Interleukin‐4 Boosts Insulin‐Induced Energy Deposits by Enhancing Glucose Uptake and Lipogenesis in Hepatocytes

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.

Interleukin-4 Improves Metabolic Abnormalities in Leptin-Deficient and High-Fat Diet Mice

“…It was speculated that body weight loss as well as restoration of metabolic phenotypes in leptin-deficient and HFD obese mice after IL-4 administration might come from other effects on peripheral organs (e.g., liver and adipose tissues, and pancreatic islets). Disruption of STAT6, downstream of IL-4, inhibits insulin action in mice, and IL-4 enhances insulin efficacy on adipocytes, hepatocytes, myoblasts, and diabetic mice [ 15 , 26 , 27 , 28 , 29 , 30 , 31 ]. Akt, a crucial member of insulin action, is also a candidate target of IL-4 signaling [ 22 , 23 ].…”

“…An association has been described between the IL-4/IL-4R genotype and type 2 diabetes as well as between IL-4 genotypes and high-density lipoprotein cholesterol [ 24 , 25 ]. IL-4 boosts insulin action in hepatocytes in vitro, and promotes myogenesis in myoblasts, resulting in greater insulin efficacy [ 26 , 27 ]. For adipocytes, IL-4 inhibits adipogenesis, promotes lipolysis, and restores insulin sensitivity against lipid-provoked insulin resistance [ 28 , 29 , 30 ].…”

Oxygenated Water Inhibits Adipogenesis and Attenuates Hepatic Steatosis in High-Fat Diet-Induced Obese Mice

“…Hepatic lipid contents were determined by H&E staining and semi-quantified by measuring the areas of lipid droplets using the MetaMorph software. The triglyceride assay was conducted as described previously [ 56 , 59 ] with modifications. In brief, liver tissues were homogenized and heated to dissolve cellular triglycerides.…”

The interplay of type 2 immunity, helminth infection and the microbiota in regulating metabolism

“…the intestine) or solely through their ability to induce a type 2 immune response. Most of the current studies focus on adipose tissue, but there is suggestion that helminths may also alter other metabolic organs, such as the liver . It would therefore be critical to determine how helminths impact these other tissues in the context of metabolic adaptation.…”

“…Most of the current studies focus on adipose tissue, but there is suggestion that helminths may also alter other metabolic organs, such as the liver. 52,93,94 It would therefore be critical to determine how helminths impact these other tissues in the context of metabolic adaptation. In conclusion, more research is needed to understand the systemic and tissuespecific metabolic adaptations associated with helminth infection to foster the possible translation of these observations into the clinic.…”