Embryonic adipose development and consequences in later life

Volume 8, Issue 5, October 2023     |     PP. 118-137      |     PDF (573 K)    |     Pub. Date: October 18, 2023
DOI: 10.54647/biology180324    62 Downloads     132583 Views  


Joseph M. Schulz, Molecular Developmental and Cell Biology (MDB) Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Alejandro Tamayo Garcia, Molecular Developmental and Cell Biology (MDB) Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Chloe Muriel Bell Moulin, Molecular Developmental and Cell Biology (MDB) Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Isabella Delia Altilio Bove, Molecular Developmental and Cell Biology (MDB) Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Xiang-Xi (Mike) Xu, Molecular Developmental and Cell Biology (MDB) Graduate Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA

Adipose tissues distribute throughout the mammalian organs, though large deposits localize at specific anatomical sites, such as visceral, subcutaneous, intermuscular, and intramuscular fats. The embryonic origin of adipose tissues has been mapped using genetic mutant mice, and multiple lineages of adipose progenitor cells are recognized. We review literature for evidence of a population of embryonic adipose progenitor cells that develop in response to the abundance of caloric supplies. This adipocyte population of embryonic or juvenal origin is a likely candidate of adipocytes accounting for obesity and metabolic pathology in adults. Thus, we suggest a mechanism underlying early caloric excess impacts on obesity and metabolic problems later in adults.

adipocyte, progenitor cells, embryonic development, metabolism, Dab2

Cite this paper
Joseph M. Schulz, Alejandro Tamayo Garcia, Chloe Muriel Bell Moulin, Isabella Delia Altilio Bove, Xiang-Xi (Mike) Xu, Embryonic adipose development and consequences in later life , SCIREA Journal of Biology. Volume 8, Issue 5, October 2023 | PP. 118-137. 10.54647/biology180324


