Enhancing adipose tissue plasticity: progenitor cell roles in metabolic health
Chouchani, E. T. & Kajimura, S. Metabolic adaptation and maladaptation in adipose tissue. Nat. Metab. 1, 189–200 (2019).
Google Scholar
Fleck, S. J. Body composition of elite American athletes. Am. J. Sports Med. 11, 398–403 (1983).
Google Scholar
Potter, A. W., Chin, G. C., Looney, D. P. & Friedl, K. E. Defining overweight and obesity by percent body fat instead of body mass index. J. Clin. Endocrinol. Metab. (2024).
Cohen, P. & Kajimura, S. The cellular and functional complexity of thermogenic fat. Nat. Rev. Mol. Cell Biol. 22, 393–409 (2021).
Google Scholar
Morigny, P., Boucher, J., Arner, P. & Langin, D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat. Rev. Endocrinol. 17, 276–295 (2021).
Google Scholar
Ghaben, A. L. & Scherer, P. E. Adipogenesis and metabolic health. Nat. Rev. Mol. Cell Biol. 20, 242–258 (2019).
Google Scholar
Karastergiou, K. & Fried, S. K. Multiple adipose depots increase cardiovascular risk via local and systemic effects. Curr. Atheroscler. Rep. 15, 361 (2013).
Google Scholar
Marcelin, G., Silveira, A. L. M., Martins, L. B., Ferreira, A. V. M. & Clément, K. Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis. J. Clin. Invest. 129, 4032–4040 (2019).
Google Scholar
Klöting, N. et al. Insulin-sensitive obesity. Am. J. Physiol. Endocrinol. Metab. 299, E506–E515 (2010).
Google Scholar
Pellegrinelli, V., Carobbio, S. & Vidal-Puig, A. Adipose tissue plasticity: how fat depots respond differently to pathophysiological cues. Diabetologia 59, 1075–1088 (2016).
Google Scholar
Favaretto, F., Bettini, S., Busetto, L., Milan, G. & Vettor, R. Adipogenic progenitors in different organs: pathophysiological implications. Rev. Endocr. Metab. Disord. 23, 71–85 (2022).
Google Scholar
Rodbell, M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J. Biol. Chem. 239, 375–380 (1964).
Google Scholar
Hollenberg, C. H. & Vost, A. Regulation of DNA synthesis in fat cells and stromal elements from rat adipose tissue. J. Clin. Invest. 47, 2485–2498 (1968).
Google Scholar
Ng, C. W., Poznanski, W. J., Borowiecki, M. & Reimer, G. Differences in growth in vitro of adipose cells from normal and obese patients. Nature 231, 445 (1971).
Google Scholar
Van, R. L., Bayliss, C. E. & Roncari, D. A. Cytological and enzymological characterization of adult human adipocyte precursors in culture. J. Clin. Invest. 58, 699–704 (1976).
Google Scholar
Bjorntorp, P. et al. Isolation and characterization of cells from rat adipose tissue developing into adipocytes. J. Lipid Res. 19, 316–324 (1978).
Google Scholar
Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249 (2008).
Google Scholar
Marcelin, G. et al. A PDGFRα-mediated switch toward CD9high adipocyte progenitors controls obesity-induced adipose tissue fibrosis. Cell Metab. 25, 673–685 (2017).
Google Scholar
Tang, W., Zeve, D., Seo, J., Jo, A. Y. & Graff, J. M. Thiazolidinediones regulate adipose lineage dynamics. Cell Metab. 14, 116–122 (2011).
Google Scholar
Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).
Google Scholar
Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15, 302–308 (2013).
Google Scholar
Jiang, Y., Berry, D. C., Tang, W. & Graff, J. M. Independent stem cell lineages regulate adipose organogenesis and adipose homeostasis. Cell Rep. 9, 1007–1022 (2014).
Google Scholar
Wang, Q. A., Tao, C., Gupta, R. K. & Scherer, P. E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat. Med. 19, 1338–1344 (2013).
Google Scholar
Rosenwald, M., Perdikari, A., Rülicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).
Google Scholar
Guimarães-Camboa, N. et al. Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell 20, 345–359.e5 (2017).
Google Scholar
Vishvanath, L. et al. Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab. 23, 350–359 (2016).
Google Scholar
Shao, M. et al. De novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity. Nat. Commun. 9, 890 (2018).
Google Scholar
Emont, M. P. & Rosen, E. D. Exploring the heterogeneity of white adipose tissue in mouse and man. Curr. Opin. Genet. Dev. 80, 102045 (2023).
Google Scholar
Vijay, J. et al. Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat. Metab. 2, 97–109 (2020).
Google Scholar
Sárvári, A. K. et al. Plasticity of epididymal adipose tissue in response to diet-induced obesity at single-nucleus resolution. Cell Metab. 33, 437–453.e5 (2021).
Google Scholar
Hepler, C. et al. Identification of functionally distinct fibro-inflammatory and adipogenic stromal subpopulations in visceral adipose tissue of adult mice. Elife 7, e39636 (2018).
Google Scholar
Merrick, D. et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364, eaav2501 (2019).
Google Scholar
Burl, R. B. et al. Deconstructing adipogenesis induced by β3-adrenergic receptor activation with single-cell expression profiling. Cell Metab. 28, 300–309.e4 (2018).
Google Scholar
Schwalie, P. C. et al. A stromal cell population that inhibits adipogenesis in mammalian fat depots. Nature 559, 103–108 (2018).
Google Scholar
Palani, N. P. et al. Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots. Nat. Metab. 5, 996–1013 (2023).
Google Scholar
Yang Loureiro, Z. et al. Wnt signaling preserves progenitor cell multipotency during adipose tissue development. Nat. Metab. 5, 1014–1028 (2023).
