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Erschienen in: Current Diabetes Reports 4/2022

10.03.2022 | Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)

It Is Not Just Fat: Dissecting the Heterogeneity of Adipose Tissue Function

verfasst von: Vissarion Efthymiou, Mary-Elizabeth Patti

Erschienen in: Current Diabetes Reports | Ausgabe 4/2022

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Abstract

Purpose of Review

The purpose of the current review is to summarize findings from the most recent and impactful studies which investigated human and mouse adipose tissue transcriptomes at a single-cell level. We provide perspective about the potential importance of data derived from these single-cell technologies in improving our understanding of the adipose organ and metabolic disease and likely future directions of this approach.

Recent Findings

The majority of single-cell or single-nuclei studies of the adipose organ so far have focused on investigating the stromal-vascular fraction (SVF) of mouse subcutaneous and intraabdominal white and interscapular brown fat depots. Few studies have also evaluated the impact of additional factors as drivers of adipose phenotypes, such as high-fat diet-induced obesity, adolescence, aging, and cold exposure. Recent studies have also investigated human cell lines and human fat biopsies across a range of body mass index (BMI) and in response to insulin resistance or T2D. These studies have identified numerous previously unexplored subpopulations of adipocyte progenitors, immune cells, and mature adipocytes in both mice and men.

Summary

Single-cell and single-nuclei technologies have brought an explosion of data that have advanced our understanding of the adipose organ in health and disease. However, we are still at the dawn of achieving a complete and comprehensive map of the mouse and human adipose organ. Multi-modal single-cell approaches to identify both anatomic localization of specific cellular populations and epigenetic mechanisms responsible for observed transcriptomic patterns are underway and will likely provide an even deeper understanding of the adipose organ in response to health and disease.
Literatur
1.
Zurück zum Zitat Alberts B, Bray D, Hopkin K, Lewis J, Raff M, Roberts K, Watson JD. Molecular biology of the cell. 2nd ed. New York: Garland Publishing Inc; 1989. Alberts B, Bray D, Hopkin K, Lewis J, Raff M, Roberts K, Watson JD. Molecular biology of the cell. 2nd ed. New York: Garland Publishing Inc; 1989.
3.
Zurück zum Zitat Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia. 2016;59(6):1075–88.CrossRefPubMedPubMedCentral Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia. 2016;59(6):1075–88.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19(10):1338–44.CrossRefPubMedPubMedCentral Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19(10):1338–44.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Asp Med. 2013;34(1):1–11.CrossRef Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Asp Med. 2013;34(1):1–11.CrossRef
6.
7.
Zurück zum Zitat Rytka JM, Wueest S, Schoenle EJ, Konrad D. The portal theory supported by venous drainage-selective fat transplantation. Diabetes. 2011;60(1):56–63.CrossRefPubMed Rytka JM, Wueest S, Schoenle EJ, Konrad D. The portal theory supported by venous drainage-selective fat transplantation. Diabetes. 2011;60(1):56–63.CrossRefPubMed
9.
Zurück zum Zitat Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL, Jensen MD. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc Natl Acad Sci U S A. 2010;107(42):18226–31.CrossRefPubMedPubMedCentral Tchoukalova YD, Votruba SB, Tchkonia T, Giorgadze N, Kirkland JL, Jensen MD. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc Natl Acad Sci U S A. 2010;107(42):18226–31.CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Lee KY, Luong Q, Sharma R, Dreyfuss JM, Ussar S, Kahn CR. Developmental and functional heterogeneity of white adipocytes within a single fat depot. EMBO J. 2019;38(3). Lee KY, Luong Q, Sharma R, Dreyfuss JM, Ussar S, Kahn CR. Developmental and functional heterogeneity of white adipocytes within a single fat depot. EMBO J. 2019;38(3).
11.
