Skip to main content

Advertisement

SpringerLink
Log in

De Novo Lipogenesis as a Source of Second Messengers in Adipocytes

  • Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Obesity is a major risk factor for type 2 diabetes. Although adipose tissue allows storage of excess calories in periods of overnutrition, in obesity, adipose tissue metabolism becomes dysregulated and can promote metabolic diseases. This review discusses recent advances in understandings how adipocyte metabolism impacts metabolic homeostasis.

Recent Findings

The ability of adipocytes to synthesize lipids from glucose is a marker of metabolic fitness, e.g., low de novo lipogenesis (DNL) in adipocytes correlates with insulin resistance in obesity. Adipocyte DNL may promote synthesis of special “insulin sensitizing” signaling lipids that act hormonally. However, each metabolic intermediate in the DNL pathway (i.e., citrate, acetyl-CoA, malonyl-CoA, and palmitate) also has second messenger functions. Mounting evidence suggests these signaling functions may also be important for maintaining healthy adipocytes.

Summary

While adipocyte DNL contributes to lipid storage, lipid precursors may have additional second messenger functions critical for maintaining adipocyte health, and thus systemic metabolic homeostasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hales C, Carroll M, Fryar C, Ogden C. Prevalence of obesity among adults and youth: United States, 2015-2016. NCHS Data Brief. 2017;288.

  2. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444(7121):875–80.

    PubMed  Google Scholar 

  3. Sullivan PW, Morrato EH, Ghushchyan V, Wyatt HR, Hill JO. Obesity, inactivity, and the prevalence of diabetes and diabetes-related cardiovascular comorbidities in the U.S., 2000-2002. Diabetes Care. 2005;28(7):1599–603.

    PubMed  Google Scholar 

  4. Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, et al. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab. 2011;96(6):1654–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl J Med. 1999;341(6):427–34.

    CAS  PubMed  Google Scholar 

  6. Ashcroft FM, Rorsman P. Diabetes mellitus and the β cell: the last ten years. Cell. 2012;148(6):1160–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Tabák AG, Herder C, Rathmann W, Brunner EJ, Kivimäki M. Prediabetes: a high-risk state for developing diabetes. Lancet. 2012;379(9833):2279–90.

    PubMed  PubMed Central  Google Scholar 

  8. Association AD. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes Care. 2018 Jan 1;41(Supplement 1):S73–85.

  9. Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1):20–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Luo L, Liu M. Adipose tissue in control of metabolism. J Endocrinol. 2016;231(3):R77–99.

    CAS  PubMed  Google Scholar 

  11. Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov. 2016;15(9):639–60.

    CAS  PubMed  Google Scholar 

  12. Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, et al. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci. 2019;13:20(9).

    Google Scholar 

  13. Joffe BI, Panz VR, Raal FJ. From lipodystrophy syndromes to diabetes mellitus. Lancet. 2001;357(9266):1379–81.

    CAS  PubMed  Google Scholar 

  14. Kwok KHM, Lam KSL, Xu A. Heterogeneity of white adipose tissue: molecular basis and clinical implications. Exp Mol Med. 2016;48:e215.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Sebo ZL, Rodeheffer MS. Assembling the adipose organ: adipocyte lineage segregation and adipogenesis in vivo. Dev Camb Engl. 2019;4:146(7).

    Google Scholar 

  16. Sanchez-Gurmaches J, Hung C-M, Guertin DA. Emerging complexities in adipocyte origins and identity. Trends Cell Biol. 2016;26(5):313–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Chau Y-Y, Bandiera R, Serrels A, Martínez-Estrada OM, Qing W, Lee M, et al. Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source. Nat Cell Biol. 2014;16(4):367–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Primeau V, Coderre L, Karelis AD, Brochu M, Lavoie M-E, Messier V, et al. Characterizing the profile of obese patients who are metabolically healthy. Int J Obes. 2011;35(7):971–81.

