ESPE Yearbook of Paediatric Endocrinology

Cell Metab 2025 Mar 4;37(3):640-655.e4 doi: 10.1016/j.cmet.2024.11.006 https://pubmed.ncbi.nlm.nih.gov/39694039

Brief Summary: This study represents a major advance in the understanding of adipose tissue (AT) heterogeneity in the context of metabolic disease. By integrating single-nucleus RNA-sequencing (snRNA-seq) and bulk transcriptomics from both visceral (VAT) and subcutaneous (SAT) adipose depots in individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), the study constructs a high-resolution cellular atlas of AT associated with health and disease states.

Traditional classification of obesity via BMI fails to distinguish individuals at differential risk of metabolic disease. This paper fills a critical gap by linking AT cellular composition and transcriptional programs to clinical phenotypes, providing mechanistic insight into why some individuals with obesity remain metabolically healthy. The study validates the hypothesis that adipocyte plasticity, rather than mass alone, is key to metabolic health. It confirms prior findings that VAT dysfunction, rather than total fat volume, is a major driver of insulin resistance and other metabolic abnormalities [1,2]. The identification of mesenchymal-like mesothelial cells (meMesoCs) and their enrichment in metabolically healthy states is novel. It supports emerging literature suggesting that mesothelial cells are not inert but participate in epithelial-to-mesenchymal transition (EMT) and potentially in adipogenesis or immune modulation [3,4]. Further, the authors discovered a ZNF804B+ anti-adipogenic progenitor population (AAPs2), which is found only in MUO women and linked with adaptive immune recruitment. This adds a new layer to understanding sexual dimorphism in metabolic disease, complementing previous murine studies [5].

References: 1. Blüher M, Metabolically Healthy Obesity, Endocrine Reviews Volume 41, Issue 3, June 2020, bnaa004, https://doi.org/10.1210/endrev/bnaa0042. Stefan N Causes, consequences, and treatment of metabolically unhealthy fat distribution. Lancet Diab Endocrinol 8(7): 616-627 (2020). https://doi.org/10.1016/S2213-8587(20)30110-83. Massier, L., Jalkanen, J., Elmastas, M. et al. An integrated single cell and spatial transcriptomic map of human white adipose tissue. Nat Commun 14, 1438 (2023). https://doi.org/10.1038/s41467-023-36983-24. Ferrero R, et al. A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion Cell Metab 36(7):1566-1585.e9 (2024) https://doi.org/10.1016/j.cmet.2024.04.0175. Ghaben, A.L., Scherer, P.E. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol 20, 242–258 (2019). https://doi.org/10.1038/s41580-018-0093-z