IL-6 trans-signaling blockade induces mature-onset obesity and insulin resistance in mice via suppression of PPARα

Background and Aims: IL-6 has been shown to play crucial roles in metabolic homeostasis and weight gain in experimental models, but the molecular mechanism(s) and the physiological and clinical relevance remain unclear. Clinical evidence has revealed statistically significant correlations of body mass index in diabetic patients with increased levels of soluble gp130 (sgp130) – a specific inhibitor of IL-6 trans-signaling, but the physiological relevance and related mechanism(s) are unknown. Here, using a sgp130 transgenic mouse model, we have examined the hypothesis that IL6 trans-signaling plays a protective role against mature-onset obesity and fatty liver in aging mice.

Methods: Sgp130Fc transgenic mice and wild type littermate control mice were maintained under normal dietary conditions and analyzed at 2, 5 and 14 months-of-age, for weight gain, glucose tolerance, liver steatosis, and metabolism related activity using metabolic cages.

Results: Peripheral blockade of trans-signaling induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding [associated with leptin resistance] and increases energy expenditure to maintain metabolic balance. However, in aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance, but without hepatic inflammation. Mechanistically, trans-signaling blockade reduced hepatic Stat3 phosphorylation and suppressed PPARa, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity.

Conclusions: Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis, and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.