    CAS  Google Scholar 

  19. Scherer PE. The many secret lives of adipocytes: implications for diabetes. Diabetologia. 2019;62(2):223–32.

    PubMed  Google Scholar 

  20. Ikeda K, Maretich P, Kajimura S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol Metab. 2018;29(3):191–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Verboven K, Wouters K, Gaens K, Hansen D, Bijnen M, Wetzels S, et al. Abdominal subcutaneous and visceral adipocyte size, lipolysis and inflammation relate to insulin resistance in male obese humans. Sci Rep. 2018;8(1):4677.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tchernof A, Després J-P. Pathophysiology of human visceral obesity: an update. Physiol Rev. 2013;93(1):359–404.

    CAS  PubMed  Google Scholar 

  23. Bjørndal B, Burri L, Staalesen V, Skorve J, Berge RK. Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. J Obes. 2011;2011:1–15.

    Google Scholar 

  24. Drolet R, Richard C, Sniderman AD, Mailloux J, Fortier M, Huot C, et al. Hypertrophy and hyperplasia of abdominal adipose tissues in women. Int J Obes 2005. 2008 Feb;32(2):283–91.

    CAS  Google Scholar 

  25. Veilleux A, Caron-Jobin M, Noël S, Laberge PY, Tchernof A. Visceral adipocyte hypertrophy is associated with dyslipidemia independent of body composition and fat distribution in women. Diabetes. 2011;60(5):1504–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lessard J, Tchernof A. Depot- and obesity-related differences in adipogenesis. Clin Lipidol. 2012;7(5):587–96.

    CAS  Google Scholar 

  27. 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.

    PubMed  PubMed Central  Google Scholar 

  28. Foster MT, Shi H, Softic S, Kohli R, Seeley RJ, Woods SC. Transplantation of non-visceral fat to the visceral cavity improves glucose tolerance in mice: investigation of hepatic lipids and insulin sensitivity. Diabetologia. 2011;54(11):2890–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Foster MT, Softic S, Caldwell J, Kohli R, de Kloet AD, Seeley RJ. Subcutaneous adipose tissue transplantation in diet-induced obese mice attenuates metabolic dysregulation while removal exacerbates It. Phys Rep. 2013;1(2).

  30. Hocking SL, Chisholm DJ, James DE. Studies of regional adipose transplantation reveal a unique and beneficial interaction between subcutaneous adipose tissue and the intra-abdominal compartment. Diabetologia. 2008;51(5):900–2.

    CAS  PubMed  Google Scholar 

  31. Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 2008;7(5):410–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Tulloch-Reid MK, Hanson RL, Sebring NG, Reynolds JC, Premkumar A, Genovese DJ, et al. Both subcutaneous and visceral adipose tissue correlate highly with insulin resistance in African Americans. Obes Res. 2004;12(8):1352–9.

    CAS  PubMed  Google Scholar 

  33. Sattar N, Gill JM. Type 2 diabetes as a disease of ectopic fat? BMC Med [Internet]. 2014 Dec [cited 2019 May 28];12(1). Available from: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0123-4

  34. Unger RH, Clark GO, Scherer PE, Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta BBA - Mol Cell Biol Lipids. 2010;1801(3):209–14.

    CAS  Google Scholar 

  35. Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol [Internet]. 2013 Jun 12 [cited 2019 May 26];4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679475/

  36. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Huh JY, Park YJ, Ham M, Kim JB. Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. Mol Cell. 2014;37(5):365–71.

    Google Scholar 

  38. Chatzigeorgiou A, Chavakis T. Immune cells and metabolism. Handb Exp Pharmacol. 2016;233:221–49.

    CAS  PubMed  Google Scholar 

  39. Xia C, Rao X, Zhong J. Role of T Lymphocytes in type 2 diabetes and diabetes-associated inflammation [Internet]. Journal of Diabetes Research. 2017 [cited 2019 Aug 25]. Available from: https://www.hindawi.com/journals/jdr/2017/6494795/

  40. Appari M, Channon KM, McNeill E. Metabolic regulation of adipose tissue macrophage function in obesity and diabetes. Antioxid Redox Signal. 2017;29(3):297–312.

    PubMed  Google Scholar 

  41. Kang YE, Kim JM, Joung KH, Lee JH, You BR, Choi MJ, et al. The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance in modest obesity and early metabolic dysfunction. PLoS One. 2016 Apr 21;11(4):e0154003.

    PubMed  PubMed Central  Google Scholar 

  42. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.

