Anatomical, Physiological, and Functional Diversity of Adipose Tissue

Human adipose tissue depots perform numerous diverse physiological functions, and are differentially linked to metabolic disease risk, yet only two major human adipocyte subtypes have been described, white and "brown/brite/beige." The diversity and lineages of adipocyte classes have been studied in mice using genetic methods that cannot be applied in humans. Here we circumvent this problem by studying the fate of single mesenchymal progenitor cells obtained from human adipose tissue. We report that a minimum of four human adipocyte subtypes can be distinguished by transcriptomic analysis, specialized for functionally distinct processes such as adipokine secretion and thermogenesis. Evidence for the presence of these adipocytes subtypes in adult humans is evidenced by differential expression of key adipokines leptin and adiponectin in isolated mature adipocytes. The human adipocytes most similar to the mouse "brite/beige" adipocytes are enriched in mechanisms that promote iron accumulation and protect from oxidative stress, and are derived from progenitors that express high levels of cytokines such as IL1B, IL8, IL11 and the IL6 family cytokine LIF, and low levels of the transcriptional repressors ID1 and ID3. Our finding of this adipocyte repertoire and its developmental mechanisms provides a high-resolution framework to analyze human adipose tissue architecture and its role in systemic metabolism and metabolic disease.

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25During energy demanding conditions, white adipocytes store triglycerides and release fatty acids through lipolysis. 26In contrast, bone marrow adipocytes (BM-Ad) increase in size during caloric restriction, suggesting this fat depot 27 exhibits precise metabolic specificity. We found subcutaneous adipocytes (SC-Ad) and BM-Ad share 28 morphological features, but possess distinct lipid metabolism. BM-Ad show enrichment in cholesterol-oriented 29 metabolism that correlates with increased free cholesterol content, while proteins involved in lipolysis were 30 downregulated. A strong down-regulation in expression of monoacylglycerol (MG) lipase was observed leading 31 to an accumulation of major MG species and accordingly the basal and induced lipolytic responses were absent in 32 BM-Ad. These features are not recapitulated in vitro using differentiated bone marrow mesenchymal stem cells. 33Since our data demonstrate that BM-Ad comprise a distinct class of adipocytes, we propose renaming them yellow 34 adipocytes. 35 36 Keywords 37Bone Marrow adipocytes / cholesterol/lipolysis / monoacylglycerol lipase / proteomic 2 and well-studied fat deposits occur in subcutaneous regions (SC-AT) and in the abdominal cavity surrounding key 3 internal organs like the pancreas and intestines (Zwick et al, 2018). Other adipose-specific deposits also form 4 around the heart, kidney, prostate in men and mammary glands in women (Zwick et al, 2018). In addition to WAT, 5 mammals also possess brown adipose tissue (BAT) located in the interscapular and supraclavicular regions, 6 representing less than 5% of the total fat mass (Leitner et al, 2017; Nedergaard et al, 2007; Saito et al, 2009; 7 Zingaretti et al, 2009). Brown adipocytes participate in non-shivering thermogenesis and possess a specific 8 morphology that includes several small lipid droplets and high mitochondria content (Bartelt & Heeren, 2014; 9 Cinti, 2001). In contrast, white adipocytes store energy as triglycerides (TG) in their unique large lipid droplet 10 (LD) after energy intake and release free fatty acids (FFA) through lipolysis in energy demanding conditions 11 (Zechner, 2015). Lipolysis occurs through a biochemical pathway that uses consecutive actions of adipose 12 triglyceride lipase (ATGL), which catalyzes the conversion of TG to diacylglycerols (DG) and hormone-sensitive 13 lipase (HSL) and hydrolyzes DAG to monoacylglycerols (MG), monoacylglycerol lipase (MAGL) and the newly 14 identified α/β hydrolase domain-containing protein 6 (ABHD6), which hydrolyzes MG to FA (Zhao et al, 2016) 15 and glycerol (Zechner, 2015). White adipocytes also have an important endocrine function as they can release 16 multiple soluble factors called adipokines, such as leptin and adiponectin (Fasshauer & Blüher, 2015). 17One intriguing adipose tissue (AT) localizes to the bone marrow called bone marrow adipose tissue (BM-AT) that 18 constitutes over 10% of the total fat mass in lean and healthy humans (Cawthorn et al, 2014). Technological 19 advances in quantitative imaging...