Google Scholar
Hinte, L. C. et al. Adipose tissue retains an epigenetic memory of obesity after weight loss. Nature (2024).
Berry, D. C., Jiang, Y. & Graff, J. M. Emerging roles of adipose progenitor cells in tissue development, homeostasis, expansion and thermogenesis. Trends Endocrinol. Metab. 27, 574–585 (2016).
Google Scholar
Clark, E. R. & Clark, E. L. Microscopic studies of the new formation of fat in living adult rabbits. Am. J. Anat. 67, 255–285 (1940).
Google Scholar
Flemming, W. On the formation and regression of fat cells in connective tissue with comment on the structure of the latter. Arch. Mikrosk. Anat. 7, 32–35 (1871).
Google Scholar
Loewe, L. Zur kenntnis des bindegewebes. Arch. Anat. Entwekngsgesch 43, 56 (1879).
Chiari, H. The individuality of adipose tissue in pathology. Trans. Chic. Pathol. Soc. 8, 65–68 (1910).
Toldt, C. Contribution to the histology and physiology of adipose tissue. Sitzber Akad. Wiss. Wien. Math. Naturwiss K1 62, 445–466 (1870).
Ryan, T. J. & Curri, S. B. The development of adipose tissue and its relationship to the vascular system. Clin. Dermatol. 7, 1–8 (1989).
Google Scholar
Hausman, G. J., Hentges, E. J. & Thomas, G. B. Differentiation of adipose tissue and muscle in hypophysectomized pig fetuses. J. Anim. Sci. 64, 1255–1261 (1987).
Google Scholar
Poissonnet, C. M., Burdi, A. R. & Bookstein, F. L. Growth and development of human adipose tissue during early gestation. Early Hum. Dev. 8, 1–11 (1983).
Google Scholar
Poissonnet, C. M., Burdi, A. R. & Garn, S. M. The chronology of adipose tissue appearance and distribution in the human fetus. Early Hum. Dev. 10, 1–11 (1984).
Google Scholar
Hausman, G. J. & Richardson, R. L. Adrenergic innervation of fetal pig adipose tissue. Histochemical and ultrastructural studies. Acta Anat. 130, 291–297 (1987).
Google Scholar
Hausman, G. J. & Thomas, G. B. Structural and histochemical aspects of perirenal adipose tissue in fetal pigs: relationships between stromal-vascular characteristics and fat cell concentration and enzyme activity. J. Morphol. 190, 271–283 (1986).
Google Scholar
Ailhaud, G. P. Cellular and molecular aspects of adipose tissue development. Annu. Rev. Nutr. 12, 207–233 (1992).
Google Scholar
Lee, Y. H., Mottillo, E. P. & Granneman, J. G. Adipose tissue plasticity from WAT to BAT and in between. Biochim. Biophys. Acta 1842, 358–369 (2014).
Google Scholar
Iyama, K., Ohzono, K. & Usuku, G. Electron microscopical studies on the genesis of white adipocytes: differentiation of immature pericytes into adipocytes in transplanted preadipose tissue. Virchows Arch. B. Cell Pathol. Incl. Mol. Pathol. 31, 143–155 (1979).
Google Scholar
Han, J. et al. The spatiotemporal development of adipose tissue. Development 138, 5027–5037 (2011).
Google Scholar
Hong, K. Y. et al. Perilipin+ embryonic preadipocytes actively proliferate along growing vasculatures for adipose expansion. Development 142, 2623–2632 (2015).
Google Scholar
Tran, K.-V. et al. The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab. 15, 222–229 (2012).
Google Scholar
Berry, R., Jeffery, E. & Rodeheffer, M. S. Perspective weighing in on adipocyte precursors. Cell Metab. 19, 8–20 (2013).
Google Scholar
McCullough, A. W. Evidence of the macrophagal origin of adipose cells in the white rat as shown by studies on starved animals. J. Morphol. 75, 193–201 (1944).
Google Scholar
Arner, P. & Rydén, M. The contribution of bone marrow-derived cells to the human adipocyte pool. Adipocyte 6, 187–192 (2017).
Google Scholar
Crossno, J. T., Majka, S. M., Grazia, T., Gill, R. G. & Klemm, D. J. Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells. J. Clin. Invest. 116, 3220–3228 (2006).
Google Scholar
Majka, S. M. et al. De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific. Proc. Natl Acad. Sci. USA 107, 14781–14786 (2010).
Google Scholar
Majka, S. M. et al. Adipose lineage specification of bone marrow-derived myeloid cells. Adipocyte 1, 215–229 (2012).
Google Scholar
Gavin, K. M. et al. De novo generation of adipocytes from circulating progenitor cells in mouse and human adipose tissue. FASEB J. 30, 1096–1108 (2016).
Google Scholar
Rydén, M. et al. Transplanted bone marrow-derived cells contribute to human adipogenesis. Cell Metab. 22, 408–417 (2015).
Google Scholar
Tchoukalova, Y. D. et al. In vivo adipogenesis in rats measured by cell kinetics in adipocytes and plastic-adherent stroma-vascular cells in response to high-fat diet and thiazolidinedione. Diabetes 61, 137–144 (2012).
Google Scholar
Wasserman, F. Die Fettorgane des Menchen. Entwicklung, Bau und systematische Stellung des sogenannten Fettgewebes. Z. Zellforsch. 3, 235–328 (1926).
Cinti, S., Cigolini, O. & Björntorp, P. A morphological study of the adipocyte precursor. J. Submicrosc. Cytol. 16, 243–251 (1984).
Google Scholar
Napolitano, L. The differentiation of white adipose cells. An electron microscope study. J. Cell Biol. 18, 663–679 (1963).
Google Scholar
Vishvanath, L., Long, J. Z., Spiegelman, B. M. & Gupta, R. K. Do adipocytes emerge from mural progenitors? Cell Stem Cell 20, 585–586 (2017).
