Abundance of a metabolically active subpopulation in dedifferentiated adipocytes inversely correlates with body mass index.

OBJECTIVE

The cellular composition and functionality of adipose tissue are key determinants of metabolic diseases associated with adipose tissue dysregulation, such as obesity. We hypothesized that distinct subpopulations with unique gene expression profiles and functional characteristics exist within human adipocytes.

METHODS

Dedifferentiated adipocytes (DFAT), obtained by ceiling culture of human adipocytes, were analyzed using single-cell RNA sequencing (10x Genomics). Clustering analysis identified one subpopulation with a particular gene signature containing muscle cell genes which was further characterized by bulk-sequencing and analyzed alongside different cohorts of human adipose tissue.

RESULTS

This subpopulation, named cluster 7 (C7), was isolated by FACS using two specific surface markers: cluster of differentiation 36 (CD36) and melanoma cell adhesion molecule (MCAM/CD146). Upon differentiation into adipocytes, the FACS-isolated CD36+/CD146+ cells (C7∗) showed an increased oxygen consumption rate compared to CD36-/CD146-cells (control cells) and non-sorted cells. Bulk RNA-sequencing revealed important pathways regulated in the differentiated C7∗ subpopulation that may contribute to its increased metabolic activity. Furthermore, the relative abundance of this specific cluster varied across eleven different human donors, demonstrating an inverse correlation between the proportion of C7∗ cells and the body mass index (BMI) of the respective donor. Importantly, a subset of genes regulated within this subpopulation also correlates with clinically relevant metabolic parameters, including weight, BMI, glycated hemoglobin, and plasma insulin, when analyzed alongside the gene expression of a large cohort of human subcutaneous adipose tissue (1759 donors).

CONCLUSION

Our results not only characterize DFAT cells derived from human adipose tissue, but also identify a specific subpopulation with increased energy expenditure that may play a role in body weight control. Future efforts to identify possible therapeutic targets or to promote the enrichment or activation of these energy-burning cells in adipose tissue might be useful in the field of cardiometabolic diseases.