    CAS  PubMed  Google Scholar 

  43. Deng T, Liu J, Deng Y, Minze L, Xiao X, Wright V, et al. Adipocyte adaptive immunity mediates diet-induced adipose inflammation and insulin resistance by decreasing adipose Treg cells. Nat Commun [Internet]. 2017 Jul 12 [cited 2019 Aug 25];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510177/

  44. Tracey ML, Li-Fen L, Cindy L, Shen L, John M, Homero R, et al. T-cell profile in adipose tissue is associated with insulin resistance and systemic Inflammation in humans. Arterioscler Thromb Vasc Biol. 2014;34(12):2637–43.

    Google Scholar 

  45. Czech MP, Tencerova M, Pedersen DJ, Aouadi M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia. 2013;56(5):949–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Morigny P, Houssier M, Mouisel E, Langin D. Adipocyte lipolysis and insulin resistance. Biochimie. 2016;125:259–66.

    CAS  PubMed  Google Scholar 

  47. Guilherme A, Henriques F, Bedard AH, Czech MP. Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus. Nat Rev Endocrinol. 2019;15(4):207–25.

    CAS  PubMed  Google Scholar 

  48. Mîinea CP, Sano H, Kane S, Sano E, Fukuda M, Peränen J, et al. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J. 2005;391(Pt 1):87–93.

    PubMed  PubMed Central  Google Scholar 

  49. Brewer PD, Romenskaia I, Kanow MA, Mastick CC. Loss of AS160 Akt substrate causes Glut4 protein to accumulate in compartments that are primed for fusion in basal adipocytes. J Biol Chem. 2011;286(30):26287–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ramm G, Larance M, Guilhaus M, James DE. A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160. J Biol Chem. 2006;281(39):29174–80.

    CAS  PubMed  Google Scholar 

  51. Chen S, Wasserman DH, MacKintosh C, Sakamoto K. Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking. Cell Metab. 2011;13(1):68–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gonzalez E, McGraw TE. Insulin signaling diverges into Akt-dependent and -independent signals to regulate the recruitment/docking and the fusion of GLUT4 vesicles to the plasma membrane. Mol Biol Cell. 2006;17(10):4484–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Krycer JR, Yugi K, Hirayama A, Fazakerley DJ, Quek L-E, Scalzo R, et al. Dynamic metabolomics reveals that insulin primes the adipocyte for glucose metabolism. Cell Rep. 2017;21(12):3536–47.

    CAS  PubMed  Google Scholar 

  54. Whelan SA, Dias WB, Thiruneelakantapillai L, Lane MD, Hart GW. Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-linked β-N-acetylglucosamine in 3T3-L1 adipocytes. J Biol Chem. 2010;285(8):5204–11.

    CAS  PubMed  Google Scholar 

  55. Park SY, Ryu J, Lee W. O-GlcNAc modification on IRS-1 and Akt2 by PUGNAc inhibits their phosphorylation and induces insulin resistance in rat primary adipocytes. Exp Mol Med. 2005;37(3):220–9.

    CAS  PubMed  Google Scholar 

  56. Ji S, Park SY, Roth J, Kim HS, Cho JW. O-GlcNAc modification of PPARγ reduces its transcriptional activity. Biochem Biophys Res Commun. 2012;417(4):1158–63.

    CAS  PubMed  Google Scholar 

  57. Wells L, Vosseller K, Hart GW. A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance. Cell Mol Life Sci CMLS. 2003;60(2):222–8.

    CAS  PubMed  Google Scholar 

  58. Mondoux MA, Love DC, Ghosh SK, Fukushige T, Bond M, Weerasinghe GR, et al. O-linked-N-acetylglucosamine cycling and insulin signaling are required for the glucose stress response in Caenorhabditis elegans. Genetics. 2011;188(2):369–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sun C, Shang J, Yao Y, Yin X, Liu M, Liu H, et al. O-GlcNAcylation: a bridge between glucose and cell differentiation. J Cell Mol Med. 2016;20(5):769–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wollaston-Hayden EE, Harris RBS, Liu B, Bridger R, Xu Y, Wells L. Global O-GlcNAc levels modulate transcription of the adipocyte secretome during chronic insulin resistance. Front Endocrinol. 2014;5:223.

