Abstract
ABSTRACTBackground: Rosmarinic acid (RA) is a natural phenol carboxylic acid with many promising biological effects. It may be a suitable candidate for improving obesity-related adipose tissue dysfunction.Objective: We aimed to investigate the therapeutic use of RA as an anti-obesity agent by measuring its effects on adipogenesis, lipolysis, and messenger RNA (mRNA) expression of major adipokines in 3T3-L1 adipocytes; and its effects on lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) secretion in macrophages and inflammatory mediators in 3T3-L1 adipocytes incubated with macrophage-conditioned medium (MCM).Methods: 3T3-L1 preadipocytes were used to explore how RA affects adipogenesis, as well as the involvement of phosphorylated extracellular signal-regulated kinase-1/2 (p-ERK1/2) and mothers against decapentaplegic homolog 3 (p-Smad3). 3T3-L1 preadipocytes were also differentiated into mature adipocytes to explore how RA affects basal and isoproterenol- and forskolin-stimulated lipolysis; and how RA affects key adipokines’ mRNA expression. RAW 264.7 macrophages were stimulated with LPS in the absence or presence of RA to explore RA’s effects on TNF-α secretion. MCM was collected and 3T3-L1 adipocytes were incubated with MCM to explore RA’s effects on interleukin-6 (IL-6), IL-1β, monocyte chemoattractant protein-1 (MCP-1), and RANTES mRNA expression.Results: During the preadipocyte differentiation process, RA suppressed peroxisome proliferator-activated receptor-γ and CCAAT/enhancer binding protein-α, and activated p-ERK1/2 and p-Smad3; inhibition of adipogenesis by RA was partially restored following treatment with p-ERK1/2 and p-Smad3 inhibitors. In mature adipocytes, RA inhibited basal lipolysis; phosphodiesterase-3 inhibitor reversed this. RA also inhibited isoproterenol- and forskolin-stimulated glycerol and free fatty acid release, and the phosphorylation of hormone-sensitive lipase and perilipin. RA had no effects on leptin, adiponectin, resistin, or visfatin mRNA expression. RA suppressed TNF-α mRNA expression and secretion in LPS-stimulated RAW 264.7 macrophages; and reduced LPS-MCM-induced IL-6, IL-1β, MCP-1, and RANTES mRNA expression in 3T3-L1 adipocytes.Conclusions: RA exerts inhibitory effects on adipogenesis, lipolysis, and inflammation. RA could be a promising natural product for improving adipose mobilization in obesity.
Highlights
Adipose tissue is a critical organ involved in regulating systemic energy balance and glucose homeostasis [1]
With the above points in mind, the aims of the present study are: (i) to explore the effects of Rosmarinic acid (RA) on two critical processes related to the key functions of adipose tissue, i.e. adipogenesis and lipolysis, and on the messenger RNA expression of major adipokines, i.e. leptin, adiponectin, resistin, and visfatin, using a 3T3-L1 adipocytes model; and (ii) to explore how RA affects lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) secretion in macrophages, as well as mRNA expression of inflammatory cytokines and chemokines in 3T3-L1 adipocytes incubated with macrophage-conditioned medium (MCM)
The primary findings of the current study are that (i) extracellular signal-regulated kinase-1/2 (ERK1/2) and Smad3-mediated signaling pathways may be involved in the inhibition of adipogenesis by RA; (ii) RA inhibited basal lipolysis via activation of PDE3, and RA suppressed ISO- and forskolin-stimulated lipolysis, accompanied by RA inhibition of the phosphorylation of hormone-sensitive lipase (HSL) and perilipin A; and (iii) RA suppressed LPS-stimulated TNF-α secretion in macrophages, as well as mRNA expression of inflammatory mediators including IL-6, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and RANTES in 3T3-L1 adipocytes exposed to MCM
Summary
Adipose tissue is a critical organ involved in regulating systemic energy balance and glucose homeostasis [1]. Rosmarinic acid (RA) is a natural phenol carboxylic acid with many promising biological effects It may be a suitable candidate for improving obesity-related adipose tissue dysfunction. Objective: We aimed to investigate the therapeutic use of RA as an anti-obesity agent by measuring its effects on adipogenesis, lipolysis, and messenger RNA (mRNA) expression of major adipokines in 3T3-L1 adipocytes; and its effects on lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) secretion in macrophages and inflammatory mediators in 3T3L1 adipocytes incubated with macrophage-conditioned medium (MCM). 3T3-L1 preadipocytes were differentiated into mature adipocytes to explore how RA affects basal and isoproterenol- and forskolin-stimulated lipolysis; and how RA affects key adipokines’ mRNA expression. MCM was collected and 3T3-L1 adipocytes were incubated with MCM to explore RA’s effects on interleukin-6 (IL-6), IL-1β, monocyte chemoattractant protein-1 (MCP-1), and RANTES mRNA expression. RA could be a promising natural product for improving adipose mobilization in obesity
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