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Schwann cells regulate brown adipose tissue innervation and remodeling through MEK/ERK signaling axis

ABSTRACT: Brown Adipose Tissue (BAT) is driven by neural innervation for thermogenesis and represents a potential therapeutic target for human obesity. However, the regulation mechanisms of BAT's neural innervation are still unclear. In this study, we validate the terminal regulation mechanism of BAT's neural innervation in which Schwann cells (SCs) control the neural innervation and remodeling of BAT by regulating the distribution of nerve endings. We found that specific ablation of Olfm4 in brown adipocytes instigates an abnormal dedifferentiation and atrophy of mature SCs, which is mediated by the activation of the MEK/ERK signaling axis. This atrophy results in a decrease in the distribution of myelinated sensory and unmyelinated sympathetic nerve endings, leading to a reduction in BAT's neural innervation and thermogenic impairment. Consequently, mice exhibit heightened sensitivity to cold and diet-induced obesity. Notably, the application of a MEK/ERK inhibitor reverses this abnormal dedifferentiation of SCs, rescuing these phenotypes. In addition, our study describes the profound remodeling process that SCs undergo in response to temperature changes, wherein SCs experience reversible dedifferentiation in response to thermal neutrality or mild cold exposure, thus modulating the remodeling of the BAT neural network. Importantly, inhibition of MEK/ERK blocks this dedifferentiation of SCs, reversing thermal neutrality-induced BAT remodeling, thereby reinforcing the central role of SCs in the complex cellular response during temperature-induced BAT remodeling. In conclusion, our study confirms the crucial regulatory role of SCs in the neural innervation and remodeling process of BAT, offering novel insights for the activation of BAT to treat obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE243317 | GEO | 2023/10/15

REPOSITORIES: GEO

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Project description:Identification of MEK-ERK or p38MAPK dependent genes in human monocyte derived dendritic cells. Dendritic cells (DC) promote tolerance or immunity depending on their maturation state. Previous studies have revealed that DC maturation is enhanced or accelerated upon MEK-ERK signaling pathway inhibition. We have now determined the contribution of MEK-ERK activation to the profile of gene expression of human immature monocyte-derived dendritic cells (MDDC) and peripheral blood myeloid DC. ERK inhibition altered the expression of genes that mediate CCL19-directed migration (CCR7) and LDL binding (CD36, SCARB1, OLR1, CXCL16) by immature DC. Besides, ERK upregulated CCL2 expression while impaired the expression of DC maturation markers (RUNX3, ITGB7, IDO1). MEK-ERK-regulated genes exhibited an over-representation of cognate sequences for the Aryl Hydrocarbon Receptor (AhR) transcription factor, and we show that AhR mediates some of the ERK-dependent transcriptional effects in DC. Therefore, MEK-ERK signaling pathway regulates antigen capture, lymph node homing and the acquisition of maturation-associated genes, and its contribution to the maintenance of the immature state of MDDC and myeloid DC is partly dependent on the activity of AhR. Since pharmacological modulation of the MEK-ERK signaling pathway has been proposed as a potential therapeutic strategy for cancer, our findings indicate that ERK inhibitors might influence the generation of anti-tumor responses through regulation of critical DC effector functions. Human peripheral blood monocytes from three independent healthy donors (DC4, DC5 and DC7) were isolated by anti-CD14-labeled magnetic microbeads. CD14+ monocytes were cultured for 5 days in RPMI 10% FCS containing GM-CSF and IL-4 to generate immature monocyte-derived dendritic cells (MDDC). Immature MDDC were exposed to MEK inhibitor, U0126, or p38MAPK inhibitor, SB203580 for 1 hour and a final dose of GM-CSF and IL-4 were added to the culture. Cells were collected for analysis after 4, 10 or 24 hours.Total RNA from each condition was extracted using the All prep DNA/RNA/protein mini kit (Qiagen) and hybridized to an Agilent Human Whole Genome (4x44) Oligo Microarray. All experimental procedures were performed following manufacturer instructions.

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Schwann cells regulate brown adipose tissue innervation and remodeling through MEK/ERK signaling axis

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