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

We have developed and validated 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. IHC/LCM-Seq provided unprecedented insight, with 14,000-16,000 transcripts identified, into the gene expression landscape of human agouti-related peptide (AgRP) neurons, which drive appetite and energy storage, and proopiomelanocortin (POMC) neurons, which suppress feeding and promote energy expenditure. These cells differed from each other, and from fertility-regulating kisspeptin neurons, in their distinct enrichments of co-transmitters, transcription factors, and receptors. The AgRP neuron transcriptome was rich in receptors for proinflammatory cytokines, metabolic hormones and growth hormone, whereas POMC neurons expressed reproductive hormone-, glucagon-like peptide– and endocannabinoid receptors. IHC/LCM-Seq, a versatile spatial transcriptomic approach for characterizing cell types in postmortem brains, opened a new window onto molecular mechanisms regulating energy homeostasis in the human hypothalamus and highlighted possible pharmacological targets for weight management.