PPARβ/δ ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation

Abstract

quinone oxidoreductase 1 (Nqo1) were increased in water-fed PPARβ/δ-null mice, suggesting that PPARβ/δ deficiency increases Nrf2 activity; and this increase was exacerbated in fructose-fed PPARβ/δ-deficient mice. These findings indicate that the combination of high fructose intake and PPARβ/δ deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue.

Transcriptional control of physiological and pathological processes by the nuclear receptor PPARβ/δ

“…In a different study, the adipose tissue of PPARβ/δ ex4 knockout mice displayed increased STAT3 phosphorylation and elevated suppressor of cytokine signaling (SOCS)3 protein levels than their wild-type littermates [165]. These findings suggest that PPARβ/δ activation might prevent the activation of STAT3 and the subsequent increase in shown to be exacerbated in fructose-fed PPARβ/δ ex4 knockout mice via nuclear factor E2-related factor 2 (Nrf2), a transcription factor that has been reported to impair insulin signaling [163].…”

“…As adipose tissue expands during obesity, there is an increase in chronic, systemic lowgrade inflammation, mainly due to greater macrophage infiltration and polarization towards the Moreover, specifically overexpressing PPARβ/δ in white adipose tissue renders mice resistant to both HFD-induced and genetically predisposed obesity, in association with a reduction in triglyceride accumulation in adipocytes and circulating NEFA and TG levels [163].…”

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

“…PPARβ/δ, the clinically enigmatic third PPAR Selective synthetic PPARβ/δ agonists are not yet clinically available; however, beneficial effects of PPARβ/δ activation on various MetS components have been reported and include both differences and similarities to PPARα and PPARγ, such as reduced inflammation (144)(145)(146).…”

Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions

“…Intriguingly, PPAR- δ agonist GW501516 decreases uptake of VLDL and expression of VLDL receptor at mRNA and protein levels through the regulation of miRNA-100 in Human Umbilical Vein Endothelial Cells [29]. Confirming the human findings, clear data from mouse model showed that PPAR β / δ -deficient mice fed with fructose exacerbated glucose intolerance and this led to macrophage infiltration, inflammation, enhanced mRNA and protein levels of CD36, and activation of the c-Jun N-terminal kinase pathway in white adipose tissue; fascinatingly, these effects were partially prevented by the PPAR β / δ activator GW501516 [30]. In addition, topical application of polymer-encapsulated GW501516 was found to have therapeutic wound healing activity, through stimulation of glutathione peroxidase 1 (GPx1) and catalase expression in fibroblasts: indeed, GPx1 and catalase are known to scavenge excessive H 2 O 2 accumulation in diabetic wound beds, preventing H 2 O 2 -induced extracellular matrix modification and facilitating keratinocyte migration [31].…”