Transcriptome profiling of human hypothalamic agouti-related protein and proopiomelanocortin neurons regulating energy homeostasis

We present and validate a pioneering ‘IHC/LCM-Seq’ method for transcriptome profiling of spatially defined neuronal cell types detected with immunohistochemistry in sections of formaldehyde-fixed human brains. Application of IHC/LCM-Seq to male human hypothalami enables the identification of 14,000–16,000 transcripts in agouti-related protein (AgRP) neurons, which drive appetite and energy storage, and proopiomelanocortin (POMC) neurons, which suppress feeding and promote energy expenditure. These cell types differ from each other, and from fertility-regulating kisspeptin neurons, in their distinct enrichments of co-transmitters, transcription factors, regulatory (lnc) RNAs and receptors. The AgRP neuron transcriptome is rich in receptors for proinflammatory cytokines, metabolic hormones and growth hormone, whereas POMC neurons express reproductive hormone-, glucagon-like peptide-, calcitonin-, and endocannabinoid receptors. IHC/LCM-Seq, a versatile spatial transcriptomic approach for characterizing cell types in postmortem human brain tissue, opens a new window onto the molecular mechanisms that regulate energy homeostasis and highlights potential pharmacological targets for weight-management strategies.