Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Clinical Studies and Practice

Impairment of body mass reduction-associated activation of brown/beige adipose tissue in patients with type 2 diabetes mellitus

Abstract

Backgrounds/Objectives:

The activity of brown/beige adipose tissue (B/BAT) is inversely proportional to body adiposity. Studies have shown that obese subjects submitted to distinct approaches aimed at reducing body mass present an increase of B/BAT activation. However, it is unknown if this beneficial effect of body mass reduction applies to patients with type 2 diabetes mellitus. In this study, we evaluated the impact of massive body mass reduction obtained as a consequence of bariatric surgery in the cold-induced activation of B/BAT in obese non-diabetic (OND) and obese diabetic (OD) subjects.

Subjects/Methods:

This is an observational study. Fourteen OND, 14 OD and 11 subjects were included in the study. All obese subjects were submitted to Roux-in-Y gastric bypass and measurements were performed before and 8 months after surgery. B/BAT was evaluated by (18F)-FDG-PET/CT scan and determination of signature transcript expression in specimens obtained in biopsies.

Results:

Before surgery, mean B/BAT activity and the expression of signature transcripts were similar between OND and OD groups. Eight months after surgery, body mass reduction was similar between the obese groups. Nevertheless, the activity of B/BAT was increased in OND and unchanged in OD subjects. This effect was correlated with a more pronounced improvement of insulin resistance, as evaluated by the hyperinsulinemic, euglycemic clamp, in OND subjects as compared with OD subjects.

Conclusions:

Body mass reduction has a more efficient effect to induce the activation of B/BAT in non-diabetic than in diabetic subjects. This effect is accompanied by more pronounced insulin sensitivity and serine 473 phosphorylation of Akt in B/BAT of non-diabetic than in diabetic subjects.

This is a preview of subscription content, access via your institution

Access options

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Betz MJ, Enerback S . Human brown adipose tissue: what we have learned so far. Diabetes 2015; 64: 2352–2360.

    Article  CAS  Google Scholar 

  2. Bartelt A, Heeren J . Adipose tissue browning and metabolic health. Nat Rev Endocrinol 2014; 10: 24–36.

    Article  CAS  Google Scholar 

  3. Vallerand AL, Lupien J, Bukowiecki LJ . Cold exposure reverses the diabetogenic effects of high-fat feeding. Diabetes 1986; 35: 329–334.

    Article  CAS  Google Scholar 

  4. Arch JR, Ainsworth AT, Cawthorne MA, Piercy V, Sennitt MV, Thody VE et al. Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature 1984; 309: 163–165.

    Article  CAS  Google Scholar 

  5. Gasparetti AL, de Souza CT, Pereira-da-Silva M, Oliveira RL, Saad MJ, Carneiro EM et al. Cold exposure induces tissue-specific modulation of the insulin-signalling pathway in Rattus norvegicus. J Physiol 2003; 552: 149–162.

    Article  CAS  Google Scholar 

  6. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463–468.

    Article  Google Scholar 

  7. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360: 1509–1517.

    Article  CAS  Google Scholar 

  8. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360: 1500–1508.

    Article  CAS  Google Scholar 

  9. Lee P, Smith S, Linderman J, Courville AB, Brychta RJ, Dieckmann W et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 2014; 63: 3686–3698.

    Article  CAS  Google Scholar 

  10. Chondronikola M, Volpi E, Borsheim E, Porter C, Annamalai P, Enerback S et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 2014; 63: 4089–4099.

    Article  CAS  Google Scholar 

  11. Kozak LP, Koza RA, Anunciado-Koza R, Mendoza T, Newman S . Inherent plasticity of brown adipogenesis in white fat of mice allows for recovery from effects of post-natal malnutrition. PLoS One 2012; 7: e30392.

    Article  CAS  Google Scholar 

  12. Enerback S . Adipose tissue metabolism in 2012: adipose tissue plasticity and new therapeutic targets. Nat Rev Endocrinol 2013; 9: 69–70.

    Article  Google Scholar 

  13. Gerhart-Hines Z, Feng D, Emmett MJ, Everett LJ, Loro E, Briggs ER et al. The nuclear receptor Rev-erbalpha controls circadian thermogenic plasticity. Nature 2013; 503: 410–413.

    Article  CAS  Google Scholar 

  14. Abreu-Vieira G, Hagberg CE, Spalding KL, Cannon B, Nedergaard J . Adrenergically stimulated blood flow in brown adipose tissue is not dependent on thermogenesis. Am J Physiol Endocrinol Metab 2015; 308: E822–E829.

    Article  Google Scholar 

  15. Hansen IR, Jansson KM, Cannon B, Nedergaard J . Contrasting effects of cold acclimation versus obesogenic diets on chemerin gene expression in brown and brite adipose tissues. Biochim Biophys Acta 2014; 1841: 1691–1699.