    Google Scholar 

  61. Eissing L, Scherer T, Tödter K, Knippschild U, Greve JW, Buurman WA, et al. De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health. Nat Commun. 2013;4:1528.

    PubMed  PubMed Central  Google Scholar 

  62. Herman MA, Peroni OD, Villoria J, Schön MR, Abumrad NA, Blüher M, et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature. 2012;484(7394):333–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Roberts R, Hodson L, Dennis AL, Neville MJ, Humphreys SM, Harnden KE, et al. Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans. Diabetologia. 2009;52(5):882–90.

    CAS  PubMed  Google Scholar 

  64. • Guilherme A, Pedersen DJ, Henchey E, Henriques FS, Danai LV, Shen Y, et al. Adipocyte lipid synthesis coupled to neuronal control of thermogenic programming. Mol Metab. 2017;6(8):781–96. This study suggests that knocking-out FASN in the DNL pathway affects the crosstalk between adipose tissue and nervous system.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Strawford A, Antelo F, Christiansen M, Hellerstein MK. Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with 2H2O. Am J Physiol Endocrinol Metab. 2004;286(4):E577–88.

    CAS  PubMed  Google Scholar 

  66. Chiu S, Mulligan K, Schwarz J-M. Dietary carbohydrates and fatty liver disease: de novo lipogenesis. Curr Opin Clin Nutr Metab Care. 2018;21(4):277–82.

    CAS  PubMed  Google Scholar 

  67. Sanders FWB, Griffin JL. De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev Camb Philos Soc. 2016;91(2):452–68.

    PubMed  Google Scholar 

  68. Harada N, Oda Z, Hara Y, Fujinami K, Okawa M, Ohbuchi K, et al. Hepatic de novo lipogenesis is present in liver-specific ACC1-deficient mice. Mol Cell Biol. 2007;27(5):1881–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A. 2004;101(19):7281–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Yore MM, Syed I, Moraes-Vieira PM, Zhang T, Herman MA, Homan EA, et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell. 2014;159(2):318–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Abel ED, Peroni O, Kim JK, Kim YB, Boss O, Hadro E, et al. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001;409(6821):729–33.

    CAS  PubMed  Google Scholar 

  72. Vijayakumar A, Aryal P, Wen J, Syed I, Vazirani RP, Moraes-Vieira PM, et al. Absence of carbohydrate response element binding protein in adipocytes causes systemic insulin resistance and impairs glucose transport. Cell Rep. 2017;21(4):1021–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kursawe R, Caprio S, Giannini C, Narayan D, Lin A, D’Adamo E, et al. Decreased transcription of ChREBP-α/β isoforms in abdominal subcutaneous adipose tissue of obese adolescents with prediabetes or early type 2 diabetes: associations with insulin resistance and hyperglycemia. Diabetes. 2013;62(3):837–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ortega-Prieto P, Postic C. Carbohydrate sensing through the transcription factor ChREBP. Front Genet. 2019;10:472.

    PubMed  PubMed Central  Google Scholar 

  75. Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K. Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. Proc Natl Acad Sci. 2001;98(24):13710–5.

    CAS  PubMed  Google Scholar 

  76. Kabashima T, Kawaguchi T, Wadzinski BE, Uyeda K. Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc Natl Acad Sci. 2003;100(9):5107–12.

    CAS  PubMed  Google Scholar 

  77. Dentin R, Tomas-Cobos L, Foufelle F, Leopold J, Girard J, Postic C, et al. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. J Hepatol. 2012;56(1):199–209.

    CAS  PubMed  Google Scholar 

  78. Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest. 2010;120(12):4316–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Guinez C, Filhoulaud G, Rayah-Benhamed F, Marmier S, Dubuquoy C, Dentin R, et al. O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes. 2011;60(5):1399–413.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Tang Y, Wallace M, Sanchez-Gurmaches J, Hsiao W-Y, Li H, Lee PL, et al. Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat Commun. 2016;7:11365.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hung C-M, Calejman CM, Sanchez-Gurmaches J, Li H, Clish CB, Hettmer S, et al. Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep. 2014;8(1):256–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Jung SM, Hung C-M, Hildebrand SR, Sanchez-Gurmaches J, Martinez-Pastor B, Gengatharan JM, et al. Non-canonical mTORC2 signaling regulates brown adipocyte lipid catabolism through SIRT6-FoxO1. Mol Cell. 2019;75(4):807–822.e8.