Google Scholar
Long, J. Z. et al. A smooth muscle-like origin for beige adipocytes. Cell Metab. 19, 810–820 (2014).
Google Scholar
Guimarães-Camboa, N. & Evans, S. M. Are perivascular adipocyte progenitors mural cells or adventitial fibroblasts? Cell Stem Cell 20, 587–589 (2017).
Google Scholar
Berry, D. C., Stenesen, D., Zeve, D. & Graff, J. M. The developmental origins of adipose tissue. Development 140, 3939–3949 (2013).
Google Scholar
Billon, N. et al. The generation of adipocytes by the neural crest. Development 134, 2283–2292 (2007).
Google Scholar
Lemos, D. R. et al. Functionally convergent white adipogenic progenitors of different lineages participate in a diffused system supporting tissue regeneration. Stem Cell 30, 1152–1162 (2012).
Google Scholar
Hudak, C. S. et al. Pref-1 marks very early mesenchymal precursors required for adipose tissue development and expansion. Cell Rep. 8, 678–687 (2014).
Google Scholar
Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).
Google Scholar
Wang, Z. V., Deng, Y., Wang, Q. A., Sun, K. & Scherer, P. E. Identification and characterization of a promoter cassette conferring adipocyte-specific gene expression. Endocrinology 151, 2933–2939 (2010).
Google Scholar
Wang, Q. A. et al. Distinct regulatory mechanisms governing embryonic versus adult adipocyte maturation. Nat. Cell Biol. 17, 1099–1111 (2015).
Google Scholar
Jeffery, E., Church, C. D., Holtrup, B., Colman, L. & Rodeheffer, M. S. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat. Cell Biol. 17, 376–385 (2015).
Google Scholar
Shao, M. et al. Fetal development of subcutaneous white adipose tissue is dependent on Zfp423. Mol. Metab. 6, 111–124 (2017).
Google Scholar
Wu, Z. et al. Cross-regulation of C/EBPα and PPARγ controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol. Cell 3, 151–158 (1999).
Google Scholar
Gupta, R. K. et al. Transcriptional control of preadipocyte determination by Zfp423. Nature 464, 619–623 (2010).
Google Scholar
Gupta, R. K. et al. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab. 15, 230–239 (2012).
Google Scholar
Chau, Y. et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat. Cell Biol. 16, 367–375 (2014).
Google Scholar
Sanchez-Gurmaches, J., Hsiao, W.-Y. & Guertin, D. A. Highly selective in vivo labeling of subcutaneous white adipocyte precursors with Prx1-Cre. Stem Cell Rep. 4, 541–550 (2015).
Google Scholar
Sanchez-Gurmaches, J. & Guertin, D. A. Adipocyte lineages: tracing back the origins of fat. Biochim. Biophys. Acta – Mol. Basis Dis. 1842, 340–351 (2014).
Google Scholar
Ferrero, R., Rainer, P. & Deplancke, B. Toward a consensus view of mammalian adipocyte stem and progenitor cell heterogeneity. Trends Cell Biol. 30, 937–950 (2020).
Google Scholar
Zeve, D., Tang, W. & Graff, J. Fighting fat with fat: the expanding field of adipose stem cells. Cell Stem Cell 5, 472–481 (2009).
Google Scholar
Gao, Z., Daquinag, A. C., Su, F., Snyder, B. & Kolonin, M. G. PDGFRα/PDGFRβ signaling balance modulates progenitor cell differentiation into white and beige adipocytes. Development 145, dev155861 (2018).
Google Scholar
Sun, C. et al. Mosaic mutant analysis identifies PDGFRα/PDGFRβ as negative regulators of adipogenesis. Cell Stem Cell 26, 707–721.e5 (2020).
Google Scholar
Cattaneo, P. et al. Parallel lineage-tracing studies establish fibroblasts as the prevailing in vivo adipocyte progenitor. Cell Rep. 30, 571–582.e2 (2020).
Google Scholar
Lee, Y. H., Petkova, A. P., Mottillo, E. P. & Granneman, J. G. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).
Google Scholar
Han, X. et al. A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting. Cell Stem Cell 28, 1160–1176.e7 (2021).
Google Scholar
Hildreth, A. D. et al. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Nat. Immunol. 22, 639–653 (2021).
Google Scholar
Raajendiran, A. et al. Identification of metabolically distinct adipocyte progenitor cells in human adipose tissues. Cell Rep. 27, 1528–1540.e7 (2019).
Google Scholar
Cho, D. S., Lee, B. & Doles, J. D. Refining the adipose progenitor cell landscape in healthy and obese visceral adipose tissue using single-cell gene expression profiling. Life Sci. Alliance 2, e201900561 (2019).
Google Scholar
Nguyen, H. P. et al. Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis. Dev. Cell 56, 1437–1451.e3 (2021).
Google Scholar
Emont, M. P. et al. A single-cell atlas of human and mouse white adipose tissue. Nature 603, 926–933 (2022).
Google Scholar
Stefkovich, M., Traynor, S., Cheng, L., Merrick, D. & Seale, P. Dpp4+ interstitial progenitor cells contribute to basal and high fat diet-induced adipogenesis. Mol. Metab. 54, 101357 (2021).
Google Scholar
Nahmgoong, H. et al. Distinct properties of adipose stem cell subpopulations determine fat depot-specific characteristics. Cell Metab. 34, 458–472.e6 (2022).
Google Scholar
Maniyadath, B., Zhang, Q., Gupta, R. K. & Mandrup, S. Adipose tissue at single-cell resolution. Cell Metab. 35, 386–413 (2023).
Google Scholar
Spallanzani, R. G. et al. Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose-tissue immune and metabolic tenors. Sci. Immunol. 4, eaaw3658 (2019).
