The hypothalamic arcuate–median eminence complex (Arc-ME) controls energy balance, fertility and growth through molecularly distinct cell types, many of which remain unknown. To catalog cell types in an unbiased way, we profiled gene expression in 20,921 individual cells in and around the adult mouse Arc-ME using Drop-seq. We identify 50 transcriptionally distinct Arc-ME cell populations, including a rare tanycyte population at the Arc-ME diffusion barrier, a new leptin-sensing neuron population, multiple agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) subtypes, and an orexigenic somatostatin neuron population. We extended Drop-seq to detect dynamic expression changes across relevant physiological perturbations, revealing cell type–specific responses to energy status, including distinct responses in AgRP and POMC neuron subtypes. Finally, integrating our data with human genome-wide association study data implicates two previously unknown neuron populations in the genetic control of obesity. This resource will accelerate biological discovery by providing insights into molecular and cell type diversity from which function can be inferred.
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We gratefully acknowledge Z. Yang, J. Madara and C. Wu for technical assistance, A. Garfield for editorial advice and P. Kharchenko for advice on SCDE. Quantitative PCR and confocal imaging were done at BIDMC's Molecular Medicine Core and Confocal Imaging Core, respectively. Funding was provided by US National Institutes of Health grants to B.B.L. (R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, BNORC Transgenic Core P30 DK046200, BADERC Transgenic Core P30 DK057521), E.D.R. (R01 DK102170, R01 DK085171, R01 DK102173), E.D.R. and L.T.T. (BNORC Functional Genomics Core P30 DK046200), L.T.T. (BADERC Pilot and Feasibility grant NIH 2P30DK057521-16) and J.M.R. (F32 DK103387); a Department of Defense grant to L.T.T. (Discovery Award W81XWH-15-1-0251); an American Heart Association Postdoctoral Fellowship to J.N.C. (14POST20100011); the Lundbeck Foundation and the Benzon Foundation (T.H.P.); the Stanley Center for Psychiatric Research (S.A.M.); and the Stanley-MGH Fellowship in Psychiatric Neuroscience (E.Z.M.).
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 Cluster composition, pars tuberalis expression of Cck, oligodendrocyte marker expression and subclustering analysis
(A) Left, all-cell tSNE plot with cells colored according to treatment group/batch. Each cluster contains cells from all batches/groups. Right, a color-keyed description of each treatment group and sample batch, including: number of mice, their sex and mean age ± S.D; number of cells analyzed from each sample; and the estimated number of cells from each sample that were input to Drop-seq. (B) Co-expression of Tshb and Cck by single cells in the pars tuberalis cell clusters. (C) Micrograph of TSHβ (magenta; top-left) and Cck-IRES-Cre::loxSTOPlox-GFP (green; top-right) immunofluorescence in the pars tuberalis. Overlay (with DAPI-stained DNA; bottom) confirms that most TSHβ immunoreactive PT cells are also CCK immunoreactive. Note that micrograph panels were separately pseudocolored and contrast adjusted. Scale bar, 50μm (D) Stages of oligodendrocyte development and a heatmap showing relative expression of genes marking those developmental stages per Marques et al. (2016). (E) All-cell subcluster tSNE plot with cells colored according to results of subclustering of non-neuronal populations, in which each spatially distinct cluster on the original tSNE plot was independently re-clustered to further describe heterogeneity. (F, G) Volcano plots comparing averaged gene expression in “mural cells” subclusters s12 (pericytes) and s13 (smooth muscle cells) and in “macrophages” subclusters s14 (microglia) and s15 (perivascular macrophages), with selected subcluster-specific marker genes labeled, including well-described markers (orange) that guided our subcluster annotation.
(A) Ependymal cell clusters derived from original tSNE plot in Supplemental Figure 1E (thumbnail). Clusters are annotated based on anatomical localization of marker genes in Figure 2B. (B) Violin plots showing ependymal cell cluster expression of previously characterized ependymal cell subtype markers. (C) Heatmap showing single-cell expression of genes differentially expressed by the ependymal cell clusters. Genes shown are each cluster’s top10 most enriched genes by fold-difference. (D) Violin plots showing ependymal cell cluster expression of novel candidate ependymal cell subtype markers.
