The C-174G Promoter Polymorphism of the IL-6 Gene Affects Energy Expenditure and Insulin Sensitivity

Abstract

1Interleukin-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 ; 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. Diabetes 52:558 -561, 2003 I nterleukin-6 (IL-6) is a multifunctional cytokine expressed in many tissues, including adipose tissue, skeletal muscle and hypothalamus, which are involved in the regulation of body energy balance. In IL-6 null mice, the lack of circulating IL-6 was associated with obesity and low energy expenditure (1). Moreover, IL-6 -deficient mice exhibited high leptin levels and leptin insensitivity, and did not lose weight or decrease food intake after leptin treatment. The promoter of the IL-6 gene is dynamically regulated at many sites, including the multiple response element (Ϫ173 to 145), which responds to interleukin-1, tumor necrosis factor-␣, and other factors (2). The recently described C-174G promoter polymorphism of the IL-6 gene has been found to influence transcriptional regulation (2,3) and plasma IL-6 levels in patients with systemic-onset juvenile chronic arthritis and in patients with primary Sjö gren's syndrome (3,4). Moreover, the C-164G polymorphism has been found to be associated with insulin resistance measured by a frequently sampled intravenous glucose tolerance test in one previous study (5).In humans, the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure has not been previously studied. Therefore, we investigated the effect of this polymorphism on energy expenditure and insulin sensitivity during fasting and during the euglycemic-hyperinsulinemic clamp in 124 healthy normoglycemic subjects.The frequency of the CC genotype was 30%, the CG genotype 44%, and the GG genotype 26% in our study subjects. Age, BMI and waist-to-hip ratio, systolic and diastolic blood pressure, fasting plasma glucose and insulin levels, and IL-6 concentration (n ϭ 72) did not differ among the genotypes (Table 1).Fasting energy expenditure was 8% lower in subjects with the CC genotype than in subjects with the CG or GG genotypes (13.68 Ϯ 1.98, 14.73 Ϯ 1.57...

A common polymorphism in the interleukin-6 gene promoter is associated with overweight

“…However, our findings are supported by recent evidence that energy expenditure and body temperature are lower in the À174 CC genotype in healthy male and female subjects. 14,31 Altogether, this indicates that our finding is not coincidental although further studies are needed to investigate if these results can be applied to random samples of a population. It also remains to be investigated whether the effect of the À174 G/ C genotype on overweight risk is confined to certain populations.…”

“…[27][28][29] Moreover, endogenous IL-6 seems to influence energy expenditure during exercise. 30 Interestingly, the data of recent studies indicate that the -174 C allele is associated with decreased energy expenditure 31 and slightly decreased body temperature. 14 Taken together, these results indicate that the À174 C allele of the IL-6 promoter decreases IL-6 production, which in turn results in decreased energy expenditure and accumulation of body fat.…”

“…10,32 In this study, there was no correlation between serum IL-6 levels and the À174 G/C genotype. An association between the À174 C allele and low circulating levels of IL-6 has been shown in some 11,23,33,34 but not all 31,35 studies. There are several possible reasons that the association between the À174 G/C genotype and circulating IL-6 is variable.…”

Obesity and polymorphisms in genes regulating human adipose tissue

“…177 Furthermore, the CÀ174C genotype has been associated with lower energy expenditure and lower rate of whole-body glucose uptake. 178 Another IL6 polymorphism, a CA repeat, has in two independent populations been reported to be associated with obesity. 179 Furthermore, polymorphisms in the IL6 receptor (IL6R) have been reported to be associated with obesity in Pima Indians and a Spanish population.…”

Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects

“…Furthermore, a recent study showed that mice completely lacking IL-6 became obese and that intracerobroventricular injection of IL-6 increased energy expenditure (31). An association between energy expenditure, insulin sensitivity, and the C174G polymorphism of the IL-6 promoter was also recently reported (32).…”