Google Scholar
Hepler, C. & Bass, J. Circadian mechanisms in adipose tissue bioenergetics and plasticity. Genes. Dev. 37, 454–473 (2023).
Google Scholar
Shao, M. et al. Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity. Cell Stem Cell 28, 685–701.e7 (2021).
Google Scholar
Buffolo, M. et al. Identification of a paracrine signaling mechanism linking CD34high progenitors to the regulation of visceral fat expansion and remodeling. Cell Rep. 29, 270–282.e5 (2019).
Google Scholar
Ferrero, R. et al. A human omentum-specific mesothelial-like stromal population inhibits adipogenesis through IGFBP2 secretion. Cell Metab. 36, 1566–1585.e9 (2024).
Google Scholar
Dong, H. et al. Identification of a regulatory pathway inhibiting adipogenesis via RSPO2. Nat. Metab. 4, 90–105 (2022).
Google Scholar
Murray, T. & Russell, T. R. Inhibition of adipose conversion in 3T3-L2 cells by retinoic acid. J. Supramol. Struct. 14, 255–266 (1980).
Google Scholar
Kim, D. M. et al. Retinoic acid inhibits adipogenesis via activation of Wnt signaling pathway in 3T3-L1 preadipocytes. Biochem. Biophys. Res. Commun. 434, 455–459 (2013).
Google Scholar
Zachara, M. et al. Mammalian adipogenesis regulator (Areg) cells use retinoic acid signalling to be non- and anti-adipogenic in age-dependent manner. EMBO J. 41, e108206 (2022).
Google Scholar
Corvera, S. Cellular heterogeneity in adipose tissues. Annu. Rev. Physiol. 83, 257–278 (2021).
Google Scholar
Zhang, Q. et al. Distinct functional properties of murine perinatal and adult adipose progenitor subpopulations. Nat. Metab. 4, 1055–1070 (2022).
Google Scholar
Mahlakõiv, T. et al. Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33. Sci. Immunol. 4, eaax0416 (2019).
Google Scholar
Shan, B. et al. Multilayered omics reveal sex- and depot-dependent adipose progenitor cell heterogeneity. Cell Metab. 34, 783–799.e7 (2022).
Google Scholar
Cannavino, J. & Gupta, R. K. Mesenchymal stromal cells as conductors of adipose tissue remodeling. Genes. Dev. 37, 781–800 (2023).
Google Scholar
Iwayama, T. et al. PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes. Dev. 29, 1106–1119 (2015).
Google Scholar
Divoux, A. et al. Distinct subpopulations of human subcutaneous adipose tissue precursor cells revealed by single-cell RNA sequencing. Am. J. Physiol. Cell Physiol. 326, C1248–C1261 (2024).
Google Scholar
Faust, I. M., Johnson, P. R. & Hirsch, J. Noncompensation of adipose mass in partially lipectomized mice and rats. Am. J. Physiol. 231, 538–544 (1976).
Google Scholar
Hedbacker, K. et al. Limitation of adipose tissue by the number of embryonic progenitor cells. Elife 9, e53074 (2020).
Google Scholar
Johnson, P. R. & Hirsch, J. Cellularity of adipose depots in six strains of genetically obese mice. J. Lipid Res. 13, 2–11 (1972).
Google Scholar
Tang, Q. Q., Otto, T. C. & Daniel Lane, M. Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc. Natl Acad. Sci. USA 100, 44–49 (2003).
Google Scholar
Jeffery, E. et al. The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity. Cell Metab. 24, 142–150 (2016).
Google Scholar
Greenwood, M. R. & Hirsch, J. Postnatal development of adipocyte cellularity in the normal rat. J. Lipid Res. 15, 474–483 (1974).
Google Scholar
Knittle, J. L. & Hirsch, J. Effect of early nutrition on the development of rat epididymal fat pads: cellularity and metabolism. J. Clin. Invest. 47, 2091–2098 (1968).
Google Scholar
Spalding, K. L. et al. Dynamics of fat cell turnover in humans. Nature 453, 783–787 (2008).
Google Scholar
Stiles, J. W., Francendese, A. A. & Masoro, E. J. Influence of age on size and number of fat cells in the epididymal depot. Am. J. Physiol. 229, 1561–1568 (1975).
Google Scholar
Hemmeryckx, B. et al. Age-associated adaptations in murine adipose tissues. Endocr. J. 57, 925–930 (2010).
Google Scholar
Rigamonti, A., Brennand, K., Lau, F. & Cowan, C. A. Rapid cellular turnover in adipose tissue. PLoS ONE 6, e17637 (2011).
Google Scholar
Kim, S. M. et al. Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 20, 1049–1058 (2014).
Google Scholar
Neese, R. A. et al. Measurement in vivo of proliferation rates of slow turnover cells by 2H2O labeling of the deoxyribose moiety of DNA. Proc. Natl Acad. Sci. USA 99, 15345–15350 (2002).
Google Scholar
Strawford, A., Antelo, F., Christiansen, M. & Hellerstein, M. K. Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O. Am. J. Physiol. Endocrinol. Metab. 3104, 577–588 (2004).
Google Scholar
White, U. A., Fitch, M. D., Beyl, R. A., Hellerstein, M. K. & Ravussin, E. Differences in in vivo cellular kinetics in abdominal and femoral subcutaneous adipose tissue in women. Diabetes 65, 1642–1647 (2016).
Google Scholar
Guillermier, C. et al. Imaging mass spectrometry demonstrates age-related decline in human adipose plasticity. JCI insight 2, e90349 (2017).
Google Scholar
Manolopoulos, K. N., Karpe, F. & Frayn, K. N. Gluteofemoral body fat as a determinant of metabolic health. Int. J. Obes. 34, 949–959 (2010).