Supplementary Figure 3 Neuron subclustering and expression of neuropeptide- and neurotransmitter-related genes
(A) Overview of neuron-only analysis, including iterative subclustering process used to resolve spatially indistinct clusters. (B) Diagram showing selection of cells for each round of subclustering. (C) Dotplot showing cluster-average expression of neuropeptide/neurotransmitter-related genes; color of the dot indicates the relative level of expression and the size of the dot indicates the percent of neurons in that cluster expressing the gene. Cluster names in gray likely originated from outside the Arc-ME (see Supplemental Figure 5A–D).
(A) Heatmap of single-cell expression of genes differentiating three POMC neuron clusters (genes selected showed >2 fold change differential expression between POMC neuron clusters). (B) Volcano plots comparing averaged gene expression of three POMC neuron clusters.
Supplementary Figure 5 Dissection scheme, regional marker expression, and RIP-Cre neuron gene expression
(A) Nissl stained mouse brain sections (from Allen Mouse Brain Atlas) marked to show dissection plan. (B) Neuron-only tSNE plot re-colored to show known vs. unknown neuron clusters. A neuron cluster was considered “known” if it generally expressed at least one previously characterized marker of Arc-ME neuron types (Agrp, Pomc, Tac2, Sst, Ghrh, or Th). (C) Expression of genes enriched in regions neighboring the Arc-ME, shown by in situ hybridization of mouse brain sagittal sections (Allen Mouse Brain Atlas; top) and by re-coloring of neuron-only tSNE plot (bottom). (D) Expression of genes enriched in Arc-ME relative to neighboring regions, shown by in situ hybridization of mouse brain sagittal sections (Allen Mouse Brain Atlas; top) and by re-coloring of neuron-only tSNE plot (bottom). (E) Histogram of gene expression in individual RIP-Cre Arc-ME neurons profiled by single-cell RNA-seq.
Supplementary Figure 6 Differential expression analysis of AgRP neuron clusters and SST neuron clusters
(A) Heatmap of single-cell expression (left) and average expression by cluster (right) of genes differentiating n13.Agrp/Gm8773 and n23.Sst/Unc13c neuron clusters. Selected genes show >2 fold-difference in expression between n13.Agrp/Gm8773 or n23.Sst/Unc13c clusters and all other arcuate neuron clusters. The n12.Agrp/Sst population expresses gene markers of both n13.Agrp/Gm8773 and n23.Sst/Unc13c clusters. (B) Left, heatmap of cluster-average expression of cluster marker genes that are differentially expressed in n13.Agrp/Gm8773 and n12.Agrp/Sst clusters. Hierarchical clustering dendrogram (right) of Arc-ME neuron subtypes using these genes reveals a gene expression program shared by n12.Agrp/Sst and other Sst-expressing arcuate populations. Dendrogram branches of arcuate clusters expressing significant Sst are colored orange. (C) Relative densities of axon innervation of various brain regions by AgRP neurons and ARCSST neurons. (D) Heatmap of single-cell expression of genes differentiating the Sst+ neuron clusters. Selected genes show >2 fold-difference in expression between Sst+ populations. (E) Heatmap of cluster-average expression, highlighting individual genes related to neuropeptide/neurotransmitter signaling, extracellular receptors, and transcriptional regulation that are differentially expressed in Sst+ clusters.
(A) Number of genes significantly affected by fasting and high-fat diet in each All-Cell cluster. (B) Volcano plots of genes affected by fasting vs. HFD in Agrp/Gm8773 neurons. (C) Comparison of fasting-induced gene expression in AgRP neuron subtypes with previously published data from pooled AgRP neurons (left) and pooled POMC neurons (right) (Henry et al., 2015). AgRP neuron subclusters correlated well with pooled AgRP neuron data (C) but not with pooled POMC neuron data (D). (C) n13.Agrp/Gm8773: slope=1.4444, r2=0.33556, n=741 genes, p=3.86e−59; n12.Agrp/Sst: slope=1.0155, r2=0.41957, n=245 genes, p=1.82e−33. (D) n13.Agrp/Gm8773: slope=-0.5117, n=38 genes, p=0.283; n12.Agrp/Sst: slope=-0.3535, n=13 genes, r2=0.03115, p=0.534. (E) Comparison of fasting-induced gene expression in POMC neuron subtypes with previously published data from pooled POMC neurons (E) and pooled AgRP neurons (F) from Henry et al. (2015). POMC neuron subclusters correlated well with pooled POMC neuron data (E) but not with pooled AgRP neuron data (F). (E) n15.Pomc/Anxa2: slope=0.82, r2=0.67463, n=12 genes, p=1.82e−33; n14.Pomc/Ttr: slope=1.522, r2=0.64653, n=10 genes, p=8.13e−5. (F) n15.Pomc/Anxa2: slope=-1.8, r2=0.93174, n=4 genes, p=2.87e−7; n14.Pomc/Ttr: slope=-0.59, r2=0.56174, n=4 genes, p=0.11. (G) Heatmap of fasting responses of all Arc-ME neurons for genes differentially expressed in at least one neuron subcluster (FDR<0.05; fold-change, FC>0.75). Top significant GO terms using DAVID Gene ontology analysis are shown. (H) Heatmap of fasting vs. HFD responses for genes differentially expressed in at least one AgRP neuron subtype or POMC neuron subtype (FDR<0.05; FC>0.75). Top significant GO terms using DAVID Gene ontology analysis are shown.
