Activation of Peroxisome Proliferator–Activated Receptor β/δ Inhibits Lipopolysaccharide-Induced Cytokine Production in Adipocytes by Lowering Nuclear Factor-κB Activity via Extracellular Signal–Related Kinase 1/2

Abstract

OBJECTIVE— Chronic activation of the nuclear factor-κB (NF-κB) in white adipose tissue leads to increased production of pro-inflammatory cytokines, which are involved in the development of insulin resistance. It is presently unknown whether peroxisome proliferator–activated receptor (PPAR) β/δ activation prevents inflammation in adipocytes. RESEARCH DESIGN AND METHODS AND RESULTS— First, we examined whether the PPARβ/δ agonist GW501516 prevents lipopolysaccharide (LPS)-induced cytokine production in differentiated 3T3-L1 adipocytes. Treatment with GW501516 blocked LPS-induced IL-6 expression and secretion by adipocytes and the subsequent activation of the signal transducer and activator of transcription 3 (STAT3)–Suppressor of cytokine signaling 3 (SOCS3) pathway. This effect was associated with the capacity of GW501516 to impede LPS-induced NF-κB activation. Second, in in vivo studies, white adipose tissue from Zucker diabetic fatty (ZDF) rats, compared with that of lean rats, showed reduced PPARβ/δ expression and PPAR DNA-binding activity, which was accompanied by enhanced IL-6 expression and NF-κB DNA-binding activity. Furthermore, IL-6 expression and NF-κB DNA-binding activity was higher in white adipose tissue from PPARβ/δ-null mice than in wild-type mice. Because mitogen-activated protein kinase–extracellular signal–related kinase (ERK)1/2 (MEK1/2) is involved in LPS-induced NF-κB activation in adipocytes, we explored whether PPARβ/δ prevented NF-κB activation by inhibiting this pathway. Interestingly, GW501516 prevented ERK1/2 phosphorylation by LPS. Furthermore, white adipose tissue from animal showing constitutively increased NF-κB activity, such as ZDF rats and PPARβ/δ-null mice, also showed enhanced phospho-ERK1/2 levels. CONCLUSIONS— These findings indicate that activation of PPARβ/δ inhibits enhanced cytokine production in adipocytes by preventing NF-κB activation via ERK1/2, an effect that may help prevent insulin resistance.

Peroxisome Proliferator-Activated Receptor β/δ (PPAR β/δ) as a Potential Therapeutic Target for Dyslipidemia

“…The increase in AMPK phosphorylation following GW501516 treatment might involve several mechanisms. Since inhibitory crosstalk between ERK1/2 and AMPK has been reported (Du et al, 2008), the increase in phospho-AMPK levels could be the result of the inhibition by GW501516 of the phosphorylation of ERK1/2 induced by the HFD, which is in agreement with our previous study reporting that www.intechopen.com GW501516 prevents LPS-induced ERK1/2 phosphorylation in adipocytes (Rodriguez-Calvo et al, 2008). It is important to note that a previous study found that obesity leads to increased hepatic ERK1/2 activity and that caloric restriction blunts this increase and improves insulin sensitivity (Zheng et al, 2009).…”

“…Furthermore, LPS receptor-deleted mice (CD14 mutants) are hypersensitive to insulin, and the development of insulin resistance, obesity and diabetes in this animal model is delayed in response to a high-fat diet (Cani et al, 2007). Experiments performed in our laboratory have demonstrated that the PPAR / agonist GW501516 inhibits LPS-induced cytokine expression and secretion by preventing NF-κB activation in adipocytes (Rodriguez-Calvo et al, 2008). Of note, NF-κB activation by LPS requires mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK)1/2 (MEK1/2) activation, since inhibition of this pathway reduces LPS-induced cytokine production in adipocytes (Chung et al, 2006).…”

Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes

“…4a). Because ERK1/2 and JNK are involved in NF-κB activation [21][22][23], we examined the activation of ERK1/2 and JNK in epididymal fat by western blot. We found that phosphorylation of ERK1/2 and JNK was decreased in rAd-GLP-1-treated ob/ob mice compared with untreated, rAd-βgal-treated and pair-fed ob/ob mice (Fig.…”

“…Indeed, there is evidence that these pathways are linked to insulin resistance in type 2 diabetes. Hyperactivation of the NF-κB pathway has been reported in white adipose tissue from the Zucker diabetic fatty rat [22], an animal model of type 2 diabetes. JNK1-deficient and NF-κB-deficient mice are protected from high-fat diet-induced insulin resistance [39,40], due to the inhibition of inflammatory cytokine production [41,42].…”

“…6c). ERK1/2 and phosphatidylinositol 3-kinase (PI3-K)/AKT are involved in LPS-induced NF-κB activation [22][23][24]. We therefore examined the effect of exendin-4 on LPS-induced activation of ERK1/2 and AKT in adipocytes.…”