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.
Highlights
The pleiotropic cytokine interleukin 4 (IL-4) harbors diverse effects on a variety of target cells[9,10,11]
IL-4 is suggested to indirectly mediate energy homeostasis through regulating adipose tissue-derived adipokines[16]. These results reveal the novel functions of IL-4 in glucose/lipid metabolism by improving insulin sensitivity, glucose tolerance, 1Department of Nursing, College of Nursing, Hungkuang University, Taichung, Taiwan. 2Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan. 3Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan. 4Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
Hsl mRNA in cells with IL-4 treatment was increased about 2 folds after 24 hr
Summary
The pleiotropic cytokine interleukin 4 (IL-4) harbors diverse effects on a variety of target cells[9,10,11]. We started to study the roles and regulation of IL-4 in energy homeostasis, aiming to explore its potential activities in modulating metabolism. IL-4 is suggested to indirectly mediate energy homeostasis through regulating adipose tissue-derived adipokines[16] These results reveal the novel functions of IL-4 in glucose/lipid metabolism by improving insulin sensitivity, glucose tolerance, www.nature.com/scientificreports/. The above findings disclose the metabolism-regulating functions of IL-4, and elucidate the interactions among cytokines/immune responses, insulin sensitivity and lipid metabolism. These observations support our speculation that IL-4 harbors the activity to attenuate the development of insulin resistance and the subsequent progression to metabolic abnormalities. The present study aimed at examining the molecular mechanism of IL-4 regulating HSL activity for further addressing the involvement of IL-4 in lipid metabolism
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