    CAS  PubMed  Google Scholar 

  83. Davies MN, O’Callaghan BL, Towle HC. Glucose activates ChREBP by increasing its rate of nuclear entry and relieving repression of its transcriptional activity. J Biol Chem. 2008;283(35):24029–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kawaguchi T, Osatomi K, Yamashita H, Kabashima T, Uyeda K. Mechanism for fatty acid “sparing” effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by amp-activated protein kinase. J Biol Chem. 2002;277(6):3829–35.

    CAS  PubMed  Google Scholar 

  85. Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008;134(6):933–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Syed I, Lee J, Moraes-Vieira PM, Donaldson CJ, Sontheimer A, Aryal P, et al. Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis. Cell Metab. 2018;27(2):419–427.e4.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kuda O, Brezinova M, Rombaldova M, Slavikova B, Posta M, Beier P, et al. Docosahexaenoic acid-derived fatty acid esters of hydroxy fatty acids (FAHFAs) with anti-inflammatory properties. Diabetes. 2016;65(9):2580–90.

    CAS  PubMed  Google Scholar 

  88. •• Hammarstedt A, Syed I, Vijayakumar A, Eliasson B, Gogg S, Kahn BB, et al. Adipose tissue dysfunction is associated with low levels of the novel palmitic acid hydroxystearic acids. Sci Rep. 2018;8(1):15757. The finding in this study suggests that a new class of lipid generated from the DNL pathway is anti-diabetic and correlates with insulin sensitivity in human.

    PubMed  PubMed Central  Google Scholar 

  89. Yang Q, Vijayakumar A, Kahn BB. Metabolites as regulators of insulin sensitivity and metabolism. Nat Rev Mol Cell Biol. 2018;19(10):654.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Song Z, Xiaoli AM, Yang F. Regulation and metabolic significance of de novo lipogenesis in adipose tissues. Nutrients. 2018;29:10(10).

    Google Scholar 

  91. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev. 1998;14(4):263–83.

    CAS  PubMed  Google Scholar 

  92. Usenik A, Legiša M. Evolution of allosteric citrate binding sites on 6-phosphofructo-1-kinase. PLoS ONE [Internet]. 2010 Nov 23 [cited 2019 Apr 16];5(11). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990764/

  93. Kim C-W, Moon Y-A, Park SW, Cheng D, Kwon HJ, Horton JD. Induced polymerization of mammalian acetyl-CoA carboxylase by MIG12 provides a tertiary level of regulation of fatty acid synthesis. Proc Natl Acad Sci U S A. 2010;107(21):9626–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res. 2009;50(Suppl):S138–43.

    PubMed  PubMed Central  Google Scholar 

  95. Williams NC, O’Neill LAJ. A Role for the Krebs Cycle Intermediate citrate in metabolic reprogramming in innate immunity and inflammation. Front Immunol [Internet]. 2018 Feb 5 [cited 2019 Apr 16];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807345/

  96. Houmard JA. Intramuscular lipid oxidation and obesity. Am J Phys Regul Integr Comp Phys. 2008;294(4):R1111–6.

    CAS  Google Scholar 

  97. Ortenblad N, Mogensen M, Petersen I, Højlund K, Levin K, Sahlin K, et al. Reduced insulin-mediated citrate synthase activity in cultured skeletal muscle cells from patients with type 2 diabetes: evidence for an intrinsic oxidative enzyme defect. Biochim Biophys Acta. 2005;1741(1–2):206–14.

    CAS  PubMed  Google Scholar 

  98. Alhindi Y, Vaanholt LM, Al-Tarrah M, Gray SR, Speakman JR, Hambly C, et al. Low citrate synthase activity is associated with glucose intolerance and lipotoxicity [Internet]. Journal of Nutrition and Metabolism. 2019 [cited 2019 Jun 9]. Available from: https://www.hindawi.com/journals/jnme/2019/8594825/

  99. Christe M, Hirzel E, Lindinger A, Kern B, von Flüe M, Peterli R, et al. Obesity affects mitochondrial citrate synthase in human omental adipose tissue. ISRN Obes. 2013;2013:826027.