Zurück zum Zitat Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. Cell. 2008;135(2):240–9.CrossRefPubMed Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. Cell. 2008;135(2):240–9.CrossRefPubMed
12.
Zurück zum Zitat Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab. 2012;15(4):480–91.CrossRefPubMedPubMedCentral Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab. 2012;15(4):480–91.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Vishvanath L, MacPherson KA, Hepler C, Wang QA, Shao M, Spurgin SB, et al. Pdgfrbeta+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 2016;23(2):350–9.CrossRefPubMed Vishvanath L, MacPherson KA, Hepler C, Wang QA, Shao M, Spurgin SB, et al. Pdgfrbeta+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 2016;23(2):350–9.CrossRefPubMed
17.
Zurück zum Zitat Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M, et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab. 2010;299(3):E506–15.CrossRefPubMed Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M, et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab. 2010;299(3):E506–15.CrossRefPubMed
18.
Zurück zum Zitat Slyper M, Porter CBM, Ashenberg O, Waldman J, Drokhlyansky E, Wakiro I, et al. A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors. Nat Med. 2020;26(5):792–802.CrossRefPubMedPubMedCentral Slyper M, Porter CBM, Ashenberg O, Waldman J, Drokhlyansky E, Wakiro I, et al. A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors. Nat Med. 2020;26(5):792–802.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Rajbhandari P, Arneson D, Hart SK, Ahn IS, Diamante G, Santos LC, et al. Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes. Elife. 2019;8. Rajbhandari P, Arneson D, Hart SK, Ahn IS, Diamante G, Santos LC, et al. Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes. Elife. 2019;8.
20.
Zurück zum Zitat Lake BB, Codeluppi S, Yung YC, Gao D, Chun J, Kharchenko PV, et al. A comparative strategy for single-nucleus and single-cell transcriptomes confirms accuracy in predicted cell-type expression from nuclear RNA. Sci Rep. 2017;7(1):6031.CrossRefPubMedPubMedCentral Lake BB, Codeluppi S, Yung YC, Gao D, Chun J, Kharchenko PV, et al. A comparative strategy for single-nucleus and single-cell transcriptomes confirms accuracy in predicted cell-type expression from nuclear RNA. Sci Rep. 2017;7(1):6031.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Wu H, Kirita Y, Donnelly EL, Humphreys BD. Advantages of single-nucleus over single-cell RNA sequencing of adult kidney: rare cell types and novel cell states revealed in fibrosis. J Am Soc Nephrol. 2019;30(1):23–32.CrossRefPubMed Wu H, Kirita Y, Donnelly EL, Humphreys BD. Advantages of single-nucleus over single-cell RNA sequencing of adult kidney: rare cell types and novel cell states revealed in fibrosis. J Am Soc Nephrol. 2019;30(1):23–32.CrossRefPubMed
22.
Zurück zum Zitat Bakken TE, Hodge RD, Miller JA, Yao Z, Nguyen TN, Aevermann B, et al. Single-nucleus and single-cell transcriptomes compared in matched cortical cell types. PLoS One. 2018;13(12):e0209648. Bakken TE, Hodge RD, Miller JA, Yao Z, Nguyen TN, Aevermann B, et al. Single-nucleus and single-cell transcriptomes compared in matched cortical cell types. PLoS One. 2018;13(12):e0209648.
24.
Zurück zum Zitat Schwalie PC, Dong H, Zachara M, Russeil J, Alpern D, Akchiche N, et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature. 2018;559(7712):103–8.CrossRefPubMed Schwalie PC, Dong H, Zachara M, Russeil J, Alpern D, Akchiche N, et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature. 2018;559(7712):103–8.CrossRefPubMed
25.
Zurück zum Zitat Merrick D, Sakers A, Irgebay Z, Okada C, Calvert C, Morley MP, et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science. 2019;364(6438). Merrick D, Sakers A, Irgebay Z, Okada C, Calvert C, Morley MP, et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science. 2019;364(6438).
26.
Zurück zum Zitat Hepler C, Shan B, Zhang Q, Henry GH, Shao M, Vishvanath L, et al. Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. Elife. 2018;7. Hepler C, Shan B, Zhang Q, Henry GH, Shao M, Vishvanath L, et al. Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. Elife. 2018;7.
27.
