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Adipocyte and Cell Biology

Prospective analyses of white adipose tissue gene expression in relation to long-term body weight changes



Transcriptome analysis of abdominal subcutaneous white adipose tissue (sWAT) has identified important obesity-associated disturbances. However, the relation between sWAT transcriptome and long-term future changes in body weight remains elusive.


To investigate sWAT transcriptome signatures before and after long-term weight changes and assess their predictive value for body weight changes.


A total of 56 women were followed longitudinally and subdivided into weight-stable (WS, n = 25), weight-gaining (WG, n = 14) and weight-losing (WL, n = 17) groups between baseline and follow-up (13 ± 1 years). The fasting sWAT transcriptome was analyzed by gene microarray at baseline and follow-up. Key genes associated with weight changes were validated using quantitative real-time PCR.


In total 285 transcripts exhibited difference (FDR < 30%) in expression fold change over time between WL and WS women. WL women displayed decreased pro-inflammatory (NLRP3) but increased insulin-response gene (FASN and GLUT4) expression over time. In comparison, 461 transcripts displayed difference in expression fold change over time between WG and WS women (P < 0.05). Genes involved in autophagic processes (CDK5, SQSTM1 and FBXL2) were generally upregulated in WG women. At baseline, 307 and 302 transcripts were differentially expressed (FDR < 30%) in WL and WG women, respectively, when independently compared against WS women. Baseline expression of adipogenic and lipogenic genes (PPARG, IRS2 and HACD2) was lower, while pro-fibrotic (COL6A1) was higher, in WL than WS women; whereas protein processing genes were lower expressed in WG than in WS women.


In adult women, long-term body weight change associates with altered sWAT transcriptome. Expression of genes associated with inflammation, insulin response, adipogenesis and lipogenesis are linked to weight loss. However, other pathways such as autophagy not only associate but also predict future weight gain suggesting that intrinsic factors in sWAT impact tissue expansion.

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  1. 1.

    Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71–82.

  2. 2.

    Kitahara CM, Flint AJ, Berrington de Gonzalez A, Bernstein L, Brotzman M, MacInnis RJ, et al. Association between class III obesity (BMI of 40–59 kg/m2) and mortality: a pooled analysis of 20 prospective studies. PLoS Med. 2014;11:e1001673.

  3. 3.

    Swinburn BA, Nyomba BL, Saad MF, Zurlo F, Raz I, Knowler WC, et al. Insulin resistance associated with lower rates of weight gain in Pima Indians. J Clin Invest. 1991;88:168–73.

  4. 4.

    Wing RR. Insulin sensitivity as a predictor of weight regain. Obes Res. 1997;5:24–9.

  5. 5.

    McLaughlin T, Abbasi F, Carantoni M, Schaaf P, Reaven G. Differences in insulin resistance do not predict weight loss in response to hypocaloric diets in healthy obese women. J Clin Endocrinol Metab. 1999;84:578–81.

  6. 6.

    Rebelos E, Muscelli E, Natali A, Balkau B, Mingrone G, Piatti P, et al. Body weight, not insulin sensitivity or secretion, may predict spontaneous weight changes in nondiabetic and prediabetic subjects: the RISC study. Diabetes. 2011;60:1938–45.

  7. 7.

    Kong LC, Wuillemin P-H, Bastard J-P, Sokolovska N, Gougis S, Fellahi S, et al. Insulin resistance and inflammation predict kinetic body weight changes in response to dietary weight loss and maintenance in overweight and obese subjects by using a Bayesian network approach. Am J Clin Nutr. 2013;98:1385–94.

  8. 8.

    Anthanont P, Jensen MD. Does basal metabolic rate predict weight gain? Am J Clin Nutr. 2016;104:959–63.

  9. 9.

    Piaggi P, Thearle MS, Bogardus C, Krakoff J. Lower energy expenditure predicts long-term increases in weight and fat mass. J Clin Endocrinol Metab. 2013;98:E703–7.

  10. 10.