    PubMed  PubMed Central  Google Scholar 

  100. Yin X, Lanza IR, Swain JM, Sarr MG, Nair KS, Jensen MD. Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J Clin Endocrinol Metab. 2014;99(2):E209–16.

    CAS  PubMed  Google Scholar 

  101. Shi L, Tu BP. Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol. 2015;33:125–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Lee JV, Shah SA, Wellen KE. Obesity, cancer, and acetyl-CoA metabolism. Drug Discov Today Dis Mech. 2013;10(1–2):e55–61.

    PubMed  PubMed Central  Google Scholar 

  103. Pietrocola F, Galluzzi L, Bravo-San Pedro JM, Madeo F, Kroemer G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 2015;21(6):805–21.

    CAS  PubMed  Google Scholar 

  104. Takahashi H, McCaffery JM, Irizarry RA, Boeke JD. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol Cell. 2006;23(2):207–17.

    CAS  PubMed  Google Scholar 

  105. Galdieri L, Vancura A. Acetyl-CoA carboxylase regulates global histone acetylation. J Biol Chem. 2012;287(28):23865–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Galdieri L, Chang J, Mehrotra S, Vancura A. Yeast phospholipase C is required for normal acetyl-CoA homeostasis and global histone acetylation. J Biol Chem. 2013;288(39):27986–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Galdieri L, Zhang T, Rogerson D, Lleshi R, Vancura A. Protein acetylation and acetyl coenzyme a metabolism in budding yeast. Eukaryot Cell. 2014;13(12):1472–83.

    PubMed  PubMed Central  Google Scholar 

  108. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009;324(5930):1076–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Cai L, Sutter BM, Li B, Tu BP. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol Cell. 2011;42(4):426–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 2014;20(2):306–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Campbell SL, Wellen KE. Metabolic signaling to the nucleus in cancer. Mol Cell. 2018;71(3):398–408.

    CAS  PubMed  Google Scholar 

  112. Muka T, Nano J, Voortman T, Braun KVE, Ligthart S, Stranges S, et al. The role of global and regional DNA methylation and histone modifications in glycemic traits and type 2 diabetes: a systematic review. Nutr Metab Cardiovasc Dis NMCD. 2016;26(7):553–66.

    CAS  PubMed  Google Scholar 

  113. Wang X, Wang L, Sun Y, Li R, Deng J, Deng J. DNA methylation and histone deacetylation regulating insulin sensitivity due to chronic cold exposure. Cryobiology. 2017;74:36–42.

    CAS  PubMed  Google Scholar 

  114. Oliva-Olivera W, Lhamyani S, Coín-Aragüez L, Alcaide-Torres J, Cardona F, El Bekay R, et al. Involvement of acetyl-CoA-producing enzymes in the deterioration of the functional potential of adipose-derived multipotent cells from subjects with metabolic syndrome. Metabolism. 2018;88:12–21.

    CAS  PubMed  Google Scholar 

  115. Daitoku H, Sakamaki J, Fukamizu A. Regulation of FoxO transcription factors by acetylation and protein–protein interactions. Biochim Biophys Acta BBA - Mol Cell Res. 2011;1813(11):1954–60.

    CAS  Google Scholar 

  116. Perrot V, Rechler MM. The coactivator p300 directly acetylates the Forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription. Mol Endocrinol. 2005;19(9):2283–98.

    CAS  PubMed  Google Scholar 

  117. Jing E, Gesta S, Kahn CR. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 2007;6(2):105–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Gonzalez E, Flier E, Molle D, Accili D, McGraw TE. Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor. Proc Natl Acad Sci. 2011;108(25):10162–7.

    CAS  PubMed  Google Scholar 

  119. Qian H, Chen Y, Nian Z, Su L, Yu H, Chen F-J, et al. HDAC6-mediated acetylation of lipid droplet-binding protein CIDEC regulates fat-induced lipid storage. J Clin Invest. 2017;127(4):1353–69.

    PubMed  PubMed Central  Google Scholar 

  120. Sivanand S, Viney I, Wellen KE. Spatiotemporal control of acetyl-CoA metabolism in chromatin regulation. Trends Biochem Sci. 2018;43(1):61–74.

