Brown and White Adipose Tissue Expression of IL6, UCP1 and SIRT1 are Associated with Alterations in Clinical, Metabolic and Anthropometric Parameters in Obese Humans

Abstract

Aim: The present study aimed to analyze the expression of IL6, UCP1 and SIRT1 in adipose tissue (WAT and BAT) in association to clinical, metabolic and anthropometric parameters in obese humans.

Methods: WAT and BAT samples from obese patients (n=27) were collected. IL6, UCP1 and SIRT1 markers were measured by qRT-PCR. The association between IL6, UCP1 and SIRT1 mRNA expression and anthropometric and clinical parameters were evaluated, using appropriate statistical tests.

Results: Our results demonstrated that high levels of IL6 are associated with altered glucose levels in the WAT (p=0.01). In contrast, high levels of IL6 in the BAT were associated with decreased % fat (p=0.01) and fat weight (p=0.02) and increased mVO₂ (p=0.02) and VO₂ (p=0.02). For UCP1, a higher expression in the BAT was observed when compared to the WAT (p=0.0001). This gene expression was associated with lower values of BMI (p=0.03), % fat (P=0.02) and fat weight (P=0.02) and increased mVO₂ (p=0.041) and VO₂ (p=0.001). In the WAT, decreased levels of SIRT1 were associated with increased fat weight (p=0.02); in the BAT, associations were found for % fat (p=0.018) and mVO₂ (p=0.03).

Conclusion: These results reveal different characteristics in the biological actions between WAT and BAT in obese humans. Increased levels of IL6, UCP1 and SIRT1 in the BAT were associated with metabolic parameters improvements.

