Single-nucleus RNA-Seq reveals a new type of brown adipocyte regulating thermogenesis

Abstract

31Adipose tissue usually is classified as either white, brown or beige/brite, based on whether it functions 32 as an energy storage or thermogenic organ (Cannon and Nedergaard, 2004; Rosen and Spiegelman, 33 2014). It serves as an important regulator of systemic metabolism, exemplified by the fact that 34 dysfunctional adipose tissue in obesity leads to a host of secondary metabolic complications such as 35 diabetes, cardiovascular diseases and cancer (Hajer et al., 2008;Lauby-Secretan et al., 2016). In addition, 36 adipose tissue is an important endocrine organ, which regulates the function of other metabolic tissues 37 through paracrine and endocrine signals (Scheele and Wolfrum, 2019;Scherer, 2006). Work in recent 38 years has demonstrated that tissue heterogeneity is an important factor regulating the functionality of 39 various organs (Cao et al., 2017;Ginhoux et al., 2016;Park et al., 2018). Here we used single nucleus 40 analysis in mice and men to deconvolute adipocyte heterogeneity. We are able to identify a novel 41 subpopulation of adipocytes whose abundance is low in mice (2-8%) and which is increased under 42 higher ambient temperatures. Interestingly, this population is abundant in humans who live close to 43 thermoneutrality. We demonstrate that this novel adipocyte subtype functions as a paracrine cell 44 regulating the activity of brown adipocytes through acetate-mediated regulation of thermogenesis. These 45 findings could explain, why human brown adipose tissue is substantially less active than mouse tissue 46 and targeting this pathway in humans might be utilized to restore thermogenic activity of this tissue. 47 Main text 49As one of the major endocrine tissues, the adipose organ is organized in different depots across the body 50 and is composed of two different types: brown adipose tissue (BAT) and white adipose tissue (WAT). 51Each is comprised of a heterogeneous cell pool, which can be stratified into two groups. First, the 52 functional cell pool of mature adipocytes, which represent 20 to 50% of the total cell content (Roh et al., 53 2018;Rosenwald et al., 2013), and second, the stromal vascular fraction (SVF), which includes 54 preadipocytes, mesenchymal stem cells, fibroblasts, macrophages, immune cells, endothelial cells and 55 vascular progenitors (Rosenwald and Wolfrum, 2014). 56 57The main parenchymal cells of the adipose organ are adipocytes, which encompass three major cell 58 types. White adipocytes store the energy taken up from the circulation into triacylglycerols. In contrast, 59 brown adipocytes, and a less thermogenic efficient-related population referred to as beige or brite 60 adipocytes, dissipate chemical energy in the form of heat to protect from cold temperature through non-61 shivering thermogenesis. This unique ability is enabled by the specific presence of uncoupling protein 62 1 (UCP1) in mitochondria (Jung et al., 2019). Notably, brown and beige/brite adipocytes share some 63 morphological, biochemical and thermogenic characteristics, such as multiple sma...

In vivo isotope tracing reveals the versatility of glucose as a brown adipose tissue substrate

“…It is possible that mitochondrial heterogeneity exists within brown adipocytes as recently suggested ( Benador et al, 2018 ; Yu et al, 2015 ), with some favoring lipid anabolism and others lipid catabolism ( Benador et al, 2019 ). Alternatively, fatty acid synthesis and oxidation may occur in different adipocytes because lineage tracing and single-cell RNA sequencing suggest heterogeneous pools of brown adipocytes may also exist ( Sanchez-Gurmaches et al, 2016 ; Song et al, 2020 ; Sun et al, 2020 ). We also observe increased glucose labeling of short-chain acyl-carnitine and medium-chain acyl-carnitine species ( Figures 5A , 5I , and 5J ) in SC BAT, which can enter mitochondria independent of CPT1 ( McDonnell et al, 2016 ; McGarry and Foster, 1971 ).…”

Toward a Consensus View of Mammalian Adipocyte Stem and Progenitor Cell Heterogeneity

“…While technically more challenging than probing ASPCs, given the fragile nature of adipocytes, experimental progress is being made, catalyzed by the ability to use the nuclear transcriptome as a proxy for that of the whole cell. Initial results clearly hint at extensive molecular and functional adipocyte heterogeneity [61]. The ultimate challenge will then be to link the scRNA-seq data from ASPCs with that of mature adipocytes to clearly infer lineages in the different adipose tissues (see Outstanding Questions).…”

Angiogenesis in Adipose Tissue: The Interplay Between Adipose and Endothelial Cells

“…AT is classified as either white (WAT), brown (BAT), or beige/brite based on whether it functions as energy storage or thermogenic organ. Adipocytes in BAT are rich in mitochondria and generate chemical energy in the form of heat ( Sun et al, 2020 ). BAT expands when an organism is exposed to prolonged cold conditions and is linked with increased insulin sensitivity ( Cypess et al, 2009 ; Van Marken Lichtenbelt et al, 2009 ).…”