    Article  CAS  Google Scholar 

  16. Nedergaard J, Cannon B . The browning of white adipose tissue: some burning issues. Cell Metab 2014; 20: 396–407.

    Article  CAS  Google Scholar 

  17. Vijgen GH, Bouvy ND, Teule GJ, Brans B, Hoeks J, Schrauwen P et al. Increase in brown adipose tissue activity after weight loss in morbidly obese subjects. J Clin Endocrinol Metab 2012; 97: E1229–E1233.

    Article  CAS  Google Scholar 

  18. Rachid B, van de Sande-Lee S, Rodovalho S, Folli F, Beltramini GC, Morari J et al. Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity. Int J Obes (Lond) 2015; 39: 1515–1522.

    Article  CAS  Google Scholar 

  19. Hardman MJ, Hull D . The action of insulin on brown adipose tissue in vivo. J Physiol 1972; 221: 85–92.

    Article  CAS  Google Scholar 

  20. Roy D, Perreault M, Marette A . Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. Am J Physiol 1998; 274: E692–E699.

    CAS  PubMed  Google Scholar 

  21. Kraegen EW, James DE, Storlien LH, Burleigh KM, Chisholm DJ . In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration. Diabetologia 1986; 29: 192–198.

    Article  CAS  Google Scholar 

  22. Hanssen MJ, van der Lans AA, Brans B, Hoeks J, Jardon KM, Schaart G et al. Short-termcold acclimation recruits brown adipose tissue in obese humans. Diabetes 2016; 65: 1179–1189.

    Article  CAS  Google Scholar 

  23. Hanssen MJ, Hoeks J, Brans B, van der Lans AA, Schaart G, van den Driessche JJ et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med 2015; 21: 863–865.

    Article  CAS  Google Scholar 

  24. de Carvalho CP, Marin DM, de Souza AL, Pareja JC, Chaim EA, de Barros Mazon S et al. GLP-1 and adiponectin: effect of weight loss after dietary restriction and gastric bypass in morbidly obese patients with normal and abnormal glucose metabolism. Obes Surg 2009; 19: 313–320.

    Article  Google Scholar 

  25. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  Google Scholar 

  26. Geloneze SR, Geloneze B, Morari J, Matos-Souza JR, Lima MM, Chaim EA et al. PGC1alpha gene Gly482Ser polymorphism predicts improved metabolic, inflammatory and vascular outcomes following bariatric surgery. Int J Obes (Lond) 2012; 36: 363–368.

    Article  CAS  Google Scholar 

  27. Nunez CE, Rodrigues VS, Gomes FS, Moura RF, Victorio SC, Bombassaro B et al. Defective regulation of adipose tissue autophagy in obesity. Int J Obes (Lond) 2013; 37: 1473–1480.

    Article  CAS  Google Scholar 

  28. Atkinson G, Batterham AM . True and false interindividual differences in the physiological response to an intervention. Exp Physiol 2015; 100: 577–588.

    Article  Google Scholar 

  29. Mori MA, Thomou T, Boucher J, Lee KY, Lallukka S, Kim JK et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest 2014; 124: 3339–3351.

    Article  CAS  Google Scholar 

  30. Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 2013; 19: 635–639.

    Article  CAS  Google Scholar 

  31. Lucas CP, Patton S, Stepke T, Kinhal V, Darga LL, Carroll-Michals L et al. Achieving therapeutic goals in insulin-using diabetic patients with non-insulin-dependent diabetes mellitus. A weight reduction-exercise-oral agent approach. Am J Med 1987; 83: 3–9.

    Article  CAS  Google Scholar 

  32. Viswanathan M, Snehalatha C, Viswanathan V, Vidyavathi P, Indu J, Ramachandran A . Reduction in body weight helps to delay the onset of diabetes even in non-obese with strong family history of the disease. Diabetes Res Clin Pract 1997; 35: 107–112.

    Article  CAS  Google Scholar 

  33. Geloneze B, Tambascia MA, Pareja JC, Repetto EM, Magna LA . The insulin tolerance test in morbidly obese patients undergoing bariatric surgery. Obes Res 2001; 9: 763–769.

    Article  CAS  Google Scholar 

  34. Umeda LM, Silva EA, Carneiro G, Arasaki CH, Geloneze B, Zanella MT . Early improvement in glycemic control after bariatric surgery and its relationships with insulin, GLP-1, and glucagon secretion in type 2 diabetic patients. Obes Surg 2011; 21: 896–901.

    Article  Google Scholar 

  35. Ross R, Bradshaw AJ . The future of obesity reduction: beyond weight loss. Nat Rev Endocrinol 2009; 5: 319–325.

    Article  Google Scholar 

  36. Modan M, Karasik A, Halkin H, Fuchs Z, Lusky A, Shitrit A et al. Effect of past and concurrent body mass index on prevalence of glucose intolerance and type 2 (non-insulin-dependent) diabetes and on insulin response. The Israel study of glucose intolerance, obesity and hypertension. Diabetologia 1986; 29: 82–89.

    Article  CAS  Google Scholar 

  37. Reisin E . Weight reduction in the management of hypertension: epidemiologic and mechanistic evidence. Can J Physiol Pharmacol 1986; 64: 818–824.

