The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity.

Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n = 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13.68 +/- 1.98, CG 14.73 +/- 1.57, GG 14.81 +/- 2.01 kcal x kg(-1) x min(-1); P = 0.012) and during the euglycemic-hyperinsulinemic clamp (CC 15.24 +/- 2.05, CG 16.62 +/- 2.06, GG 16.66 +/- 2.50 kcal x kg(-1) x min(-1); P = 0.007). Moreover, subjects homozygous for the C allele had lower rates of whole-body glucose uptake than carriers of the G allele (CC 50.95 +/- 13.91, CG 59.40 +/- 14.17, GG 59.21 +/- 15.93 micro mol x kg(-1) x min(-1); P = 0.016). The rates of both oxidative (P = 0.013) and nonoxidative (P = 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies.

[1]  C. Ohlsson,et al.  Interleukin-6-deficient mice develop mature-onset obesity , 2002, Nature Medicine.

[2]  I. Vauhkonen,et al.  Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands. , 1998, The Journal of clinical investigation.

[3]  I. Vauhkonen,et al.  Impaired free fatty acid suppression during hyperinsulinemia is a characteristic finding in familial combined hyperlipidemia, but insulin resistance is observed only in hypertriglyceridemic patients. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[4]  F. Green,et al.  Cooperative Influence of Genetic Polymorphisms on Interleukin 6 Transcriptional Regulation* , 2000, The Journal of Biological Chemistry.

[5]  D. Papanicolaou,et al.  Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia. , 2000, Arthritis and rheumatism.

[6]  J S Yudkin,et al.  The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. , 1998, The Journal of clinical investigation.

[7]  N. Rothwell,et al.  Leptin affects food intake via CRF-receptor-mediated pathways , 1998, Nature Neuroscience.

[8]  W. Ricart,et al.  Interleukin-6 gene polymorphism and insulin sensitivity. , 2000, Diabetes.

[9]  Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. , 2001, The Journal of clinical endocrinology and metabolism.

[10]  S. Rose-John,et al.  Sympathetic neurons can produce and respond to interleukin 6. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  C. Plata-salamán.  Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. , 2000, Nutrition.

[12]  D. Papanicolaou,et al.  Exercise stimulates interleukin-6 secretion: inhibition by glucocorticoids and correlation with catecholamines. , 1996, The American journal of physiology.

[13]  M. Laakso,et al.  Insulin Resistance, Body Fat Distribution, and Sex Hormones in Men , 1994, Diabetes.

[14]  A. Pasternack,et al.  Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL6 gene in primary Sjögren's syndrome and correlate with the clinical manifestations of the disease. , 2001, Rheumatology.

[15]  J. Bülow,et al.  Thermogenic response to epinephrine in the forearm and abdominal subcutaneous adipose tissue. , 1992, The American journal of physiology.

[16]  B V Howard,et al.  Reduced rate of energy expenditure as a risk factor for body-weight gain. , 1988, The New England journal of medicine.

[17]  M. Laakso,et al.  Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. , 1994, The Journal of clinical investigation.

[18]  J S Yudkin,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-�, in Vivo* , 2022 .

[19]  T. van der Poll,et al.  Endocrinologic and metabolic effects of interleukin-6 in humans. , 1995, The American journal of physiology.

[20]  D. Papanicolaou,et al.  Dose effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. , 1997, Neuroendocrinology.

[21]  S. Heymsfield,et al.  Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. , 2002, The Journal of clinical endocrinology and metabolism.

[22]  S. Woods,et al.  Model for the regulation of energy balance and adiposity by the central nervous system. , 1995, The American journal of clinical nutrition.