α-MSH and Foxc2 promote fatty acid oxidation through C/EBPβ negative transcription in mice adipose tissue

Abstract

Alpha melanocyte stimulating hormone (α-MSH) and Forkhead box C2 protein (Foxc2) enhance lipolysis in multiple tissues. However, their relationship in adipose fatty acid oxidation (FAO) remains unclear. Here, we demonstrated that α-MSH and Foxc2 increased palmitate oxidation to CO2 in white (WAT) and brown adipose tissue (BAT). C/EBPβ expression was reduced by α-MSH and Foxc2. FFA level was elevated by α-MSH and pc-Foxc2 treatment along with increased FAO in white and brown adipocytes. The expression of FAO key enzymes, medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were increased in α-MSH and pc-Foxc2 group. Combination of α-MSH and Foxc2 treatment synergistically promoted FAO through increasing the activity of CPT-1 and phosphorylation of ACC. We found C/EBPβ bind to MC5R and Foxc2 promoter regions and inhibited FAO. cAMP level was increased by α-MSH and Foxc2 individually treated or combined treatment. Furthermore, cAMP/PKA pathway-specific inhibitor (H89) blocked the FAO, despite in α-MSH and Foxc2 both added group. While forskolin, the cAMP agonist, promoted FAO and enhanced the effect of α-MSH and Foxc2. Collectively, α-MSH and Foxc2 mutual promote FAO in WAT and BAT via cAMP/PKA signal pathway. And C/EBPβ as a transcription suppressor inhibits α-MSH and Foxc2 expression and FAO.

ColXV promotes adipocyte differentiation via inhibiting DNA methylation and cAMP/PKA pathway in mice

“…Because of the repressing effect of CREB on ColXV, we detected the role of cAMP/PKA signal pathway in ColXV function. Results show that the promoting effect of ColXV on adipogenesis and repressing effect on lipolysis is through inhibiting cAMP/PKA signaling pathway, consistent our previous finding that cAMP/PKA signal pathway activation inhibited adipogenic markers C/EBPβ, PPARγ and FABP4 [ 42 ].…”

αMSH inhibits adipose inflammation via reducing FoxOs transcription and blocking Akt/JNK pathway in mice

“…αMSH in adipose tissue is known for its antioxidant and anti-inflammatory properties, which can abate LPS-induced inflammation and obesity [ 24 , 25 ]. Previous studies in our lab revealed that αMSH accelerates preadipocyte proliferation by alleviating ER stress-induced Leptin resistance, and it promotes fatty acid oxidation in adipose tissues together with transcription factor Foxc2 [ 26 , 27 ]. In addition, transcription factors Foxo1, Foxo3a, Foxo4 and Foxo6 in mammals have been found to promote inflammatory cascades in adipose tissues and maintain immune system homeostasis [ 28 – 31 ].…”

RNA-seq Analysis of Wild-Type vs. FOXC2-Deficient Melanoma Cells Reveals a Role for the FOXC2 Transcription Factor in the Regulation of Multiple Oncogenic Pathways

“…In addition to offering molecular insight into the previously described oncogenic activities of FOXC2, the RNA-seq dataset described herein highlights potentially novel tumor-promoting functions for this transcription factor as well. Of note, although previous work has demonstrated FOXC2-associated regulation of glycolysis (12), fatty acid oxidation (30), and mitochondrial metabolism (31), a role for FOXC2 in other metabolic pathways has not been reported to date. Interestingly, our differential gene expression analyses suggest the likelihood that FOXC2 also contributes to amino acid metabolism, as several GO Terms and Kegg Pathways related to amino acid biosynthesis and metabolism were significantly enriched with genes upregulated in the FOXC2-expressing B16-F1 cell line.…”