Interleukin-6 gene transfer reverses body weight gain and fatty liver in obese mice

Abstract

Interleukin-6 (IL-6) is a multifunctional protein and has a major influence on energy metabolism. The current study was designed to assess the therapeutic effect of overexpression of Il-6 gene through gene transfer on high fat diet-induced obese mice. Hydrodynamic delivery of 1 μg pLIVE-IL6 plasmid per mouse into C57BL/6 obese mice resulted in peak level at 10 ng/ml of circulating IL-6 1 day after gene transfer and above 1n g/ml thereafter for a period of 6 weeks. Persistent Il-6 gene expression did not affect food intake but induced a significant reduction in body weight and improved obesity-associated hepatic steatosis. Il-6 gene delivery enhanced thermogenic gene expression and elevated protein levels of phosphorylated STAT3, PGC1α and UCP1 in brown adipose tissue. Il-6 overexpression elevated mRNA levels of lipolysis genes, triggered phosphorylation of STAT3, AMPK, and ACC, and increased expression of genes involved in fatty acid oxidation in skeletal muscle. IL-6 did not affect macrophage infiltration but maintained the M2 macrophage population in adipose tissue. Collectively, these results suggest that overexpression of the Il-6 gene by hydrodynamic gene delivery induces weight loss and alleviates obesity-induced fatty liver and insulin resistance, supporting the notion that gene transfer is a valid approach in managing obesity epidemics.

Role of Exercise in the Activation of Brown Adipose Tissue

“…T cells) and non-immune cells, mainly adipose tissue and skeletal muscle [60] . IL-6 acts on a wide range of tissues through the modulation of cell growth and differentiation [60] .…”

“…T cells) and non-immune cells, mainly adipose tissue and skeletal muscle [60] . IL-6 acts on a wide range of tissues through the modulation of cell growth and differentiation [60] . For instance, in WAT, IL-6 increases lipolysis [61] , whereas in skeletal muscle, it increases glycolysis and improves insulin sensibility [62] .…”

“…On the other hand, a relation between IL-6 and BAT metabolism has been documented. In rats, the overexpression of the IL-6 gene increases the thermogenic gene expression and elevates protein levels of UCP-1 in BAT, which is mediated by phosphorylation of the signal transducer and activator of transcription 3 (pSTAT3) [60,66] . These molecular changes were accompanied by weight loss without modifying food intake and insulin resistance, or visceral adipose tissue reduction.…”

Platelet-activating factor modulates fat storage in the liver induced by a high-refined carbohydrate-containing diet

“…Il-6 could also control the lipid accumulation [42] and its reduction after 8 weeks of HC diet appears to imply in more triglycerides in the liver. Moreover, this cytokines was already described to have an anti-inflammatory response [43].…”

The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease

“…On the other hand, another important inflammatory factor in NAFLD patients is the tumor necrosis factor (TNF-). Researchers have demonstrated that the severity of NAFLD might be associated with the increased level of TNF- in NAFLD patients (29,30). TNF could bind to trimerized TNF receptor type I and activate NF-B via the inhibitor of the nuclear factor kappa-B kinase (IKK) pathway.…”