive to leptin during obesity is crucial for developing targeted treatments, as most leptin-responsive neurons lose sensitivity in this condition.
• What they did: Using spatial transcriptomics and single-nucleus RNA sequencing in obese mice, researchers identified a Lepr+/Glp1r+ neuron subset that maintains leptin sensitivity and projects to inhibit orexigenic Agrp neurons.
• The result: Deleting Lepr from these neurons abolishes leptin’s appetite-suppressing effects, increases hyperphagia and obesity, and unexpectedly reduces hypothalamic microglial activation, highlighting their role in controlling obesity-related responses.