    DeLany JP, Bray GA, Harsha DW, Volaufova J. Energy expenditure and substrate oxidation predict changes in body fat in children. Am J Clin Nutr. 2006;84:862–70.

  11. 11.

    Arner P, Bernard S, Salehpour M, Possnert G, Liebl J, Steier P, et al. Dynamics of human adipose lipid turnover in health and metabolic disease. Nature. 2011;478:110–3.

  12. 12.

    Tchoukalova YD, Koutsari C, Karpyak MV, Votruba SB, Wendland E, Jensen MD. Subcutaneous adipocyte size and body fat distribution. Am J Clin Nutr. 2008;87:56–63.

  13. 13.

    Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453:783–7.

  14. 14.

    Reilly SM, Saltiel AR. Adapting to obesity with adipose tissue inflammation. Nat Rev Endocrinol. 2017;13:633–43.

  15. 15.

    Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9:367–77.

  16. 16.

    Arner P, Andersson DP, Bäckdahl J, Dahlman I, Rydén M. Weight gain and impaired glucose metabolism in women are predicted by inefficient subcutaneous fat cell lipolysis. Cell Metab. 2018;28:45–54.e3.

  17. 17.

    Clément K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA, et al. Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 2004;18:1657–69.

  18. 18.

    Dahlman I, Linder K, Arvidsson Nordström E, Andersson I, Lidén J, Verdich C, et al. Changes in adipose tissue gene expression with energy-restricted diets in obese women. Am J Clin Nutr. 2005;81:1275–85.

  19. 19.

    Dahlman I, Forsgren M, Sjögren A, Nordström EA, Kaaman M, Näslund E, et al. Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-alpha. Diabetes. 2006;55:1792–9.

  20. 20.

    Mutch DM, Temanni MR, Henegar C, Combes F, Pelloux V, Holst C, et al. Adipose gene expression prior to weight loss can differentiate and weakly predict dietary responders. PLoS ONE. 2007;2:e1344.

  21. 21.

    Márquez-Quiñones A, Mutch DM, Debard C, Wang P, Combes M, Roussel B, et al. Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake. Am J Clin Nutr. 2010;92:975–84.

  22. 22.

    Mardinoglu A, Heiker JT, Gärtner D, Björnson E, Schön MR, Flehmig G, et al. Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue. Sci Rep. 2015;5:14841.

  23. 23.

    Armenise C, Lefebvre G, Carayol J, Bonnel S, Bolton J, Di Cara A, et al. Transcriptome profiling from adipose tissue during a low-calorie diet reveals predictors of weight and glycemic outcomes in obese, nondiabetic subjects. Am J Clin Nutr. 2017;106:736–46.

  24. 24.

    Linné Y, Dahlman I, Hoffstedt J. beta1-Adrenoceptor gene polymorphism predicts long-term changes in body weight. Int J Obes. 2005;29:458–62.

  25. 25.

    Kolaczynski JW, Morales LM, Moore JH, Considine RV, Pietrzkowski Z, Noto PF, et al. A new technique for biopsy of human abdominal fat under local anaesthesia with Lidocaine. Int J Obes Relat Metab Disord. 1994;18:161–6.

  26. 26.

    Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009;37(Web Server issue):W305–11.

  27. 27.

    Capel F, Klimcáková E, Viguerie N, Roussel B, Vítková M, Kováciková M, et al. Macrophages and adipocytes in human obesity: adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization. Diabetes. 2009;58:1558–67.

  28. 28.

    Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.

  29. 29.

    Akiyama M, Okada Y, Kanai M, Takahashi A, Momozawa Y, Ikeda M, et al. Genome-wide association study identifies 112 new loci for body mass index in the Japanese population. Nat Genet. 2017;49:1458–67.

  30. 30.

    He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41:1012–21.

  31. 31.

    Alligier M, Meugnier E, Debard C, Lambert-Porcheron S, Chanseaume E, Sothier M, et al. Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans. J Clin Endocrinol Metab. 2012;97:E183–92.

  32. 32.

