A negative feedback loop between TET2 and leptin in adipocyte regulates body weight.

Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

Adipose stem cells control obesity-induced T cell infiltration into adipose tissue.

T cell infiltration into white adipose tissue (WAT) drives obesity-induced adipose inflammation, but the mechanisms of obesity-induced T cell infiltration into WAT remain unclear. Our single-cell RNA sequencing reveals a significant impact of adipose stem cells (ASCs) on T cells. Transplanting ASCs from obese mice into WAT enhances T cell accumulation. C-C motif chemokine ligand 5 (CCL5) is upregulated in ASCs as early as 4 weeks of high-fat diet feeding, coinciding with the onset of T cell infiltration into WAT during obesity. ASCs and bone marrow transplantation experiments demonstrate that CCL5 from ASCs plays a crucial role in T cell accumulation during obesity. The production of CCL5 in ASCs is induced by tumor necrosis factor alpha via the nuclear factor κB pathway. Overall, our findings underscore the pivotal role of ASCs in regulating T cell accumulation in WAT during the early phases of obesity, emphasizing their importance in modulating adaptive immunity in obesity-induced adipose inflammation.

Exploration and identification of anoikis-related genes in polycythemia vera.

Background: Polycythemia Vera (PV) is a type of typical Myeloproliferative Neoplasms (MPNs) characterized with excessive erythropoiesis and thrombosis. Anoikis is a special programmed cell death mode induced by the adhesion disorder between cells and extracellular matrix (ECM) or adjacent cells facilitating cancer metastasis. However, few studies have focused on the role of anoikis in PV, especially on the development of PV. Methods: The microarray and RNA-seq results were screened from the Gene Expression Omnibus (GEO) database and the anoikis-related genes (ARGs) were downloaded from Genecards. The functional enrichment analysis of intersecting differentially expressed genes (DEGs) and protein-protein interaction (PPI) network analysis were performed to discover hub genes. The hub genes expression was tested in the training (GSE136335) and validation cohort (GSE145802), and RT-qPCR was performed to verify the gene expression in PV mice. Results: In the training GSE136335, a total of 1,195 DEGs was obtained from Myeloproliferative Neoplasm (MPN) patients compared with controls, among which 58 were anoikis-related DEGs. The significant enrichment of the apoptosis and cell adhesion pathways (i.e., cadherin binding) were shown in functional enrichment analysis. The PPI network was conducted to identify top five hub genes (CASP3, CYCS, HIF1A, IL1B, MCL1). The expression of CASP3 and IL1B were significantly upregulated both in validation cohort and PV mice and downregulated after treatment, suggesting that CASP3 and IL1B could be important indicators for disease surveillance. Conclusion: Our research revealed a relationship between anoikis and PV for the first time by combined analysis of gene level, protein interaction and functional enrichment, allowing novel insights into mechanisms of PV. Moreover, CASP3 and IL1B may become promising indicators of PV development and treatment.