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

Abstract

Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 −/− ) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 −/− and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 −/− mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 −/− and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 −/− mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 −/− relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans

“…Numerous studies have demonstrated a positive association between serum LBP concentration and obesityassociated metabolic disturbances, including insulin resistance, in humans [29][30][31][32][33]. However, a discrepancy between circulating concentrations of innate immune system proteins in obese patients and the metabolic phenotype of the corresponding knockout mice has also been reported for lipocalin-2 [34,35] and IL-6 [4,36]. Other mouse models with loss of function of proinflammatory factors leading to impaired inflammation, such as the dominant-negative Tnfa transgenic mouse [37] and Fsp27-deficient mice [38], show reduced inflammation in adipose tissue associated with weight loss, but also insulin resistance.…”

Lack of Oncostatin M Receptor β Leads to Adipose Tissue Inflammation and Insulin Resistance by Switching Macrophage Phenotype

“…However, chronic treatment of mice with IL-6 does not affect the insulin signaling in the skeletal muscle (42). In addition, IL-6-deficient mice showed systemic insulin resistance (34,44). Therefore, the role of IL-6 in the development of systemic insulin resistance is controversial.…”

Brain IL-6—Where Amylin and GLP-1 Antiobesity Signaling Congregate

“…However, there are indications that IL-6 in the CNS also plays a role to suppress body fat in healthy individuals. Mature-onset obesity has been observed in IL-6 knockout mice fed a low-fat diet, and this effect appears to be exerted at the level of the CNS (13,14). Transgenic mice overexpressing IL-6 in the brain and rodents receiving brain delivery of IL-6 become obesity resistant (15)(16)(17).…”

“…Recent evidence indicates that increased production of IL-6 in the hypothalamus can mediate decreases in food intake and body weight as well as increased leptin sensitivity in response to amylin and GLP-1 (3,8,19). Earlier data indicate that brain IL-6 by itself can decrease body fat mass (13,14).…”