Abstract
Type 2 diabetes mellitus (T2DM), with dysregulated hepatic gluconeogenesis as the major cause of fasting hyperglycemia, is closely associated with chronic inflammation. We previously demonstrated interleukin-4 (IL-4) improves insulin sensitivity and glucose tolerance while reducing lipid deposits. The present study examined the in vitro effects of IL-4 on insulin signaling molecules, glucose uptake, and lipid metabolism in hepatocytes, as well as in vivo effects on hepatic adiposity, for elucidating the roles of IL-4 in hepatic energy metabolism. Potential interaction between IL-4 and insulin in regulating hepatic metabolism was also investigated. Our results showed that IL-4 enhanced Akt and GSK-3α/β phosphorylations, which in turn promoted glycogen synthesis. IL-4 not only potentiated basal glucose uptake by upregulating glucose transporter 2 expression but also promoted insulin-induced glucose uptake. Additionally, IL-4 increased triglyceride contents through facilitating free fatty acid uptake and expression/activity of lipogenic enzymes. The major effects of IL-4 on the liver were to promote energy storage by boosting insulin-stimulated glucose uptake and lipid synthesis. This study provides evidence to implicate the novel roles of IL-4 in mediating hepatic glucose and lipid metabolism, interactions between immune responses and metabolic homeostasis, and the involvement of IL-4 in metabolic abnormalities.
Highlights
Type 2 diabetes mellitus (T2DM) is a common endocrine disease
Phosphorylated signal transducer and activator of transcription 6 (STAT6) (p-STAT6) and GATA-binding protein 3 (GATA3) were increased in HepG2 (Figure 1(b)) and Huh7 (Figure 1(c)) cells under IL-4 treatment
The correlation between inflammation and metabolic conditions is first addressed by Hotamisligil et al They reported that tumor necrosis factor-α (TNF-α) in adipocytes of obese animals is markedly increased, and TNF-α neutralization leads to a decrease of insulin resistance [2]
Summary
Type 2 diabetes mellitus (T2DM) is a common endocrine disease. The etiology leading to this metabolic disease is still an enigma insulin resistance has been implicated to play an important role [1]. The concept of interaction between inflammation and metabolic abnormalities is initiated by Hotamisligil et al [2]. They demonstrate that proinflammatory cytokine tumor necrosis factor-α (TNF-α) is markedly increased in adipocytes of obese animals. Excess glucose and macronutrient intake can produce oxidative stress which results in the increased circulatory proinflammatory cytokines, such as TNF-α and interleukin-6 (IL-6). These upregulated cytokines, together with the excess free fatty acids (FFAs) released from adipose tissue into the bloodstream and liver, impair insulin sensitivity and induce hepatic gluconeogenesis
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