Mechanism of Interleukin-4 Reducing Lipid Deposit by Regulating Hormone-Sensitive Lipase

Abstract

Accumulating evidence indicates that inflammation participates in the pathophysiological progress from insulin resistance, obesity, metabolic abnormalities, and type 2 diabetes mellitus. Our previous study reveals that interleukin-4 (IL-4) inhibits adipogenesis and promotes lipolysis to decrease lipid deposits by enhancing the activity of hormone sensitive lipase (HSL). The present study further dissects and characterizes the molecular mechanism of IL-4 in regulating HSL expression and lipolytic activity in the terminal differentiated 3T3-L1 mature adipocytes. Our results showed that IL-4 increased cAMP which then enhanced PKA activity and subsequent phosphorylation of HSL and perilipin. The phosphorylated HSL (p-HSL) translocated from cytoplasm to the surface of lipid droplets and exhibited lipolytic function. After being phosphorylated, p-perilipin also facilitated lipolysis through interacting with p-HSL. The in vitro findings were further verified by in vivo study in which IL-4 exhibited pro-lipolytic activity and enhanced HSL activity. In summary, the net outcome of IL-4 treatment is to reduce lipid storage by promoting lipolysis through enhancing HSL activity via cAMP/PKA pathway, the major route leading to lipolysis.

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

“…By integrating our data and findings from mice fed with a HFD for differential periods [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], it was demonstrated that adipose tissue and the liver are more susceptible to a HFD at the early phase in the sequential events of DIO leading to metabolic dysregulation. First of all, excess glucose and nutrients are stored as triglycerides in the liver and adipose tissue, causing organ-specific insulin resistance, hepatic steatosis and adipose enlargement at this stage.…”

“…Cell lysates were prepared as described previously [ 55 , 56 , 57 , 58 ]. In brief, protein extracts from epididymal fat tissues were obtained after the tissues were homogenized using T-PER tissue protein extraction reagent (Pierce, Rockford, IL, USA) supplied with phosphatase and protease inhibitors (Roche, Indianapolis, IN, USA).…”

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 ].…”

“…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 ]. Disruption of STAT6 impairs insulin actions in mice, and IL-4 administered intraperitoneally improves glucose and lipid metabolism in streptozotocin and high-fat diet (HFD) mice [ 15 , 31 ].…”

Interleukin-4 Promotes Myogenesis and Boosts Myocyte Insulin Efficacy

“…Combining the conclusions from our study [10–15], IL-4 promotes glucose tolerance and insulin sensitivity through boosting insulin signaling by altering Akt and GSK-3 β activities and counteracting the effects of pro-inflammatory cytokines. In addition, IL-4 is involved in lipid metabolism by inhibiting adipogenesis and promoting lipolysis [47]. IL-4 is also characterized to promote insulin signaling in hepatocytes [18], and insulin signaling is impaired in mice with deficiency of IL-4 downstream STAT6 [48].…”