Key words

IL6 - UCP1 - SIRT1 - metabolism - obesity

• References

• 1 Kelly T, Yang W, Chen C-S et al. Global burden of obesity in 2005 and projections to 2030. International Journal of Obesity 2008; 32: 1431-1437
• 2 Klop B, Elte JW, Cabezas MC. Dyslipidemia in obesity: mechanisms and potential targets. Nutrients 2013; 5: 1218-1240
• 3 Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunological reviews 2012; 249: 218-238
• 4 Santos SH, Andrade JM, Fernandes LR et al. Oral Angiotensin-(1-7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-kappaB in rats fed with high-fat diet. Peptides 2013; 46: 47-52
• 5 de Pinho L, Andrade JM, Paraiso A et al. Diet composition modulates expression of sirtuins and renin-angiotensin system components in adipose tissue. Obesity (Silver Spring, Md) 2013; 21: 1830-1835
• 6 Santos SH, Fernandes LR, Pereira CS et al. Increased circulating angiotensin-(1-7) protects white adipose tissue against development of a proinflammatory state stimulated by a high-fat diet. Regulatory peptides 2012; 178: 64-70
• 7 Ozyigit LP, Morita H, Akdis M. Innate lymphocyte cells in asthma phenotypes. Clinical and translational allergy 2015; 5: 23
• 8 Fonseca-Alaniz MH, Takada J, Alonso-Vale MI et al. The adipose tissue as a regulatory center of the metabolism. Arquivos brasileiros de endocrinologia e metabologia 2006; 50: 216-229
• 9 Oelkrug R, Polymeropoulos ET, Jastroch M. Brown adipose tissue: physiological function and evolutionary significance. Journal of comparative physiology B, Biochemical, systemic, and environmental physiology 2015; 185: 587-606
• 10 Papanicolaou DA, Wilder RL, Manolagas SC et al. The pathophysiologic roles of interleukin-6 in human disease. Annals of internal medicine 1998; 128: 127-237
• 11 van Gool J, van Vugt H, Helle M et al. The relation among stress, adrenalin, interleukin 6 and acute phase proteins in the rat. Clinical immunology and immunopathology 1990; 57: 200-210
• 12 Rahmouni K. Obesity-associated hypertension: recent progress in deciphering the pathogenesis. Hypertension 2014; 64: 215-221
• 13 Ricquier D. Uncoupling protein 1 of brown adipocytes, the only uncoupler: a historical perspective. Frontiers in endocrinology 2011; 2: 85
• 14 Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nature medicine 2013; 19: 1252-1263
• 15 Kozak LP, Anunciado-Koza R. UCP1: its involvement and utility in obesity. Int J Obes (Lond) 2008; 32 (Suppl. 07) S32-S38
• 16 Stanford KI, Middelbeek RJ, Townsend KL et al Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. The Journal of clinical investigation 2013; 123: 215-223
• 17 Li X. SIRT1 and energy metabolism. Acta biochimica et biophysica Sinica. 2013; 45: 51-60
• 18 Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends in endocrinology and metabolism: TEM 2014; 25: 138-145
• 19 Qiang L, Wang L, Kon N et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppargamma. Cell 2012; 150: 620-632
• 20 Boutant M, Joffraud M, Kulkarni SS et al. SIRT1 enhances glucose tolerance by potentiating brown adipose tissue function. Molecular metabolism 2015; 4: 118-131
• 21 Andrade JM, Frade AC, Guimaraes JB et al. Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. European journal of nutrition 2014; 53: 1503-1510
• 22 Stephens JW, Hurel SJ, Acharya J et al. An interaction between the interleukin-6-174G>C gene variant and urinary protein excretion influences plasma oxidative stress in subjects with type 2 diabetes. Cardiovascular diabetology 2004; 3: 2
• 23 Marsland AL, Prather AA, Petersen KL et al. Antagonistic characteristics are positively associated with inflammatory markers independently of trait negative emotionality. Brain, behavior, and immunity 2008; 22: 753-761
• 24 Morimoto A, Nishimura R, Kanda A et al. Waist circumference estimation from BMI in Japanese children. Diabetes research and clinical practice 2007; 75: 96-98
• 25 Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. The Proceedings of the Nutrition Society 2001; 60: 329-339
• 26 Lowell BB, Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature 2000; 404: 652-660
• 27 Kern PA, Ranganathan S, Li C et al. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. American journal of physiology Endocrinology and metabolism 2001; 280: E745-E751
• 28 Glund S, Deshmukh A, Long YC et al. Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes 2007; 56: 1630-1637
• 29 Bastard JP, Maachi M, Van Nhieu JT et al. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. The Journal of clinical endocrinology and metabolism 2002; 87: 2084-2089
• 30 Heliovaara MK, Teppo AM, Karonen SL et al. Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute-phase proteins associate with glucose and lipid metabolism in healthy subjects. Diabetes, obesity & metabolism 2005; 7: 729-736
• 31 Li G, Klein RL, Matheny M et al. Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats. Neuroscience 2002; 115: 879-889
• 32 Saito M, Okamatsu-Ogura Y, Matsushita M 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
• 33 Cypess AM, Lehman S, Williams G et al. Identification and importance of brown adipose tissue in adult humans. The New England journal of medicine 2009; 360: 1509-1517
• 34 Feldmann HM, Golozoubova V, Cannon B et al. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell metabolism 2009; 9: 203-209
• 35 Dalgaard LT, Pedersen O. Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes. Diabetologia 2001; 44: 946-965
• 36 Fisler JS, Warden CH. Uncoupling proteins, dietary fat and the metabolic syndrome. Nutrition & metabolism 2006; 3: 38
• 37 Lee P, Swarbrick MM, Ho KK. Brown adipose tissue in adult humans: a metabolic renaissance. Endocrine reviews 2013; 34: 413-438
• 38 Virtanen KA, Lidell ME, Orava J et al. Functional brown adipose tissue in healthy adults. The New England journal of medicine 2009; 360: 1518-1525
• 39 Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature 2006; 444: 868-874
• 40 de Kreutzenberg SV, Ceolotto G, Papparella I et al. Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes 2010; 59: 1006-1015
• 41 Metoyer CF, Pruitt K. The role of sirtuin proteins in obesity. Pathophysiology: the official journal of the International Society for Pathophysiology/ISP 2008; 15: 103-108
• 42 Lavu S, Boss O, Elliott PJ et al. Sirtuins – novel therapeutic targets to treat age-associated diseases. Nature reviews Drug discovery 2008; 7: 841-853
• 43 Schulz TJ, Tseng YH. Brown adipose tissue: development, metabolism and beyond. The Biochemical journal 2013; 453: 167-178
• 44 Picard F, Kurtev M, Chung N et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004; 429: 771-776
• 45 Lagouge M, Argmann C, Gerhart-Hines Z et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127: 1109-1122
• 46 Alberdi G, Rodriguez VM, Miranda J et al. Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. Food chemistry 2013; 141: 1530-1535
• 47 Karastergiou K, Smith SR, Greenberg AS et al. Sex differences in human adipose tissues – the biology of pear shape. Biology of sex differences 2012; 3: 13
• 48 Gomez-Serrano M, Camafeita E, Garcia-Santos E et al. Proteome-wide alterations on adipose tissue from obese patients as age-, diabetes- and gender-specific hallmarks. Scientific reports 2016; 6: 25756
• 49 Gesta S, Bluher M, Yamamoto Y et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proceedings of the National Academy of Sciences of the United States of America 2006; 103: 6676-6681
• 50 Grove KL, Fried SK, Greenberg AS et al. A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice. International journal of obesity 2010; 34: 989-1000
• 51 van Nas A, Guhathakurta D, Wang SS et al. Elucidating the role of gonadal hormones in sexually dimorphic gene coexpression networks. Endocrinology 2009; 150: 1235-1249