Google Scholar
Vague, J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am. J. Clin. Nutr. 4, 20–34 (1956).
Google Scholar
Vague, J. Significance of obesity in medical practice. Mars Med 90, 179–189 (1953).
Google Scholar
Shungin, D. et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 518, 187–196 (2015).
Google Scholar
Karpe, F. & Pinnick, K. E. Biology of upper-body and lower-body adipose tissue-link to whole-body phenotypes. Nat. Rev. Endocrinol. 11, 90–100 (2015).
Google Scholar
Mejhert, N. & Rydén, M. Novel aspects on the role of white adipose tissue in type 2 diabetes. Curr. Opin. Pharmacol. 55, 47–52 (2020).
Google Scholar
Snijder, M. B. et al. Larger thigh and hip circumferences are associated with better glucose tolerance: the Hoorn study. Obes. Res. 11, 104–111 (2003).
Google Scholar
Virtue, S. & Vidal-Puig, A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome – an allostatic perspective. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1801, 338–349 (2010).
Google Scholar
Klein, S., Gastaldelli, A., Yki-Järvinen, H. & Scherer, P. E. Why does obesity cause diabetes? Cell Metab. 34, 11–20 (2022).
Google Scholar
Hagberg, C. E. & Spalding, K. L. White adipocyte dysfunction and obesity-associated pathologies in humans. Nat. Rev. Mol. Cell Biol. 25, 270–289 (2023).
Google Scholar
Yazıcı, D. & Sezer, H. Insulin resistance, obesity and lipotoxicity. Adv. Exp. Med. Biol. 960, 277–304 (2017).
Google Scholar
Svedberg, J., Strömblad, G., Wirth, A., Smith, U. & Björntorp, P. Fatty acids in the portal vein of the rat regulate hepatic insulin clearance. J. Clin. Invest. 88, 2054–2058 (1991).
Google Scholar
Rytka, J. M., Wueest, S., Schoenle, E. J. & Konrad, D. The portal theory supported by venous drainage-selective fat transplantation. Diabetes 60, 56–63 (2011).
Google Scholar
Jensen, M. D., Cardin, S., Edgerton, D. & Cherrington, A. Splanchnic free fatty acid kinetics. Am. J. Physiol. Endocrinol. Metab. 284, E1140–E1148 (2003).
Google Scholar
Lee, M. J., Wu, Y. & Fried, S. K. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol. Asp. Med. 34, 1–11 (2013).
Google Scholar
Tran, T. T., Yamamoto, Y., Gesta, S. & Kahn, C. R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008).
Google Scholar
Macotela, Y. et al. Intrinsic differences in adipocyte precursor cells from different white fat depots. Diabetes 61, 1691–1699 (2012).
Google Scholar
Katz, L. S., Geras-Raaka, E. & Gershengorn, M. C. Heritability of fat accumulation in white adipocytes. Am. J. Physiol. Endocrinol. Metab. 307, E335–E344 (2014).
Google Scholar
Lee, K. Y. et al. Tbx15 defines a glycolytic subpopulation and white adipocyte heterogeneity. Diabetes 66, 2822–2829 (2017).
Google Scholar
Item, F. & Konrad, D. Visceral fat and metabolic inflammation: the portal theory revisited. Obes. Rev. 13, 30–39 (2012).
Google Scholar
Ding, H. et al. Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16. Nat. Commun. 7, 11533 (2016).
Google Scholar
Tang, H. N. et al. Plasticity of adipose tissue in response to fasting and refeeding in male mice. Nutr. Metab. 14, 3 (2017).
Google Scholar
Merlotti, C., Ceriani, V., Morabito, A. & Pontiroli, A. E. Subcutaneous fat loss is greater than visceral fat loss with diet and exercise, weight-loss promoting drugs and bariatric surgery: a critical review and meta-analysis. Int. J. Obes. 41, 672–682 (2017).
Google Scholar
Camastra, S. & Ferrannini, E. Role of anatomical location, cellular phenotype and perfusion of adipose tissue in intermediary metabolism: a narrative review. Rev. Endocr. Metab. Disord. 23, 43–50 (2022).
Google Scholar
Hirsch, J. & Han, P. W. Cellularity of rat adipose tissue: effects of growth, starvation, and obesity. J. Lipid Res. 10, 77–82 (1969).
Google Scholar
Salans, L. B., Cushman, S. W. & Weismann, R. E. Studies of human adipose tissue adipose cell size and number in nonobese and obese patients. J. Clin. Invest. 52, 929–941 (1973).
Google Scholar
Hirsch, J. & Batchelor, B. Adipose tissue cellularity in human obesity. Clin. Endocrinol. Metab. 5, 299–311 (1976).
Google Scholar
Moreno-Castellanos, N. et al. The cytoskeletal protein septin 11 is associated with human obesity and is involved in adipocyte lipid storage and metabolism. Diabetologia 60, 324–335 (2017).
Google Scholar
Hansson, B. et al. Adipose cell size changes are associated with a drastic actin remodeling. Sci. Rep. 9, 12941 (2019).
Google Scholar
Kim, J. I. et al. During adipocyte remodeling, lipid droplet configurations regulate insulin sensitivity through F-actin and G-actin reorganization. Mol. Cell. Biol. 39, e00210-19 (2019).
Google Scholar
Li, Q. & Spalding, K. L. The regulation of adipocyte growth in white adipose tissue. Front. cell Dev. Biol. 10, (2022).
Czech, M. P. Cellular basis of insulin insensitivity in large rat adipocytes. J. Clin. Invest. 57, 1523–1532 (1976).
Google Scholar
Olefsky, J. M. Effects of fasting on insulin binding, glucose transport, and glucose oxidation in isolated rat adipocytes: relationships between insulin receptors and insulin action. J. Clin. Invest. 58, 1450–1460 (1976).
