Obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 pathway

Abstract

Objective Our previous results have shown that obesity-induced excessive palmitic acid (PA) can promote the expression of KLF7, which plays a vital role in regulation of inflammation, glucose metabolism. But the exact mechanism of PA up-regulating the expression of KLF7 is not clear yet. This study is intend to explore whether PA promoting KLF7 expression through GPRs/NF-κB signaling pathway, causing inflammation and glucose metabolism disorders. Methods Cells were blocked GPRs/NF-κB under PA stimulation in vitro to demonstrate the molecular mechanism of PA up-regulates KLF7 expression. The regulatory effect of p65 on KLF7 was detected by luciferase reporter gene assay. Blocking GPRs/NF-κB in diet-induced obesity mice to detect the expression of KLF7, inflammatory cytokines and glucose metabolism related factors, clarifying the effects of GPRs/NF-κB on KLF7 in vivo. Results In 3T3-L1 adipocytes and HepG2 cells, PA could up-regulate the expression of KLF7 by promoting the GPR40/120-NF-κB signaling pathway, leading to inflammation and reduced glucose consumption (p < 0.05 for both). Luciferase reporter gene assay and ChIP assay showed that p65 could transcriptionally up-regulates the expression of KLF7. In high-fat diet (HFD) mice, after intraperitoneal injection of GPR40 or GPR120 blocker, the levels of p-p65 and KLF7 in epididymal white adipose tissue and liver were significantly decreased (p < 0.05 for both). Pharmacological inhibition of p-p65 significantly attenuated KLF7 expression and improved glucose tolerant and insulin sensitive (p < 0.05 for both). Conclusions Our results indicate that obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 signaling pathway.

KLF7 promotes adipocyte inflammation and glucose metabolism disorder by activating the PKCζ/NF‐κB pathway

“…Interestingly, our previous studies showed that an increase in the palmitic acid content in the obesity context led to NF-κB subunit p65 activation; moreover, this outcome was found to be mediated through the p65-specific receptor GPR40/120, which binds the promoter region of the KLF7 gene to activates its expression, and notably, KLF7 can also bind the promoter region of IL-6 to activate its expression and ultimately induce adipocyte inflammation. 13,31 According to the experimental results of the previous study, we also revealed a regulatory loop in obesity-induced inflammation: an increase in lipolysis due to obesity increased the palmitic acid content in plasma and the expression and release of IL-6 by activating a positive regulatory loop between p65 and KLF7.…”

Lipid Aldehydes 4-Hydroxynonenal and 4-Hydroxyhexenal Exposure Differentially Impact Lipogenic Pathways in Human Placenta

“…Interestingly, FASN is also upregulated by 4-HNE, which would lead to increased palmitic acid biosynthesis. An excess of palmitate leads to inflammation and can cause lipotoxicity [ 52 , 53 , 54 ] via lipid accumulation, which can negatively impact placental function. As PPARγ is stimulated by oxidized lipids in term placentas and other tissues [ 55 , 56 ], the accumulation of 4-HNE may further increase esterification pathways, programming the placenta to preferentially store and accrue lipids.…”

Positive Effects of Adiponectin, BDNF, and GLP-1 on Cortical Neurons Counteracting Palmitic Acid Induced Neurotoxicity

“…PA has been shown to induce impaired glucose metabolism, inflammatory responses [ 3 ], insulin sensitivity attenuation [ 4 ], and the autophagic flux pathway in neurons [ 5 ]. A recent study found that PA could aggravate memory loss and neuroinflammation by stimulating the production of pro-inflammatory cytokines, such as tumor necrosis factor alpha [ 6 ], through the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway [ 7 ]. High levels of PA promote cell death, impaired neural differentiation, mitochondrial dysfunction, and abnormal neurite outgrowth [ 8 ].…”