[ 1 ] Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK. Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem 1997; 272:5128-32.
[ 2 ] Arner P, Spalding KL. Fat cell turnover in humans. Biochem Biophys Res Commun. 2010; 396:101-4.
[ 3 ] Berry R, Jeffery E, Rodeheffer MS. Weighing in on adipocyte precursors. Cell Metab. 2014; 19:8-20.
[ 4 ] Billon N, Monteiro MC, Dani C. Developmental origin of adipocytes: new insights into a pending question. Biol Cell. 2008;100:563-75.
[ 5 ] Billon N, Dani C. Developmental origins of the adipocyte lineage: new insights from genetics and genomics studies. Stem Cell Rev Rep. 2012 Mar; 8(1):55-66.
[ 6 ] Boden, G., Chen, X., Kolaczynski, J. W. & Polansky, M. Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J Clin Invest. 1997; 100:1107-1113.
[ 7 ] Börgeson E, Boucher J, Hagberg CE. Of mice and men: Pinpointing species differences in adipose tissue biology. Front Cell Dev Biol. 2022; 10:1003118.
[ 8 ] Bost F, Aouadi M, Caron L, Binétruy B. The role of MAPKs in adipocyte differentiation and obesity. Biochimie. 2005; 8 7:51-6.
[ 9 ] Burgermeister E, Seger R. MAPK kinases as nucleo-cytoplasmic shuttles for PPARgamma. Cell Cycle. 2007; 6:1539-48.
[ 10 ] Ceddia RB, Koistinen HA, Zierath JR, Sweeney G. Analysis of paradoxical observations on the association between leptin and insulin resistance. The FASEB Journal. 2002; 16:1163–76.
[ 11 ] Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003; 111:1409-21.
[ 12 ] Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science. 1996 Nov 15; 274(5290):1185-8.
[ 13 ] Cristancho AG, Lazar MA. Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol. 2011; 12:722-34.
[ 14 ] Deckelbaum RJ, Williams CL. Childhood obesity: the health issue. Obes Res. 2001; 9 Suppl 4:239S-43S.
[ 15 ] Di Spiezio, A. et al. The LepR-mediated leptin transport across brain barriers controls food reward. Mol Metab. 2018; 8:13-22.
[ 16 ] Efrat M, Tepper S, Birk RZ. From fat cell biology to public health preventive strategies - pinpointing the critical period for obesity prevention. J Pediatr Endocrinol Metab. 2013; 26:197-209.
[ 17 ] El-Haschimi K, Pierroz DD, Hileman SM, Bjørbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest. 2000; 105:1827-32.
[ 18 ] Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med. 2004; 10:355-61.
[ 19 ] Floyd ZE, Stephens JM. Controlling a master switch of adipocyte development and insulin sensitivity: covalent modifications of PPARγ. Biochim Biophys Acta. 2012; 1822:1090-5.
[ 20 ] Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995; 83:803-12.
[ 21 ] Garcia-Galiano D, Borges BC, Allen SJ, Elias CF. PI3K signalling in leptin receptor cells: Role in growth and reproduction. J Neuroendocrinol. 2019; 31:e12685.
[ 22 ] Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell. 2007; 131:242-56.
[ 23 ] Gorska E, Popko K, Stelmaszczyk-Emmel A, Ciepiela O, Kucharska A, Wasik M. Leptin receptors. Eur J Med Res. 2010 Nov 4;15 Suppl 2(Suppl 2):50-4.
[ 24 ] Greenfield JR, Chisholm DJ. Endocrinology. Thiazolidinediones - mechanisms of action. Aust Prescr. 2004; 27:67-70.
[ 25 ] Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review. Nutr J. 2014 Feb 14;13:17.
[ 26 ] Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995 Jul 28; 269(5223):543-6.
[ 27 ] He W, Barak Y, Hevener A, Olson P, Liao D, Le J, Nelson M, Ong E, Olefsky JM, Evans RM. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A. 2003; 100:15712-7.
[ 28 ] Hinds Jr, T. D. et al. Adipose-Specific PPARα Knockout Mice Have Increased Lipogenesis by PASK-SREBP1 Signaling and a Polarity Shift to Inflammatory Macrophages in White Adipose Tissue. Cells. 2021; 11:4.
[ 29 ] Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science. 1996; 274:2100-3.
[ 30 ] Jeffery E, Berry R, Church CD, Yu S, Shook BA, Horsley V, Rosen ED, Rodeheffer MS. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte. 2014; 3:206-11.
[ 31 ] Jeffery E, Church CD, Holtrup B, Colman L, Rodeheffer MS. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol. 2015; 17:376-85.
[ 32 ] Jo J, Gavrilova O, Pack S, Jou W, Mullen S, Sumner AE, Cushman SW, Periwal V. Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth. PLoS Comput Biol. 2009; 5:e1000324.
[ 33 ] Jones, J. R. et al. Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proc Natl Acad Sci U S A. 2005; 102:6207–6212.
[ 34 ] Kang S, Kong X, Rosen ED. Adipocyte-specific transgenic and knockout models. Methods Enzymol. 2014; 537:1-16.
[ 35 ] Kielar D, Clark JS, Ciechanowicz A, Kurzawski G, Sulikowski T, Naruszewicz M. Leptin receptor isoforms expressed in human adipose tissue. Metabolism. 1998 Jul; 47(7):844-7.
[ 36 ] Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obesity Reviews. 2007; 8:21-34.
[ 37 ] Knittle JL, Hirsch J. Effect of early nutrition on the development of rat epididymal fat pads: cellularity and metabolism. J Clin Invest. 1968; 47:2091-8.
[ 38 ] Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Kadowaki T, et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell. 1999 Oct; 4(4):597-609.
[ 39 ] Kopelman PG. Obesity as a medical problem. Nature. 2000; 404:635-43.
[ 40 ] Lebovitz HE. Thiazolidinediones: the Forgotten Diabetes Medications. Curr Diab Rep. 2019; 19:151.
[ 41 ] Leonardini A, Laviola L, Perrini S, Natalicchio A, Giorgino F. Cross-Talk between PPARgamma and Insulin Signaling and Modulation of Insulin Sensitivity. PPAR Res. 2009; 2009:818945.
[ 42 ] 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 May 13;20(9):2358.
[ 43 ] Louveau I, Perruchot MH, Bonnet M, Gondret F. Invited review: Pre- and postnatal adipose tissue development in farm animals: from stem cells to adipocyte physiology. Animal. 2016 Nov; 10(11):1839-1847.