    Wang Y, O’Connell JR, McArdle PF, Wade JB, Dorff SE, Shah SJ, et al. From the Cover: Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc Natl Acad Sci USA. 2009;106:226–31.

  33. 33.

    Torre-Villalvazo I, Cervantes-Pérez LG, Noriega LG, Jiménez JV, Uribe N, Chávez-Canales M, et al. Inactivation of SPAK kinase reduces body weight gain in mice fed a high-fat diet by improving energy expenditure and insulin sensitivity. Am J Physiol Endocrinol Metab. 2018;314:E53–65.

  34. 34.

    Ikeda M, Kanao Y, Yamanaka M, Sakuraba H, Mizutani Y, Igarashi Y, et al. Characterization of four mammalian 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis. FEBS Lett. 2008;582:2435–40.

  35. 35.

    Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol. 2009;29:1575–91.

  36. 36.

    Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, et al. Variations in DNA elucidate molecular networks that cause disease. Nature. 2008;452:429–35.

  37. 37.

    Chang L, Adams RD, Saltiel AR. The TC10-interacting protein CIP4/2 is required for insulin-stimulated Glut4 translocation in 3T3L1 adipocytes. Proc Natl Acad Sci USA. 2002;99:12835–40.

  38. 38.

    Fan R, Toubal A, Goñi S, Drareni K, Huang Z, Alzaid F, et al. Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes. Nat Med. 2016;22:780–91.

  39. 39.

    Cuffe H, Liu M, Key C-CC, Boudyguina E, Sawyer JK, Weckerle A, et al. Targeted deletion of adipocyte Abca1 (ATP-Binding Cassette Transporter A1) impairs diet-induced obesity. Arterioscler Thromb Vasc Biol. 2018;38:733–43.

  40. 40.

    Frisdal E, Le Goff W. Adipose ABCG1: A potential therapeutic target in obesity? Adipocyte. 2015;4:315–8.

  41. 41.

    Wei H, Tarling EJ, McMillen TS, Tang C, LeBoeuf RC. ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction. J Lipid Res. 2015;56:2337–47.

  42. 42.

    Dahlman I, Rydén M, Brodin D, Grallert H, Strawbridge RJ, Arner P. Numerous genes in loci associated with body fat distribution are linked to adipose function. Diabetes. 2016;65:433–7.

  43. 43.

    Murphy J, Moullec G, Santosa S. Factors associated with adipocyte size reduction after weight loss interventions for overweight and obesity: a systematic review and meta-regression. Metab Clin Exp. 2017;67:31–40.

  44. 44.

    Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19:349–64.

  45. 45.

    Zhang Y, Sowers JR, Ren J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol. 2018;14:356–76.

  46. 46.

    Kovsan J, Blüher M, Tarnovscki T, Klöting N, Kirshtein B, Madar L, et al. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab. 2011;96:E268–77.

  47. 47.

    Jansen HJ, van Essen P, Koenen T, Joosten LAB, Netea MG, Tack CJ, et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology. 2012;153:5866–74.

  48. 48.

    Kosacka J, Kern M, Klöting N, Paeschke S, Rudich A, Haim Y, et al. Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol Cell Endocrinol. 2015;409:21–32.

  49. 49.

    Shigunov P, Sotelo-Silveira J, Kuligovski C, de Aguiar AM, Rebelatto CK, Moutinho JA, et al. PUMILIO-2 is involved in the positive regulation of cellular proliferation in human adipose-derived stem cells. Stem Cells Dev. 2012;21:217–27.

  50. 50.

    Sun K, Tordjman J, Clément K, Scherer PE. Fibrosis and adipose tissue dysfunction. Cell Metab. 2013;18:470–7.

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The work presented in this article is supported by Novo Nordisk Foundation Grant NNF18OC0033896, the Swedish Diabetes Foundation grant DIA2016-095, Swedish Research Council, Strategic Research found in Diabetes and the Regional County Council, and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant no.115372).

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Correspondence to Ingrid Dahlman.

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