(A) DEPICT –log10 p values for enrichment each Arc-ME cell type for height, menarche, and menopause. (B) DEPICT –log10 p values for Arc-ME neuron types. Dotted line at p=0.01.
Supplementary Figures 1–8 (PDF 2910 kb)
Supplementary Table 1: The number and percentage representation of cells within each all-cell and neuron cluster parsed by experiment, age, sex, and dietary intervention.
Number and percentage are presented in reference to total cells/neurons evaluated (top) or total Arc-ME cells/neurons (bottom) to account for dissection artifacts. Likely sex-of-origin of Fasted and Re-fed cells was determined using MLSeq package (see Online Methods). Red lettering indicates non-arcuate cell clusters. (XLSX 93 kb)
Supplementary Table 2: For each all-cell cluster, a table of fold-change values for genes differentially expressed with false-discovery rate (FDR) <25% in at least one comparison, sorted based on specificity (i.e., number of positive fold-change values) and average expression.
Fold-change values with FDR>25% are indicated by zeroes. (XLSX 38327 kb)
Supplementary Table 3: For each all-cell subcluster, a table of fold-change values for genes differentially expressed with false-discovery rate (FDR) <25% in at least one comparison, sorted based on specificity (i.e., number of positive fold-change values) and average expression.
Fold-change values with FDR>25% are indicated by zeroes. (XLSX 98822 kb)
Supplementary Table 4: For each neuronal cluster, a table of fold-change values for genes differentially expressed with false-discovery rate (FDR) <25% in at least one comparison, sorted based on specificity (i.e., number of positive fold-change values) and average expression.
Fold-change values with FDR>25% are indicated by zeroes. (XLSX 61278 kb)
For each all-cell cluster from fed vs. fasted mice, tables of fold-change values, false-discovery rates (FDR), and fold-change values with at least one significant comparison (FDR<25%). (XLSX 4484 kb)
For each all-cell cluster from low-fat diet vs. high-fat diet fed mice, tables of fold-change values, false-discovery rates (FDR), and fold-change values with at least one significant comparison (FDR<25%). (XLSX 3630 kb)
For each neuronal cluster from fed vs. fasted mice, tables of fold-change values, false-discovery rates (FDR), and fold-change values with at least one significant comparison (FDR<25%). (XLSX 6084 kb)
For each neuronal cluster from low-fat diet vs. high-fat diet fed mice, tables of fold-change values, false-discovery rates (FDR), and fold-change values with at least one significant comparison (FDR<25%). (XLSX 4280 kb)
(DEPICT_GWAS Sources Tab) Overview of GWAS p value cutoffs used to define loci, the number of resulting DEPICT loci (defined by linkage disequilibrium r2>0.5), the number of genes in DEPICT loci, PubMed identifiers of the publications from which the GWAS summary statistics were sourced, and links to the GWAS summary statistics file. For the GWAS only waist hip ratio summary statistics, please contact the authors. (TRH_Lef1_CandidateObesityGenes Tab) Evidence in support of inclusion as candidate gene for obesity with increased expression in the n25.Trh/Lef1 neuron cluster, adapted from Vimaleswaran et al. DEPICT_Statistics tab. (Slc17a6_Trhr_CandidateObesityGen Tab) Evidence in support of inclusion as candidate gene for obesity with increased expression in the n32.Slc17a6/Trhr neuron cluster, adapted from Vimaleswaran et al. (DEPICT_Statistics Tab) Summary DEPICT p-values and FDR for included GWAS phenotypes represented in Figure 8 and Supplemental Figure 8. (XLSX 37 kb)
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Campbell, J., Macosko, E., Fenselau, H. et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat Neurosci 20, 484–496 (2017). https://doi.org/10.1038/nn.4495
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