Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice

Abstract

High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the liver steatosis, whereas restoration of IL-6 in DIO IL-6-/- mice up-regulates hepatic lipogenic enzymes and aggravates steatosis. We further examined the effects of chronic low doses of murine IL-6 on hepatic lipid metabolism in WT mice in DIO. IL-6 was delivered twice daily in C57BL/6J DIO mice for 15 days. The status and expression of IL-6-signalling mediators and targets were investigated in relation to the steatosis and lipid content in blood and in liver. IL-6 administration in DIO mice markedly raised circulating levels of lipids, glucose and leptin, elevated fat liver content and aggravated steatosis. Under IL-6 treatment there was hepatic Stat3 activation and increased gene expression of Socs3 and Tnf-alpha whereas the gene expression of endogenous IL-6, IL-6-receptor, Stat3, Cpt1 and the enzymes involved in lipogenesis was suppressed. These data further implicate IL-6 in fatty liver disease modulation in the context of DIO, and indicate that continuous stimulation with IL-6 attenuates the IL-6-receptor response, which is associated with high serum levels of leptin, glucose and lipids, the lowering levels of lipogenic and Cpt1 hepatic enzymes and with increased Tnf-alpha hepatic expression, a scenario evoking that observed in IL-6-/- mice exposed to DIO and in obese Zucker rats.

The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism

“…In these animals, a compensatory increase in many other cytokines has been reported . In contrast, low‐dose application of murine IL‐6 in mice leads to hepatic steatosis . Subchronic IL‐6 administration in IL‐6‐deficient mice exacerbated hepatic steatosis by increasing lipogenesis .…”

“…(21) In contrast, low-dose application of murine IL-6 in mice leads to hepatic steatosis. (44) Subchronic IL-6 administration in IL-6-deficient mice exacerbated hepatic steatosis by increasing lipogenesis. (45) Importantly, neutralization of IL-6 with neutralizing antibodies in HFD-fed mice improved glucose tolerance and ameliorated liver fat content.…”

Hydroxyeicosapentaenoic acids and epoxyeicosatetraenoic acids attenuate early occurrence of nonalcoholic fatty liver disease

“…IL‐1β secreted from adipose tissue can regulate fat–liver crosstalk in obesity (Nov et al , ). IL‐6 administration can elevate fat liver content and aggravated steatosis in HFD‐induced obese mice despite the expression of lipogenic genes being suppressed (Gavito et al , ). A clinical trial found that ω‐3 PUFA supplementation reduced the expression of IL‐6, IL‐8, TNFα and toll‐like receptor 4 in adipose tissue of obese pregnant women (Haghiac et al , ).…”

Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis

“…(B-C) Average energy intake and food intake (n = 6 independent experiments in different rats). (D) Subregions of rats identified by pDXA [64]. Fat mass % and lean mass % of the rats in the different groups were measured.…”

“…(C-D) The mRNA expression levels of NPY and POMC in the hypothalamus. The levels of MC3R and MC4R protein were determined [64]. Data are the mean ± SEM.…”