    CAS  PubMed  Google Scholar 

  121. Sharma S, Taliyan R. Histone deacetylase inhibitors: future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res. 2016;113:320–6.

    CAS  PubMed  Google Scholar 

  122. Ye J. Improving insulin sensitivity with HDAC inhibitor. Diabetes. 2013;62(3):685–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Xiao C, Giacca A, Lewis GF. Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. Diabetes. 2011;60(3):918–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Carrer A, Parris JLD, Trefely S, Henry RA, Montgomery DC, Torres A, et al. Impact of a high-fat diet on tissue acyl-CoA and histone acetylation levels. J Biol Chem. 2017;292(8):3312–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Berwick DC, Hers I, Heesom KJ, Moule SK, Tavaré JM. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J Biol Chem. 2002;277(37):33895–900.

    CAS  PubMed  Google Scholar 

  126. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000;106(2):171–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Kim Y-B, Kotani K, Ciaraldi TP, Henry RR, Kahn BB. Insulin-stimulated protein kinase C lambda/zeta activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction. Diabetes. 2003;52(8):1935–42.

    CAS  PubMed  Google Scholar 

  128. Hirschey MD, Zhao Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol Cell Proteomics MCP. 2015;14(9):2308–15.

    CAS  PubMed  Google Scholar 

  129. Choudhary C, Weinert BT, Nishida Y, Verdin E, Mann M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. 2014;15(8):536–50.

    CAS  PubMed  Google Scholar 

  130. Yu J, Sadhukhan S, Noriega LG, Moullan N, He B, Weiss RS, et al. Metabolic characterization of a Sirt5 deficient mouse model. Sci Rep. 2013;3:2806.

    PubMed  PubMed Central  Google Scholar 

  131. Nishida Y, Rardin MJ, Carrico C, He W, Sahu AK, Gut P, et al. SIRT5 regulates both cytosolic and mitochondrial protein malonylation with glycolysis as a major target. Mol Cell. 2015;59(2):321–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang G, Meyer JG, Cai W, Softic S, Li ME, Verdin E, et al. Regulation of UCP1 and mitochondrial metabolism in brown adipose tissue by reversible succinylation. Mol Cell. 2019;74(4):844–857.e7.

    CAS  PubMed  Google Scholar 

  133. Wang G, Meyer JG, Cai W, Li ME, Softic S, Kahn CR. Sirt5 plays a critical role in mitochondrial protein acylation and mitochondrial metabolic homeostasis in brown fat. Diabetes. 2018;67(Supplement 1):274-OR.

    Google Scholar 

  134. Bruning U, Morales-Rodriguez F, Kalucka J, Goveia J, Taverna F, Queiroz KCS, et al. Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. Cell Metab. 2018;28(6):866–880.e15.

    CAS  PubMed  Google Scholar 

  135. Mumby SM. Reversible palmitoylation of signaling proteins. Curr Opin Cell Biol. 1997;9(2):148–54.

    CAS  PubMed  Google Scholar 

  136. Iwanaga T, Tsutsumi R, Noritake J, Fukata Y, Fukata M. Dynamic protein palmitoylation in cellular signaling. Prog Lipid Res. 2009;48(3–4):117–27.

    CAS  PubMed  Google Scholar 

  137. Hu JS, James G, Olson EN. Protein fatty acylation: a novel mechanism for association of proteins with membranes and its role in transmembrane regulatory pathways. BioFactors Oxf Engl. 1988;1(3):219–26.

    CAS  Google Scholar 

  138. Resh MD. Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim Biophys Acta. 1999 Aug 12;1451(1):1–16.

    CAS  PubMed  Google Scholar 

  139. Smotrys JE, Linder ME. Palmitoylation of intracellular signaling proteins: regulation and function. Annu Rev Biochem. 2004;73:559–87.