Google Scholar
Smith, U. Studies of human adipose tissue in culture. I. Incorporation of glucose and release of glycerol. Anat. Rec. 172, 597–602 (1972).
Google Scholar
Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).
Google Scholar
Reilly, S. M. & Saltiel, A. R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 13, 633–643 (2017).
Google Scholar
Jo, J. et al. Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Comput. Biol. 5, e1000324 (2009).
Google Scholar
Faust, I. M., Johnson, P. R., Stern, J. S. & Hirsch, J. Diet-induced adipocyte number increase in adult rats: a new model of obesity. Am. J. Physiol. 235, E279–E286 (1978).
Google Scholar
Wang, S. et al. Adipocyte Piezo1 mediates obesogenic adipogenesis through the FGF1/FGFR1 signaling pathway in mice. Nat. Commun. 11, 2303 (2020).
Google Scholar
Arner, P. et al. Variations in the size of the major omentum are primarily determined by fat cell number. J. Clin. Endocrinol. Metab. 98, E897–E901 (2013).
Google Scholar
Saavedra-Peña, R. D. M., Taylor, N., Flannery, C. & Rodeheffer, M. S. Estradiol cycling drives female obesogenic adipocyte hyperplasia. Cell Rep. 42, 112390 (2023).
Google Scholar
Steiner, B. M., Benvie, A. M., Lee, D., Jiang, Y. & Berry, D. C. Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner. Nat. Commun. 15, 6622 (2024).
Google Scholar
Liu, C. et al. Fibroblast growth factor 6 promotes adipocyte progenitor cell proliferation for adipose tissue homeostasis. Diabetes 72, 467–482 (2023).
Google Scholar
Fujiwara, T., Yoshioka, S., Yoshioka, T., Ushiyama, I. & Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes 37, 1549–1558 (1988).
Google Scholar
Kim, J.-Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).
Google Scholar
Arner, P. & Spalding, K. L. Biochemical and biophysical research communications fat cell turnover in humans. Biochem. Biophys. Res. Commun. 396, 101–104 (2010).
Google Scholar
White, U. & Ravussin, E. Dynamics of adipose tissue turnover in human metabolic health and disease. Diabetologia 62, 17–23 (2019).
Google Scholar
Maumus, M. et al. Evidence of in situ proliferation of adult adipose tissue-derived progenitor cells: influence of fat mass microenvironment and growth. J. Clin. Endocrinol. Metab. 93, 4098–4106 (2008).
Google Scholar
Andersson, D. P., Arner, E., Hogling, D. E., Rydén, M. & Arner, P. Abdominal subcutaneous adipose tissue cellularity in men and women. Int. J. Obes. 41, 1564–1569 (2017).
Google Scholar
Tchoukalova, Y. D. et al. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Proc. Natl Acad. Sci. USA 107, 18226–18231 (2010).
Google Scholar
Hoffstedt, J. et al. Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity. Diabetologia 53, 2496–2503 (2010).
Google Scholar
Gustafson, B., Hedjazifar, S., Gogg, S., Hammarstedt, A. & Smith, U. Insulin resistance and impaired adipogenesis. Trends Endocrinol. Metab. 26, 193–200 (2015).
Google Scholar
Hardy, O. T. et al. Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity. Surg. Obes. Relat. Dis. 7, 60–67 (2011).
Google Scholar
Acosta, J. R. et al. Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes. Diabetologia 59, 560–570 (2016).
Google Scholar
Bäckdahl, J. et al. Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin. Cell Metab. 33, 1869–1882.e6 (2021).
Google Scholar
Rydén, M., Andersson, D. P., Bergström, I. B. & Arner, P. Adipose tissue and metabolic alterations: regional differences in fat cell size and number matter, but differently: a cross-sectional study. J. Clin. Endocrinol. Metab. 99, E1870–E1876 (2014).
Google Scholar
Rabhi, N. et al. Obesity-induced senescent macrophages activate a fibrotic transcriptional program in adipocyte progenitors. Life Sci. Alliance 5, e202101286 (2022).
Google Scholar
Shin, S. et al. Dynamic control of adipose tissue development and adult tissue homeostasis by platelet-derived growth factor receptor alpha. Elife 9, e56189 (2020).
Google Scholar
Lin, J. Z., Rabhi, N. & Farmer, S. R. Myocardin-related transcription factor a promotes recruitment of ITGA5+ profibrotic progenitors during obesity-induced adipose tissue fibrosis. Cell Rep. 23, 1977–1987 (2018).
Google Scholar
Shan, B. et al. Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity. Nat. Metab. 2, 1332–1349 (2020).
Google Scholar
Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).
Google Scholar
Marcelin, G. et al. Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet. Autophagy 16, 2156–2166 (2020).
Google Scholar
Carthy, J. M. TGFβ signaling and the control of myofibroblast differentiation: implications for chronic inflammatory disorders. J. Cell. Physiol. 233, 98–106 (2018).
Google Scholar
McDonald, M. E. et al. Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes. Cell 160, 105–118 (2015).
Google Scholar
Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).
Google Scholar
Tang, Y. et al. BMP4 mediates the interplay between adipogenesis and angiogenesis during expansion of subcutaneous white adipose tissue. J. Mol. Cell Biol. 8, 302–312 (2016).
Google Scholar
Qian, S. W. et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc. Natl Acad. Sci. USA 110, E798–E807 (2013).
Google Scholar
Hoffmann, J. M. et al. BMP4 gene therapy enhances insulin sensitivity but not adipose tissue browning in obese mice. Mol. Metab. 32, 15–26 (2020).
Google Scholar
Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017).
