Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity

Abstract

Obesity-related insulin resistance may be caused by adipokines such as IL-6, which is known to be elevated with the insulin resistance syndrome. A previous study reported that IL-6 knockout mice (IL-6−/−) developed maturity onset obesity, with disturbed carbohydrate and lipid metabolism, and increased leptin levels. Because IL-6 is associated with insulin resistance, one might have expected IL-6−/− mice to be more insulin sensitive. We examined body weights of growing and older IL-6−/− mice and found them to be similar to wild-type (IL-6+/+) mice. Dual-energy X-ray absorptiometry analysis at 3 and 14 mo revealed no differences in body composition. There were no differences in fasting blood insulin and glucose or in triglycerides. To further characterize these mice, we fed 11-mo-old IL-6−/− and IL-6+/+ mice a high- (HF)- or low-fat diet for 14 wk, followed by insulin (ITT) and glucose tolerance tests (GTT). An ITT showed insulin resistance in the HF animals but no difference due to genotype. In the GTT, IL-6−/− mice demonstrated elevated postinjection glucose levels by 60% compared with IL-6+/+ but only in the HF group. Although IL-6−/− mice gained weight and white adipose tissue (WAT) with the HF diet, they gained less weight than the IL-6+/+ mice. Total lipoprotein lipase activity in WAT, muscle, and postheparin plasma was unchanged in the IL-6 −/− mice compared with IL-6+/+ mice. There were no differences in plasma leptin or TNF-α due to genotype. Plasma adiponectin was ∼53% higher (71.7 ± 14.1 μg/ml) in IL-6−/− mice than in IL-6+/+ mice but only in the HF group. Thus these data show that IL-6−/− mice do not demonstrate obesity, fasting hyperglycemia, or abnormal lipid metabolism, although HF IL-6−/− mice demonstrate elevated glucose after a GTT.

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

“…The present data are in accordance with some [18,41], but not all [17,42] previous studies in IL-6-deficient mice. It should be noted that in the more recent study [42], the IL-6-deficient mice did not develop obesity.…”

“…Our observation that Il6 −/− mice become obese is consistent with some [16], but not all [17] nutrient homeostasis leading to protection from dietinduced obesity [15]. These recent data [15] are consistent with the notion that IL-6-deficient mice would display an obese phenotype, since chronic IL-6 prevents obesity due to enhanced leptin action.…”

“…Il6 −/− mice become obese at 4 months of age due to increased adipocyte size It is not clear whether Il6 −/− mice develop mature-onset obesity [16,17]. We demonstrated that Il6 −/− mice developed increased body mass relative to littermate control mice between the ages of 14 and 17 weeks (Fig.…”

“…Verification of genotype was determined by PCR (Electronic supplementary material [ESM] Fig. 1) using primers reported previously [17] and by measuring serum IL-6, which was undetectable in Il6 −/− mice, but averaged 6.0±3.0 pg/ml in Il6 +/+ mice. Male mice were maintained on a standard chow diet (14.3 MJ/kg, 76% of energy from carbohydrate, 5% from fat, 19% from protein; Specialty Feeds, Glen Forrest, WA, Australia) until 8 weeks of age.…”

“…While initial studies demonstrated that Il6 knockout (Il6 −/− ) mice display mature-onset obesity [16], subsequent studies did not verify this phenotype [17]. It is also unclear whether these mice display insulin resistance.…”