    CAS  PubMed  Google Scholar 

  140. Ren W, Jhala US, Du K. Proteomic analysis of protein palmitoylation in adipocytes. Adipocyte. 2013;2(1):17–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Du K, Murakami S, Sun Y, Kilpatrick CL, Luscher B. DHHC7 palmitoylates glucose transporter 4 (Glut4) and regulates Glut4 membrane translocation. J Biol Chem. 2017;292(7):2979–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Ren W, Sun Y, Du K. Glut4 palmitoylation at Cys223 plays a critical role in Glut4 membrane trafficking. Biochem Biophys Res Commun. 2015;460(3):709–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Richard AJ, Stephens JM. Emerging roles of JAK-STAT signaling pathways in adipocytes. Trends Endocrinol Metab. 2011;22(8):325–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. de Jong JMA, Sun W, Pires ND, Frontini A, Balaz M, Jespersen NZ, et al. Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nat Metab. 2019;1(8):830–43.

    Google Scholar 

  145. • Zhao S, Torres A, Henry RA, Trefely S, Wallace M, Lee JV, et al. ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep. 2016;17(4):1037–52. This study suggests altering the acetyl-CoA-generating pathway affects adipogenic gene expression and whole body metabolism in certain conditions.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. • Fernandez S, Viola JM, Torres A, Wallace M, Trefely S, Zhao S, et al. Adipocyte ACLY facilitates dietary carbohydrate handling to maintain metabolic homeostasis in females. Cell Rep. 2019;27(9):2772–2784.e6 This study suggests altering the acetyl-CoA-generating pathway affects adipogenic gene expression and whole body metabolism in certain conditions.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell. 2015 Jan;27(1):57–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Li X, Yu W, Qian X, Xia Y, Zheng Y, Lee J-H, et al. Nucleus-translocated ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Mol Cell. 2017;66(5):684–697.e9.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Vysochan A, Sengupta A, Weljie AM, Alwine JC, Yu Y. ACSS2-mediated acetyl-CoA synthesis from acetate is necessary for human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2017;114(8):E1528–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Huang Z, Zhang M, Plec AA, Estill SJ, Cai L, Repa JJ, et al. ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. Proc Natl Acad Sci U S A. 2018;115(40):E9499–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Bulusu V, Tumanov S, Michalopoulou E, van den Broek NJ, MacKay G, Nixon C, et al. Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Rep. 2017;18(3):647–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Mao J, Yang T, Gu Z, Heird WC, Finegold MJ, Lee B, et al. aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proc Natl Acad Sci U S A. 2009;106(41):17576–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lee KY, Russell SJ, Ussar S, Boucher J, Vernochet C, Mori MA, et al. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes. 2013;62(3):864–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Mullican SE, Tomaru T, Gaddis CA, Peed LC, Sundaram A, Lazar MA. A novel adipose-specific gene deletion model demonstrates potential pitfalls of existing methods. Mol Endocrinol Baltim Md. 2013;27(1):127–34.

    CAS  Google Scholar 

  155. Lodhi IJ, Yin L, Jensen-Urstad APL, Funai K, Coleman T, Baird JH, et al. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity. Cell Metab. 2012;16(2):189–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Guilherme A, Pedersen DJ, Henriques F, Bedard AH, Henchey E, Kelly M, et al. Neuronal modulation of brown adipose activity through perturbation of white adipocyte lipogenesis. Mol Metab. 2018;16:116–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Nuotio-Antar AM, Poungvarin N, Li M, Schupp M, Mohammad M, Gerard S, et al. FABP4-Cre Mediated Expression of Constitutively Active ChREBP Protects Against Obesity, Fatty Liver, and Insulin Resistance. Endocrinology. 2015 Nov;156(11):4020–32.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Amelia K. Luciano and John A. Haley for critically reading the manuscript. We also thank other members of the Guertin Lab for helpful discussion.

Funding

D.A.G is currently supported by grants from the NIH (R01DK094004, R01CA196986, and R01DK116005) and by a Leukemia and Lymphoma Society Career Development Award.

Author information

Authors and Affiliations

  1. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA, 01605, USA

    Wen-Yu Hsiao & David A. Guertin

Authors
  1. Wen-Yu Hsiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David A. Guertin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Guertin.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsiao, WY., Guertin, D.A. De Novo Lipogenesis as a Source of Second Messengers in Adipocytes. Curr Diab Rep 19, 138 (2019). https://doi.org/10.1007/s11892-019-1264-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-019-1264-9

Keywords

Search

Navigation