ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 11.7 | DOI: 10.1530/ey.18.11.7

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

eLife 2020;9:e55851.

Timshel et al. describe a novel strategy for integrating single-cell RNA-sequencing (scRNA-seq) data with GWAS data on BMI associated genetic variants, and thereby identify 26 exclusively neuronal cell types that are significantly enriched for BMI heritability.

The authors developed two scRNA-seq computational toolkits (CELLEX and CELLECT) for genetic identification of likely etiologic cell types and applied them to scRNA-seq data from 727 mouse cell types (380 cell types representing adult mouse organs especially the nervous system and 347 cell types from adult mouse hypothalamus [1,2]). Combining these data with publicly available BMI GWAS summary statistics from >457 000 individuals in the UK Biobank study [3] they identified 26 BMI GWAS-enriched neuronal cell types mapping to 8 brain regions, which share transcriptional signatures related to obesity. Interestingly, some of the enriched cell types localize to nuclei processing sensory stimuli and directing actions related to feeding behavior and to areas, which are important for learning and memory.

Furthermore, they identified 4 enriched cell types in the hypothalamus, expressing Sf1 (linked to disrupted leptin-signaling and hyperglycemia [4;5]), Cckbr and Bdnf (related to NTRK-monogenic obesity in humans and to normal energy homeostasis in mice [6]). There was no enrichment in neurons expressing the Pomc gene, but nominal enrichment in 4/5 Pomc+ cell populations. In line with previous findings [7,8], no enrichment of genetic variants associated with BMI in non-neuronal cell types was found.

In consideration of the selected scRNA-seq dataset from late postnatal, adult and predominantly wild-type mice, and the limitation to only detect enriched gene expression, these in silico findings provide an important contribution to the understanding of BMI heritability, showing that susceptibility to obesity is enriched in neuronal cell types regulating integration of sensory stimuli, learning and memory, thereby highlighting the need for mechanistic follow-up studies.

References: 1. Tabula Muris Consortium; Overall coordination; Logistical coordination; Organ collection and processing; Library preparation and sequencing; Computational data analysis; Cell type annotation; Writing group; Supplemental text writing group; Principal investigators. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature; 2018: 562:367–372.2. Zeisel A, Hochgerner H, Lönnerberg P, Johnsson A, Memic F, van der Zwan J, Häring M, Braun E, Borm LE, La Manno G, Codeluppi S, Furlan A, Lee K, Skene N, Harris KD, Hjerling-Leffler J, Arenas E, Ernfors P, Marklund U, Linnarsson S. Molecular Architecture of the Mouse Nervous System. Cell, 2018: 174:999–1014.3. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J, Adrian Cortes 1 10, Samantha Welsh 11, Alan Young 12, Mark Effingham 11, Gil McVean 1 12, Stephen Leslie 4 5, Allen N, Donnelly P, Marchini J. The UK Biobank resource with deep phenotyping and genomic data. Nature 2018; 562:203–209.4. Kim KW, Zhao L, Donato Jr J, Kohno D, Xu Y, Elias CF, Lee C, Parker KL, Elmquistal JK. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. PNAS 2011; 108:10673–10678.5. Meek TH, Nelson JT, Matsen ME, Dorfman MD, Guyenet SJ, Vincent Damian V, Allison MB, Scarlett JM, Nguyen HT, Thaler JP, Olson DP, Myers Jr MG, Schwartz MW, Morton GJ. Functional identification of a neurocircuit regulating blood glucose. PNAS 2016; 113: E2073–E2082.6. Kamitakahara A, Xu B, Simerly R. Ventromedial hypothalamic expression of Bdnf is required to establish normal patterns of afferent GABAergic connectivity and responses to hypoglycemia. Molecular Metabolism 2015; 5(2):91–101.7. Campbell JN, Macosko EZ, Fenselau H, Pers TH, Lyubetskaya A, Tenen D, Goldman M, Verstegen AMJ, Resch JM, McCarroll SA, Rosen ED, Lowell BB, Tsai LT. A molecular census of arcuate hypothalamus and median eminence cell types. Nature Neuroscience 2017; 20: 484–496.8. Watanabe K, Mirkov MU, de Leeuw CA, van den Heuvel MP, Posthuma D. Genetic mapping of cell type specificity for complex traits. Nature Communications 2019; 10: 3222.

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