    Article  CAS  Google Scholar 

  38. Saneei P, Hashemipour M, Kelishadi R, Rajaei S, Esmaillzadeh A . Effects of recommendations to follow the Dietary Approaches to Stop Hypertension (DASH) diet v. usual dietary advice on childhood metabolic syndrome: a randomised cross-over clinical trial. Br J Nutr 2013; 110: 2250–2259.

    Article  CAS  Google Scholar 

  39. Cole TG, Bowen PE, Schmeisser D, Prewitt TE, Aye P, Langenberg P et al. Differential reduction of plasma cholesterol by the American Heart Association Phase 3 Diet in moderately hypercholesterolemic, premenopausal women with different body mass indexes. Am J Clin Nutr 1992; 55: 385–394.

    Article  CAS  Google Scholar 

  40. Lau DC, Teoh H . Benefits of modest weight loss on the management of type 2 diabetes mellitus. Can J Diabetes 2013; 37: 128–134.

    Article  Google Scholar 

  41. Peng L, Wang J, Li F . Weight reduction for non-alcoholic fatty liver disease. Cochrane Database Syst Rev 2011; CD003619.

  42. Salinari S, Bertuzzi A, Asnaghi S, Guidone C, Manco M, Mingrone G . First-phase insulin secretion restoration and differential response to glucose load depending on the route of administration in type 2 diabetic subjects after bariatric surgery. Diabetes Care 2009; 32: 375–380.

    Article  CAS  Google Scholar 

  43. Henry RR, Gumbiner B . Benefits and limitations of very-low-calorie diet therapy in obese NIDDM. Diabetes Care 1991; 14: 802–823.

    Article  CAS  Google Scholar 

  44. Tremaroli V, Karlsson F, Werling M, Stahlman M, Kovatcheva-Datchary P, Olbers T et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab 2015; 22: 228–238.

    Article  CAS  Google Scholar 

  45. Marfella R, Esposito K, Siniscalchi M, Cacciapuoti F, Giugliano F, Labriola D et al. Effect of weight loss on cardiac synchronization and proinflammatory cytokines in premenopausal obese women. Diabetes Care 2004; 27: 47–52.

    Article  CAS  Google Scholar 

  46. Chondronikola M, Volpi E, Borsheim E, Porter C, Saraf MK, Annamalai P et al. Brown adipose tissue activation is linked to distinct systemic effects on lipid metabolism in humans. Cell Metab 2016; 23: 1200–1206.

    Article  CAS  Google Scholar 

  47. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013; 123: 3404–3408.

    Article  CAS  Google Scholar 

  48. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009; 58: 1526–1531.

    Article  CAS  Google Scholar 

  49. Robinson L, Ojha S, Symonds ME, Budge H . Body mass index as a determinant of brown adipose tissue function in healthy children. J Pediatr 2014; 164: 318–322 e1.

    Article  Google Scholar 

  50. Champigny O, Ricquier D, Blondel O, Mayers RM, Briscoe MG, Holloway BR . Beta 3-adrenergic receptor stimulation restores message and expression of brown-fat mitochondrial uncoupling protein in adult dogs. Proc Natl Acad Sci USA 1991; 88: 10774–10777.

    Article  CAS  Google Scholar 

  51. Sidossis LS, Porter C, Saraf MK, Borsheim E, Radhakrishnan RS, Chao T et al. Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 2015; 22: 219–227.

    Article  CAS  Google Scholar 

  52. Doniach D . Possible stimulation of thermogenesis in brown adipose tissue by thyroid-stimulating hormone. Lancet 1975; 2: 160–161.

    Article  CAS  Google Scholar 

  53. Lahesmaa M, Orava J, Schalin-Jantti C, Soinio M, Hannukainen JC, Noponen T et al. Hyperthyroidism increases brown fat metabolism in humans. J Clin Endocrinol Metab 2014; 99: E28–E35.

    Article  Google Scholar 

  54. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014; 19: 302–309.

    Article  CAS  Google Scholar 

  55. Whittle AJ, Jiang M, Peirce V, Relat J, Virtue S, Ebinuma H et al. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nat Commun 2015; 6: 8951.

    Article  CAS  Google Scholar 

  56. Scheen AJ, Van Gaal LF . Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Endocrinol 2014; 2: 911–922.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E Roman and G Ferraz from the University of Campinas for technical assistance. Support for the study was provided by the Fundação de Amparo a Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico and grants from the Trust in Science Initiative from Glaxo-Smithkline, UK. The Laboratories of Cell Signaling and Experimental Endocrinology belong to the Obesity and Comorbidities Research Center and the National Institute of Science and Technology—Diabetes and Obesity.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L A Velloso.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodovalho, S., Rachid, B., De-Lima-Junior, J. et al. Impairment of body mass reduction-associated activation of brown/beige adipose tissue in patients with type 2 diabetes mellitus. Int J Obes 41, 1662–1668 (2017). https://doi.org/10.1038/ijo.2017.152

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2017.152

This article is cited by

Search

Quick links