Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells

Abstract

Single-cell sequencing technologies have revealed an unexpectedly broad repertoire of cells required to mediate complex functions in multicellular organisms. Despite the multiple roles of adipose tissue in maintaining systemic metabolic homeostasis, adipocytes are thought to be largely homogenous with only 2 major subtypes recognized in humans so far. Here we report the existence and characteristics of 4 distinct human adipocyte subtypes, and of their respective mesenchymal progenitors. The phenotypes of these distinct adipocyte subtypes are differentially associated with key adipose tissue functions, including thermogenesis, lipid storage, and adipokine secretion. The transcriptomic signature of “brite/beige” thermogenic adipocytes reveals mechanisms for iron accumulation and protection from oxidative stress, necessary for mitochondrial biogenesis and respiration upon activation. Importantly, this signature is enriched in human supraclavicular adipose tissue, confirming that these cells comprise thermogenic depots in vivo, and explain previous findings of a rate-limiting role of iron in adipose tissue browning. The mesenchymal progenitors that give rise to beige/brite adipocytes express a unique set of cytokines and transcriptional regulators involved in immune cell modulation of adipose tissue browning. Unexpectedly, we also find adipocyte subtypes specialized for high-level expression of the adipokines adiponectin or leptin, associated with distinct transcription factors previously implicated in adipocyte differentiation. The finding of a broad adipocyte repertoire derived from a distinct set of mesenchymal progenitors, and of the transcriptional regulators that can control their development, provides a framework for understanding human adipose tissue function and role in metabolic disease.

Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473

“…While lineage tracing cannot be performed in humans, relevant information can be derived from multipotent mesenchymal adipocyte progenitors present within adipose tissue. In previous studies, we observed that human adipocyte progenitor cells associated with the adipose tissue microvasculature differentiate into diverse functional subtypes 10 , 21 , and that the human thermogenic fat differentiation program is cell autonomous and depot-related 8 . In this paper, we leveraged these finding to investigate the gene expression signatures of progenitors and differentiated adipocytes from different human adipose tissue depots to define genes associated with the development of thermogenic adipocytes.…”

FTO Intronic SNP Strongly Influences Human Neck Adipocyte Browning Determined by Tissue and PPARγ Specific Regulation: A Transcriptome Analysis

“…Human brown adipocytes differentiated in distinct adipose tissues express thermogenic genes at moderate levels under unstimulated conditions [2,14]. The ratio of brown and white adipocytes is partially determined during the early differentiation of mesenchymal progenitors into adipocyte subtypes, which is strongly influenced by genetic predisposition [19,20]. This can be quantified in a given tissue or cell culture sample by determining BATLAS score based on the expression of 98 brown and 21 white-specific genes, which were selected by a combined analysis of gene expression signatures in murine brown, beige, and white adipocytes and human tissue samples [21].…”

FTO intronic SNP strongly influences human neck adipocyte browning determined by tissue and PPARγ specific regulation: a transcriptome analysis

“…Human brown adipocytes differentiated in distinct adipose tissues express thermogenic genes at moderate levels under unstimulated conditions [2,14]. The ratio of brown and white adipocytes is partially determined during the early differentiation of mesenchymal progenitors into adipocyte subtypes which is strongly influenced by genetic predisposition [19,20]. This can be quantified in a given tissue or cell culture sample by determining BATLAS score based on the expression of 98 brown and 21 white-specific genes, which were selected by a combined analysis of gene expression signatures in mouse brown, beige and white adipocytes and human tissue samples [21].…”