Google Scholar
Hasegawa, Y. et al. Repression of adipose tissue fibrosis through a PRDM16-GTF2IRD1 complex improves systemic glucose homeostasis. Cell Metab. 27, 180–194.e6 (2018).
Google Scholar
Wang, W. et al. A PRDM16-driven metabolic signal from adipocytes regulates precursor cell fate. Cell Metab. 30, 174–189.e5 (2019).
Google Scholar
Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).
Google Scholar
Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes. Dev. 22, 1397–1409 (2008).
Google Scholar
Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
Google Scholar
Harms, M. J. et al. PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program. Genes. Dev. 29, 298–307 (2015).
Google Scholar
Ohno, H., Shinoda, K., Ohyama, K., Sharp, L. Z. & Kajimura, S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504, 163–167 (2013).
Google Scholar
Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).
Google Scholar
Halberg, N. et al. Hypoxia-inducible factor 1 induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 29, 4467–4483 (2009).
Google Scholar
Sun, K., Halberg, N., Khan, M., Magalang, U. J. & Scherer, P. E. Selective inhibition of hypoxia-inducible factor 1 ameliorates adipose tissue dysfunction. Mol. Cell. Biol. 33, 904–917 (2013).
Google Scholar
Sun, K., Tordjman, J., Clément, K. & Scherer, P. E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).
Google Scholar
Hu, E., Kim, J. B., Sarraf, P. & Spiegelman, B. M. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ. Science 274, 2100–2103 (1996).
Google Scholar
Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).
Google Scholar
Tak, P. P. & Firestein, G. S. NF-κB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11 (2001).
Google Scholar
Joffin, N. et al. Mitochondrial metabolism is a key regulator of the fibro-inflammatory and adipogenic stromal subpopulations in white adipose tissue. Cell Stem Cell 28, 702–717.e8 (2021).
Google Scholar
Kusminski, C. M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat. Med. 18, 1539–1549 (2012).
Google Scholar
Luong, Q., Huang, J. & Lee, K. Y. Deciphering white adipose tissue heterogeneity. Biology 8, 23 (2019).
Google Scholar
Sanchez-Gurmaches, J. & Guertin, D. A. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat. Commun. 5, 4099 (2014).
Google Scholar
Sebo, Z. L., Jeffery, E., Holtrup, B. & Rodeheffer, M. S. A mesodermal fate map for adipose tissue. Dev 145, dev166801 (2018).
Google Scholar
Lee, K. Y. et al. Developmental and functional heterogeneity of white adipocytes within a single fat depot. EMBO J. 38, e99291 (2019).
Google Scholar
Krueger, K. C., Costa, M. J., Du, H. & Feldman, B. J. Characterization of Cre recombinase activity for in vivo targeting of adipocyte precursor cells. Stem Cell Rep. 3, 1147–1158 (2014).
Google Scholar
Cristancho, A. G. & Lazar, M. A. Forming functional fat: a growing understanding of adipocyte differentiation. Nat. Rev. Mol. Cell Biol. 12, 722–734 (2011).
Google Scholar
Marcelin, G., Gautier, E. L. & Clement, K. Adipose tissue fibrosis in obesity: etiology and challenges. Annu. Rev. Physiol. 84, 135–155 (2022).
Google Scholar
Djian, P., Roncari, D. A. K. & Hollenberg, C. H. Influence of anatomic site and age on the replication and differentiation of rat adipocyte precursors in culture. J. Clin. Invest. 72, 1200–1208 (1983).
Google Scholar
Wang, H., Kirkland, J. L. & Hollenberg, C. H. Varying capacities for replication of rat adipocyte precursor clones and adipose tissue growth. J. Clin. Invest. 83, 1741–1746 (1989).
Google Scholar
Sztalryd, C. & Faust, I. Depot-specific features of adipocyte progenitors revealed by primary cultures plated at low density. Int. J. Obes. 14, 165–175 (1990).
Google Scholar
Grégoire, F., Todoroff, G., Hauser, N. & Remacle, C. The stroma-vascular fraction of rat inguinal and epididymal adipose tissue and the adipoconversion of fat cell precursors in primary culture. Biol. Cell 69, 215–222 (1990).
Google Scholar
Hauner, H., Wabitsch, M. & Pfeiffer, E. F. Differentiation of adipocyte precursor cells from obese and nonobese adult women and from different adipose tissue sites. Horm. Metab. Res. Suppl. 19, 35–39 (1988).
Google Scholar
Maslowska, M. H., Sniderman, A. D., MacLean, L. D. & Cianflone, K. Regional differences in triacylglycerol synthesis in adipose tissue and in cultured preadipocytes. J. Lipid Res. 34, 219–228 (1993).
Google Scholar
Roncari, D. A. K., Lau, D. C. W. & Kindler, S. Exaggerated replication in culture of adipocyte precursors from massively obese persons. Metabolism 30, 425–427 (1981).
Google Scholar
Grégoire, F. M., Johnson, P. R. & Greenwood, M. R. Comparison of the adipoconversion of preadipocytes derived from lean and obese Zucker rats in serum-free cultures. Int. J. Obes. Relat. Metab. Disord. 19, 664–670 (1995).
Google Scholar
Guilak, F. et al. Clonal analysis of the differentiation potential of human adipose-derived adult stem cells. J. Cell. Physiol. 206, 229–237 (2006).
Google Scholar
Mitchell, J. B. et al. Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers. Stem Cell 24, 376–385 (2006).
Google Scholar
Zuk, P. A. et al. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13, 4279–4295 (2002).
Google Scholar
Planat-Benard, V. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 109, 656–663 (2004).
Google Scholar
Hong, L., Peptan, I. A., Colpan, A. & Daw, J. L. Adipose tissue engineering by human adipose-derived stromal cells. Cells Tissues Organs 183, 133–140 (2006).
