Adipocyte development and differentiation have an important role in the aetiology of obesity and its co-morbidities. Although multiple studies have investigated the adipogenic stem and precursor cells that give rise to mature adipocytes, our understanding of their in vivo origin and properties is incomplete. This is partially due to the highly heterogeneous and unstructured nature of adipose tissue depots, which has proven difficult to molecularly dissect using classical approaches such as fluorescence-activated cell sorting and Cre-lox lines based on candidate marker genes. Here, using the resolving power of single-cell transcriptomics in a mouse model, we reveal distinct subpopulations of adipose stem and precursor cells in the stromal vascular fraction of subcutaneous adipose tissue. We identify one of these subpopulations as CD142 adipogenesis-regulatory cells, which can suppress adipocyte formation in vivo and in vitro in a paracrine manner. We show that adipogenesis-regulatory cells are refractory to adipogenesis and that they are functionally conserved in humans. Our findings point to a potentially critical role for adipogenesis-regulatory cells in modulating adipose tissue plasticity, which is linked to metabolic control, differential insulin sensitivity and type 2 diabetes.

Adipose tissue usually is classified as either white, brown or beige/brite, based on whether it functions as an energy storage or thermogenic organ (Cannon and Nedergaard, 2004;Rosen and Spiegelman, 2014). It serves as an important regulator of systemic metabolism, exemplified by the fact that dysfunctional adipose tissue in obesity leads to a host of secondary metabolic complications such as diabetes, cardiovascular diseases and cancer (Hajer et al., 2008;Lauby-Secretan et al., 2016). In addition, adipose tissue is an important endocrine organ, which regulates the function of other metabolic tissues through paracrine and endocrine signals (Scheele and Wolfrum, 2019;Scherer, 2006). Work in recent years has demonstrated that tissue heterogeneity is an important factor regulating the functionality of various organs (Cao et al., 2017;Ginhoux et al., 2016;Park et al., 2018). Here we used single nucleus analysis in mice and men to deconvolute adipocyte heterogeneity. We are able to identify a novel subpopulation of adipocytes whose abundance is low in mice (2-8%) and which is increased under higher ambient temperatures. Interestingly, this population is abundant in humans who live close to thermoneutrality. We demonstrate that this novel adipocyte subtype functions as a paracrine cell regulating the activity of brown adipocytes through acetate-mediated regulation of thermogenesis. These findings could explain, why human brown adipose tissue is substantially less active than mouse tissue and targeting this pathway in humans might be utilized to restore thermogenic activity of this tissue..

Current GWAS have primarily focused on testing association of single SNPs. To only test for association of single SNPs has limited utility and is insufficient to dissect the complex genetic structure of many common diseases. To meet conceptual and technical challenges raised by GWAS, we propose gene and pathway-based GWAS as complementary to the current single SNP-based GWAS. This publication develops three statistics for testing association of genes and pathways with disease: linear combination test, quadratic test and decorrelation test which take correlations among SNPs within a gene or genes within a pathway into account. The null distribution of the proposed statistics is examined and the statistics are applied to GWAS of rheumatoid arthritis in the Wellcome Trust Case Control Consortium and the North American Rheumatoid Arthritis Consortium studies. The preliminary results show that the proposed gene and pathway-based GWAS offer several remarkable features. First, not only can they identify the genes that have large genetic effects, but also they can detect new genes in which each single SNP conferred a small amount of disease risk, and their joint actions can be implicated in the development of diseases. Second, gene and pathway-based analysis can allow the formation of the core of pathway definition of complex diseases and unravel the functional bases of an association finding. Third, replication of association findings at the gene or pathway level is much easier than replication at the individual SNP level.

Highlights d In-depth analysis of pure brown, brite, and white adipocyte transcriptomes d Identification of a signature that can classify brown and white adipose depots d BATLAS is a web tool that can be used to characterize complex fat tissues d BATLAS can predict the brown adipocyte content in mixed populations of adipocytes