Zurück zum Zitat • Sarvari AK, Van Hauwaert EL, Markussen LK, Gammelmark E, Marcher AB, Ebbesen MF, et al. Plasticity of epididymal adipose tissue in response to diet-induced obesity at single-nucleus resolution. Cell Metab. 2021;33(2):437–53 e5. This study identifies a distinct cluster of adipocytes that is uniquely present in the epididymal fat of lean (but not diet-induced obese) mice and provides evidence about the transcriptional regulatory network of adipocyte differentiation in vivo. • Sarvari AK, Van Hauwaert EL, Markussen LK, Gammelmark E, Marcher AB, Ebbesen MF, et al. Plasticity of epididymal adipose tissue in response to diet-induced obesity at single-nucleus resolution. Cell Metab. 2021;33(2):437–53 e5. This study identifies a distinct cluster of adipocytes that is uniquely present in the epididymal fat of lean (but not diet-induced obese) mice and provides evidence about the transcriptional regulatory network of adipocyte differentiation in vivo.
28.
Zurück zum Zitat Nguyen HP, Lin F, Yi D, Xie Y, Dinh J, Xue P, et al. Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis. Dev Cell. 2021;56(10):1437–51 e3. Nguyen HP, Lin F, Yi D, Xie Y, Dinh J, Xue P, et al. Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis. Dev Cell. 2021;56(10):1437–51 e3.
29.
Zurück zum Zitat Burl RB, Ramseyer VD, Rondini EA, Pique-Regi R, Lee YH, Granneman JG. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling. Burl RB, Ramseyer VD, Rondini EA, Pique-Regi R, Lee YH, Granneman JG. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling.
30.
Zurück zum Zitat Zhang Z, Shao M, Hepler C, Zi Z, Zhao S, An YA, et al. Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice. J Clin Invest. 2019;129(12):5327–42.CrossRefPubMedPubMedCentral Zhang Z, Shao M, Hepler C, Zi Z, Zhao S, An YA, et al. Dermal adipose tissue has high plasticity and undergoes reversible dedifferentiation in mice. J Clin Invest. 2019;129(12):5327–42.CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Song A, Dai W, Jang MJ, Medrano L, Li Z, Zhao H, et al. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J Clin Invest. 2020;130(1):247–57.CrossRefPubMed Song A, Dai W, Jang MJ, Medrano L, Li Z, Zhao H, et al. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J Clin Invest. 2020;130(1):247–57.CrossRefPubMed
32.
Zurück zum Zitat Sun W, Dong H, Balaz M, Slyper M, Drokhlyansky E, Colleluori G, et al. snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis. Nature. 2020;587(7832):98–102.CrossRefPubMed Sun W, Dong H, Balaz M, Slyper M, Drokhlyansky E, Colleluori G, et al. snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis. Nature. 2020;587(7832):98–102.CrossRefPubMed
33.
Zurück zum Zitat •• Shamsi F, Piper M, Ho LL, Huang TL, Gupta A, Streets A, et al. Vascular smooth muscle-derived Trpv1(+) progenitors are a source of cold-induced thermogenic adipocytes. Nat Metab. 2021;3(4):485–95. This study provides evidence about a novel lineage of progenitors that can give rise to highly thermogenic brown adipocytes. These newly identified progenitors are of a vascular smooth muscle origin and distinct from the previously known Pdgfr-α-positive progenitors. •• Shamsi F, Piper M, Ho LL, Huang TL, Gupta A, Streets A, et al. Vascular smooth muscle-derived Trpv1(+) progenitors are a source of cold-induced thermogenic adipocytes. Nat Metab. 2021;3(4):485–95. This study provides evidence about a novel lineage of progenitors that can give rise to highly thermogenic brown adipocytes. These newly identified progenitors are of a vascular smooth muscle origin and distinct from the previously known Pdgfr-α-positive progenitors.
34.
Zurück zum Zitat Angueira AR, Sakers AP, Holman CD, Cheng L, Arbocco MN, Shamsi F, et al. Defining the lineage of thermogenic perivascular adipose tissue. Nat Metab. 2021;3(4):469–84.CrossRefPubMedPubMedCentral Angueira AR, Sakers AP, Holman CD, Cheng L, Arbocco MN, Shamsi F, et al. Defining the lineage of thermogenic perivascular adipose tissue. Nat Metab. 2021;3(4):469–84.CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Suwandhi L, Altun I, Karlina R, Miok V, Wiedemann T, Fischer D, et al. Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population. Nat Commun. 2021;12(1):1588.CrossRefPubMedPubMedCentral Suwandhi L, Altun I, Karlina R, Miok V, Wiedemann T, Fischer D, et al. Asc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population. Nat Commun. 