[ 44 ] Lowell BB. PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell. 1999; 99:239-42.
[ 45 ] Madsen MS, Siersbæk R, Boergesen M, Nielsen R, Mandrup S. Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading. Mol Cell Biol. 2014; 34:939–54.
[ 46 ] Majka SM, Barak Y, Klemm DJ. Concise review: adipocyte origins: weighing the possibilities. Stem Cells. 2011 Jul; 29(7):1034-40.
[ 47 ] Martínez-Sánchez N. There and Back Again: Leptin Actions in White Adipose Tissue. Int J Mol Sci. 2020; 21:6039.
[ 48 ] Meek TH, Morton GJ. Leptin, diabetes, and the brain. Indian J Endocrinol Metab. 2012; 16: S534-S42.
[ 49 ] Moore R, Cai KQ, Tao W, Smith ER, Xu XX. Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues. BMC Dev Biol. 2013 Oct 29; 13:39.
[ 50 ] Muhlhausler B, Smith SR. Early-life origins of metabolic dysfunction: role of the adipocyte. Trends Endocrinol Metab. 2009 Mar; 20(2):51-7.
[ 51 ] Park H-K, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism. 2015; 64:24–34.
[ 52 ] Picó C, Palou M, Pomar CA, Rodríguez AM, Palou A. Leptin as a key regulator of the adipose organ. Rev Endocr Metab Disord. 2022; 23:13–30.
[ 53 ] Ramos-Lobo AM, Donato Jr J. The role of leptin in health and disease. Temperature. (Austin) 2017; 4:258-91.
[ 54 ] Rangwala SM, Rhoades B, Shapiro JS, Rich AS, Kim JK, Shulman GI, Kaestner KH, Lazar MA. Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity. Dev Cell. 2003; 5:657-63.
[ 55 ] Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol. 2000; 16:145-71.
[ 56 ] Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell. 1999; 4: 611-7.
[ 57 ] Russell CD, Petersen RN, Rao SP, Ricci MR, Prasad A, Zhang Y, Brolin RE, Fried SK. Leptin expression in adipose tissue from obese humans: depot-specific regulation by insulin and dexamethasone. Am J Physiol. 1998 Sep;275(3):E507-15.
[ 58 ] Sanchez-Gurmaches J, Guertin DA. Adipocyte lineages: tracing back the origins of fat. Biochim Biophys Acta. 2014 Mar; 1842(3):340-51.
[ 59 ] Sanchez-Gurmaches J, Guertin DA. Adipocytes arise from multiple lineages that are heterogeneously and dynamically distributed. Nat Commun. 2014 Jun 19;5:4099.
[ 60 ] Sanchez-Gurmaches J, Hung CM, Guertin DA. Emerging Complexities in Adipocyte Origins and Identity. Trends Cell Biol. 2016 May;26(5):313-26.
[ 61 ] Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirli C, Strazzabosco M. Stimulation of nuclear receptor peroxisome proliferator-activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology. 2015 Nov;62(5):1551-62.
[ 62 ] Sebo ZL, Jeffery E, Holtrup B, Rodeheffer MS. A mesodermal fate map for adipose tissue. Development. 2018 Aug 17; 145(17):dev166801.
[ 63 ] Sebo ZL, Rodeheffer MS. Assembling the adipose organ: adipocyte lineage segregation and adipogenesis in vivo. Development. 2019 Apr 4;146(7):dev172098.
[ 64 ] Shimabukuro M. Leptin Resistance and Lipolysis of White Adipose Tissue: An Implication to Ectopic Fat Disposition and Its Consequences. J Atheroscler Thromb. 2017; 24:1088-9.
[ 65 ] Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Näslund E, Britton T, Concha H, Hassan M, Rydén M, Frisén J, Arner P. Dynamics of fat cell turnover in humans. Nature. 2008; 453(7196):783-7.
[ 66 ] Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell. 1996; 87:377-89.
[ 67 ] Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001; 104:531-43.
[ 68 ] Stenkula KG, Erlanson-Albertsson C. Adipose cell size: importance in health and disease. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2018; 315:R284–R295.
[ 69 ] Stubbs RJ, Tolkamp BJ. Control of energy balance in relation to energy intake and energy expenditure in animals and man: an ecological perspective. Br J Nutr. 2006; 95:657-76.
[ 70 ] Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011; 121:2094-101.
[ 71 ] Sweeney G, Keen J, Somwar R, Konrad D, Garg R, Klip A. High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in l6 rat skeletal muscle cells. Endocrinology. 2001 Nov;142(11):4806-12.
[ 72 ] Tao W, Moore R, Meng Y, Yeasky TM, Smith ER, Xu XX. Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice. Sci Rep. 2016(a) Oct 25; 6:35947.
[ 73 ] Tao W, Moore R, Smith ER, Xu XX. Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice. Front Cell Dev Biol. 2016(b) Nov 25; 4:129.
[ 74 ] Tao W, Moore R, Meng Y, Smith ER, Xu XX. Endocytic adaptors Arh and Dab2 control homeostasis of circulatory cholesterol. J Lipid Res. 2016(c) May;57(5):809-17.
[ 75 ] Tarantal AF, Berglund L. Obesity and lifespan health--importance of the fetal environment. Nutrients. 2014; 6:1725-36.
[ 76 ] Tenenbaum-Gavish K, Hod M. Impact of maternal obesity on fetal health. Fetal Diag Ther. 2013; 34:1-7.
[ 77 ] Tsujikawa M, Kimura S. Effect of early feeding on cellularity of rat adipose tissue. J Nutr Sci Vitaminol (Tokyo). 1980; 26(5):475-82.
[ 78 ] Varga T, Czimmerer Z, Nagy L. PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta 2011; 1812:1007–22.
[ 79 ] Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013; 19:1338-44.
[ 80 ] Wang P. et al. Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass- and Obesity-Associated (FTO) Downregulation during Energy Restriction. Molecular Medicine 2011; 17: 523–32.
[ 81 ] Wang W. et al. Efficacy and safety of thiazolidinediones in diabetes patients with renal impairment: a systematic review and meta-analysis. Sci Rep 2017; 7:1717.
[ 82 ] White U, Ravussin E. Dynamics of adipose tissue turnover in human metabolic health and disease. Diabetologia. 2019; 62:17–23.
[ 83 ] Ye RZ, Richard G, Gévry N, Tchernof A, Carpentier AC. Fat Cell Size: Measurement Methods, Pathophysiological Origins, and Relationships With Metabolic Dysregulations. Endocr Rev. 2022; 43:35–60.