Google Scholar
Holtrup, B. et al. Puberty is an important developmental period for the establishment of adipose tissue mass and metabolic homeostasis. Adipocyte 6, 224–233 (2017).
Google Scholar
Birsoy, K. et al. Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis. Development 138, 4709–4719 (2011).
Google Scholar
Crandall, D. L., Hausman, G. J. & Kral, J. G. A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 4, 211–232 (1997).
Google Scholar
Knittle, J. L., Timmers, K., Ginsberg-Fellner, F., Brown, R. E. & Katz, D. The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J. Clin. Invest. 63, 239–246 (1979).
Google Scholar
Andersson, D. P. et al. Changes in subcutaneous fat cell volume and insulin sensitivity after weight loss. Diabetes Care 37, 1831–1836 (2014).
Google Scholar
Bjorntorp, P. et al. Effect of an energy-reduced dietary regimen in relation to adipose tissue cellularity in obese women. Am. J. Clin. Nutr. 28, 445–452 (1975).
Google Scholar
Jones, J. E. C. et al. The adipocyte acquires a fibroblast-like transcriptional signature in response to a high fat diet. Sci. Rep. 10, 2380 (2020).
Google Scholar
Roh, H. C. et al. Adipocytes fail to maintain cellular identity during obesity due to reduced PPARγ activity and elevated TGFβ-SMAD signaling. Mol. Metab. 42, 101086 (2020).
Google Scholar
Skurk, T., Alberti-Huber, C., Herder, C. & Hauner, H. Relationship between adipocyte size and adipokine expression and secretion. J. Clin. Endocrinol. Metab. 92, 1023–1033 (2007).
Google Scholar
Meyer, L. K., Ciaraldi, T. P., Henry, R. R., Wittgrove, A. C. & Phillips, S. A. Adipose tissue depot and cell size dependency of adiponectin synthesis and secretion in human obesity. Adipocyte 2, 217–226 (2013).
Google Scholar
Lundgren, M. et al. Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’. Diabetologia 50, 625–633 (2007).
Google Scholar
Smith, U. Effect of cell size on lipid synthesis by human adipose tissue in vitro. J. Lipid Res. 12, 65–70 (1971).
Google Scholar
Franck, N. et al. Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual. Diabetologia 50, 1716–1722 (2007).
Google Scholar
Laurencikiene, J. et al. Regulation of lipolysis in small and large fat cells of the same subject. J. Clin. Endocrinol. Metab. 96, E2045–E2059 (2011).
Google Scholar
Potts, J. L. et al. Impaired postprandial clearance of triacylglycerol-rich lipoproteins in adipose tissue in obese subjects. Am. J. Physiol. 268, E588–E594 (1995).
Google Scholar
Lecoutre, S. et al. Importance of the microenvironment and mechanosensing in adipose tissue biology. Cells 11, 2310 (2022).
Google Scholar
Wang, L. et al. YAP and TAZ protect against white adipocyte cell death during obesity. Nat. Commun. 11, 5455 (2020).
Google Scholar
Pellegrinelli, V. et al. Human adipocyte function is impacted by mechanical cues. J. Pathol. 233, 183–195 (2014).
Google Scholar
El Ouarrat, D. et al. TAZ is a negative regulator of PPARγ activity in adipocytes and TAZ deletion improves insulin sensitivity and glucose tolerance. Cell Metab. 31, 162–173.e5 (2020).
Google Scholar
Gealekman, O. et al. Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation 123, 186–194 (2011).
Google Scholar
Seo, J. B. et al. Knockdown of Ant2 reduces adipocyte hypoxia and improves insulin resistance in obesity. Nat. Metab. 1, 86–97 (2019).
Google Scholar
Trayhurn, P. Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu. Rev. Nutr. 34, 207–236 (2014).
Google Scholar
Petrus, P. et al. Glutamine links obesity to inflammation in human white adipose tissue. Cell Metab. 31, 375–390.e11 (2020).
Google Scholar
Lecoutre, S. et al. Glutamine metabolism in adipocytes: a bona fide epigenetic modulator of inflammation. Adipocyte 9, 620–625 (2020).
Google Scholar
Maqdasy, S. et al. Impaired phosphocreatine metabolism in white adipocytes promotes inflammation. Nat. Metab. 4, 190–202 (2022).
Google Scholar
Böhm, A. et al. Metabolic signatures of cultured human adipocytes from metabolically healthy versus unhealthy obese individuals. PLoS ONE 9, e93148 (2014).
Google Scholar
Hanzu, F. A. et al. Obesity rather than regional fat depots marks the metabolomic pattern of adipose tissue: an untargeted metabolomic approach. Obesity 22, 698–704 (2014).
Google Scholar
Schöttl, T., Kappler, L., Fromme, T. & Klingenspor, M. Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status. Mol. Metab. 4, 631–642 (2015).
Google Scholar
Schöttl, T. et al. Proteomic and metabolite profiling reveals profound structural and metabolic reorganization of adipocyte mitochondria in obesity. Obesity 28, 590–600 (2020).
Google Scholar
Lotta, L. A. et al. A cross-platform approach identifies genetic regulators of human metabolism and health. Nat. Genet. 53, 54–64 (2021).
Google Scholar
Miyazaki, Y. et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J. Clin. Endocrinol. Metab. 87, 2784–2791 (2002).
Google Scholar
Franklin, R. M., Ploutz-Snyder, L. & Kanaley, J. A. Longitudinal changes in abdominal fat distribution with menopause. Metabolism 58, 311–315 (2009).
Google Scholar
Davis, S. R. et al. Understanding weight gain at menopause. Climacteric 15, 419–429 (2012).
Google Scholar
Lovejoy, J. C., Champagne, C. M., De Jonge, L., Xie, H. & Smith, S. R. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int. J. Obes. 32, 949–958 (2008).
Google Scholar
link