2021;12(1):1588.CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Ramirez AK, Dankel SN, Rastegarpanah B, Cai W, Xue R, Crovella M, et al. Single-cell transcriptional networks in differentiating preadipocytes suggest drivers associated with tissue heterogeneity. Nat Commun. 2020;11(1):2117.CrossRefPubMedPubMedCentral Ramirez AK, Dankel SN, Rastegarpanah B, Cai W, Xue R, Crovella M, et al. Single-cell transcriptional networks in differentiating preadipocytes suggest drivers associated with tissue heterogeneity. Nat Commun. 2020;11(1):2117.CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat • Vijay J, Gauthier MF, Biswell RL, Louiselle DA, Johnston JJ, Cheung WA, et al. Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat Metab. 2020;2(1):97–109. This study provides evidence about depot-specific differences of human adipose tissue (visceral vs. subcutaneous) at the single-cell level. It identifies a subtype of adipogenic progenitor cells that are enriched in adipose tissue of patients with T2D. • Vijay J, Gauthier MF, Biswell RL, Louiselle DA, Johnston JJ, Cheung WA, et al. Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat Metab. 2020;2(1):97–109. This study provides evidence about depot-specific differences of human adipose tissue (visceral vs. subcutaneous) at the single-cell level. It identifies a subtype of adipogenic progenitor cells that are enriched in adipose tissue of patients with T2D.
38.
Zurück zum Zitat Hildreth AD, Ma F, Wong YY, Sun R, Pellegrini M, O’Sullivan TE. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Nat Immunol. 2021;22(5):639–53.CrossRefPubMedPubMedCentral Hildreth AD, Ma F, Wong YY, Sun R, Pellegrini M, O’Sullivan TE. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Nat Immunol. 2021;22(5):639–53.CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, Beguinot F, Miele C. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci. 2019;20(9):2358.CrossRefPubMedCentral Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, Beguinot F, Miele C. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci. 2019;20(9):2358.CrossRefPubMedCentral
42.
Zurück zum Zitat Gowri SM, Antonisamy B, Geethanjali FS, Thomas N, Jebasingh F, Paul TV, Karpe F, Osmond C, Fall CHD, Vasan SK. Distinct opposing associations of upper and lower body fat depots with metabolic and cardiovascular disease risk markers. Int J Obes. 2021;45:2490–8.CrossRef Gowri SM, Antonisamy B, Geethanjali FS, Thomas N, Jebasingh F, Paul TV, Karpe F, Osmond C, Fall CHD, Vasan SK. Distinct opposing associations of upper and lower body fat depots with metabolic and cardiovascular disease risk markers. Int J Obes. 2021;45:2490–8.CrossRef
43.
44.
Zurück zum Zitat Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution. Science. 2019;363(6434):1463–7.CrossRefPubMedPubMedCentral Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, et al. Slide-seq: a scalable technology for measuring genome-wide expression at high spatial resolution. Science. 2019;363(6434):1463–7.CrossRefPubMedPubMedCentral
45.
Zurück zum Zitat Stahl PL, Salmen F, Vickovic S, Lundmark A, Navarro JF, Magnusson J, et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science. 2016;353(6294):78–82.CrossRefPubMed Stahl PL, Salmen F, Vickovic S, Lundmark A, Navarro JF, Magnusson J, et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science. 2016;353(6294):78–82.CrossRefPubMed
46.
Zurück zum Zitat Chen S, Lake BB, Zhang K. High-throughput sequencing of the transcriptome and chromatin accessibility in the same cell. Nat Biotechnol. 2019;37(12):1452–7.CrossRefPubMedPubMedCentral Chen S, Lake BB, Zhang K. High-throughput sequencing of the transcriptome and chromatin accessibility in the same cell. Nat Biotechnol. 2019;37(12):1452–7.CrossRefPubMedPubMedCentral
Metadaten
Titel
It Is Not Just Fat: Dissecting the Heterogeneity of Adipose Tissue Function
verfasst von
Vissarion Efthymiou
Mary-Elizabeth Patti
Publikationsdatum
10.03.2022
Verlag
Springer US
Erschienen in
Current Diabetes Reports / Ausgabe 4/2022
Print ISSN: 1534-4827
Elektronische ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-022-01455-2

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